HU182738B - Process for producing the novel oxyme derivatives of 7-amino-thiazolil-acetamido-3-substituted-cef-3-em-4-carboxylic acides - Google Patents

Abstract

The compounds correspond to the formula: <IMAGE> in which the symbols R, R1 and A have the meaning given in Claim 1. They are prepared by reacting compounds of formula II and III: <IMAGE> or a functional derivative of III, in which A' represents H or an ester which can be removed by acid hydrolysis or by hydrogenolysis, R<2> represents a group which can be removed in the same way or a chloroacetyl group and R'1 is defined like R2 or represents a saturated or unsaturated C1-C4 alkyl and when R'1 represents ClCH2CO-, R2 also represents this group; the removable groups A', R2 and R'1 are then removed by acid hydrolysis, hydrogenolysis and/or treatment with thiourea. The compounds and their salts of the carboxylic group have a good antibiotic activity and can be used for the treatment of various infectious diseases.

Description

The present invention relates to a process for the preparation of the new oxime derivatives of the formula I as well as the pharmaceutically acceptable salts thereof at the 4-position of the carboxyl group of 7-aminothiazolylacetamido-3-substituted-cef-3-em-4-carboxylic acids.

In the formula, R p is C 1-4 alkyl, R _a , chloro, methoxy, C 1-4 alkylthio, or R 11 -O-NH- wherein R 1 is C 1-4 alkyl. In the compounds of formula I, the -ORp group is in the color position.

More particularly, the present invention relates to a process for the preparation of compounds of the formula I in the color configuration. The latter in which R is chloro or methoxy, R _{L is C} 1-4 alkyl. ¹

The invention also relates to a process for the preparation of compounds of the formula I 'in the color configuration. In formula B, R _{p is} C 1 -C 4 alkyl, R 1 -C 4 alkylthio or R ₄ -CO-RH-, where R 1 is C 1 -C 4 alkyl.

Examples of the substituents Rp include methyl, ethyl, propyl, isopropyl, butyl. sec-butyl and tert-butyl.

Examples of the substituent R 1 include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, acetamido, propionylamino, butyrylamino and isobutyrylamino. '

Examples of the substituents Rn include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

Salts of the 4-carboxylic acid include alkali metal salts, particularly the sodium salt.

Of particular interest among the compounds of formula Ιδ are those compounds of formula I in which Rp is C1-C4 alkyl, R1 is methylthio or acetamido.

Among the compounds of the general formula, the following are particularly noteworthy:

- the isomer of 7- (5- / 2-aminothiazol-4-yl) -2-methoxyliminoacetamide-3-methoxy-oef-3-em-4-carboxylic acid and its alkali metal salts,

The azine isomer of 7 "/ 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido-7-chloro-cef-3-em-4-carboxylic acid and its alkali metal salts,

- 7 "/ 2 - * / 2-Aminothiazol-4-yl / -2- (methoxyimino) -acetamido-3-acetamido-cef-3-em-4-carboxylic acid Syn isomer and alkali metal salts thereof.

The compounds of the general formula I * may exist in two tautomeric forms. One of them is represented by the formula ,λ, while the other is represented by the formula I ₂ . In the latter formula, R _a , R p are, of course, as defined above.

Numerous 3-substituted-cef-3-emi-4-carboxylic acid derivatives are known in the art. J. Am. Chem. Soc. 96, 4986-7 (1974), the authors disclose 7- &quot; -tetamido-cef-3-em-4-carboxylic acids which contain a chloro or methoxy group at the 3 & However, these compounds are the 7th

At position -2182,738 they contain a side chain very different from the claimed compounds.

Can we mention the 2 13? No. 899 Azamu and French Patent No. 2,123,544, which disclose 7-acetamido-cef-3-em-4-carboxylic acids which also have a different side chain at the 7-position.

The novel oxime derivatives of formula I * are prepared according to the invention by reacting a compound of formula II wherein R _a is as defined above and A * is a hydrogen atom or an ester forming group readily removable by acidic hydrolysis or hydrogenolysis. with an acid (its color isomer) or a functional derivative of such an acid, wherein R 2 is a group which is readily removable by acid hydrolysis or hydrogenolysis, preferably a trityl group, R 1 is a C 1 -C 4 saturated alkyl group; (the syn isomer of this compound) where R _a , R *,, R ₂ and A 'are as defined above, R ₁ , R ₂ , R ³ , is reacted with an acid hydrolyzating aze, a hydrogenolysis agent and / or thiourea; a compound of the general formula wherein R _a and Ry are as defined above, at the 4-position carboxyl where A is hydrogen, optionally salted with a pharmaceutically acceptable base in a manner known per se.

In particular, the present invention uses a compound of formula II as starting material wherein R _a is chlorine or methoxy.

Examples of radicals which can be easily removed by acid hydrolysis or hydrogenolysis as mentioned in the meaning of R'n and R ₂ include, for example, tert-butoxycarbonyl, trityl, benzyl, benzhydryl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranyl. .

The ester forming group mentioned in A * which can be easily removed by acid hydrolysis or hydrogenolysis may be, for example, diphenylmethyl, benzhydryl, tert-butyl, benzyl, p-methoxybenzyl or trichloroethyl,

Preferably, the starting compound of formula II is reacted with a functional derivative of the acid of formula III, such as anhydride or chlorine of aav. The anhydride can also be formed in the reaction mixture itself by reacting the acid with isobutyl ester of chloroformate or dicyclohexylcarbodlimide. Other halides or anhydrides may be formed in the reaction mixture with other alkyl chloroformic acid esters, dialkylcarbodiimides or other dicycloalkylcarbodimides. However, other acid derivatives such as an acid azide, aavamide, or a reactive ester such as an ester with hydroxysuccinimide, p-nitrophenol or 2,4-dinitrophenol may also be used as reagents. In case. when the compound of formula II is reacted with an acid anhydride of the acid of formula III or an isobutyl ester of chloroformate, the reaction is preferably carried out in the presence of a basic compound.

As the basic compound we may use, for example, an alkali metal carbonate or a tertiary organic base such as N-methylmorpholine or pyridine or a trialkylamine such as triethylamine or tert-n-butylamine.

-3182.738

The purpose of converting the compound of formula IV into the compound of formula I is to replace the azo substituent R ₂ with a hydrogen atom. When R »^ present tess a readily removable by acid hydrolysis or hidrogenolizisael csofórt or chloroacetyl and / or, if A 'is a readily removable hidroizissel or hidrogenolizisael group. Then in the compounds of formula IV General I is converted to _a compound of formula R * i and Substituents' are also replaced with hydrogen.

The said conversion is carried out in the case where R'y and R ₂ represents an easily removable group by acid hydrolysis of '^ is hydrogen or an acidic hydrolysis' sel easily removable group IV compound with one or more with an acid hydrolyzing agent.

In the case where R 'and R _{2 are} hydrogenolysis groups which are readily removable and A 1 or H ₂ groups are hydrogen or are readily removable by hydrogenolysis, the compound of formula IV is reacted with one or more hydrogenolysis solvents.

The compound of formula IV is reacted with one or more acidic hydrolysing agents and one or more hydrogenolysing agents if at least one of the substituents R'1, R2 and A * is one which is readily removable by acid hydrolysis and at least one of these substituents is readily removable by hydrogenolysis.

In the case where R ₂ is chloroacetyl and R'η is chloroacetyl or a C 1 -C 4 saturated or unsaturated alkyl group, the compound of formula IV is reacted with thiourea and then, when A 'is not hydrogen, with an acidic hydrolyzing agent or a hydrogenolysing agent.

The acid hydrolyzing agent used for the conversion of the compound of formula IV is, for example, formic acid, trifluoroacetic acid or acetic acid. These acids are used either in anhydrous form or in aqueous solution. We can also use a mixture of oinc and acetic acid for this purpose. '

When R't and R _{2 are} tert-butoxycarbonyl or trityl, or when n-benzhydryl, tert-butyl, or p-methoxybenzyl, these groups are preferably removed with the following anhydrous trifluoroacetic acid with the following acid hydrolysers or aqueous formic acid or aqueous acetic acid.

When R ', R ₂ and A' are trichloroethyl, the zinc-acetic acid system is preferably used as the hydrolysis agent for the band.

When R ₁ and R _{2 are} benzhydryl or carbobenzyloxy, or when R _1, R p and A * are benzyl, the hydrogenolysis agent is preferably hydrogen in the presence of a catalyst.

Preferably, the compound of formula IV containing E2 as a chloroacetyl group and as R 1 as a chloroacetyl group or C 1-4 alpha group is reacted with thiourea in a neutral or acidic medium. This method is described in Masaki, JACS 90, 4508 (1968).

The compounds of formula Ia may be converted into salts by conventional methods known in the art. It may be reacted to form salt

For example, an inorganic base such as sodium or potassium hydroxide or sodium bicarbonate or a salt of a substituted or unsubstituted aliphatic carboxylic acid such as diethyl acetic acid, dimethylacetic acid, ethylhexanoic acid or especially acetic acid.

These acids are preferably converted to the sodium salt.

As starting materials for salt formation, solvates of free acids may be used instead of the free acids.

The salt formation is preferably carried out in a solvent such as water, ethyl ether, methanol, ethanol or acetone, or a mixture of such solvents.

The salts thus obtained are amorphous or crystalline, depending on the reaction conditions.

The crystalline salts are prepared by reacting the free acids preferably with one of the aforementioned aliphatic carboxylic acids, preferably sodium acetate.

Preferably, the sodium salt is prepared in an organic solvent, optionally containing small amounts of water, such as methanol.

The compounds of formula I have very good antibiotic activity. They are active against Gram positive bacteria such as staphylococci and streptococci, but also against Gram negative bacteria. especially coli bacteria. and bacteria of the Klebsiella, Salmonella and Proteus groups. A particular advantage of the compounds of the general formula is that they are also effective against penicillin-resistant staphylococci.

Because of this property, the compounds of formula Ia are useful as active ingredients in pharmaceutical formulations. Medicaments produced by these compounds, in particular compositions having an antibiotic effect, are useful in the treatment of any disease caused by a drug-sensitive microorganism. Particularly useful are staphylococcal infections such as staphylococcal blood poisoning, staphylococcal infection on the face or skin, purulent dermatitis, infected or healed wounds, malignancies, connective tissue inflammation, stomach ulcer, acute primary or for the treatment of pulmonary degeneration.

The said pharmaceutical compositions can also be used to treat coli bacilli, infections caused by microorganisms belonging to the Proteus, Klebsiella and Salmonella groups, as well as other diseases caused by Gram-negative bacteria.

The following compounds of formula (I) have been found to be particularly useful as active ingredients in such formulations:

- 7- / 2- / 2-aminothiazol-4-yl / 2-metoxilmino-acetamido7-3-nietoxl-ceph-3-em-4-carboxylic acid syn isomer _f

- 7- (2- / 2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-chloro-cef-3-em-4-carboxylic acid, azine isomer,

- 7- [5- (2-Aminothiazol-4-yl) -2-methoxyimiboacetamido] -3-acetamido-cef-3-em-4-carboxylic acid, azine isomer and compounds with alkali metals, alkaline earth metals, pharmaceutically acceptable salts thereof with magnesium, ammonia and organic amino bases.

Can be prepared as pharmaceutically 5182.738 sati compositions using the compounds of formula the pharmaceutically acceptable as defined above, containing at least one compound _of formula I as active ingredient.

Such compositions may be applied buccally, rectally, parenterally, intramuscularly or topically, in the latter case topically to the skin or mucous membranes.

Said drugs may be prepared in the form of any formulation conventionally used in human medicine. Thus, for example, uncoated or sugar coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams and gels may be prepared. They are prepared in the usual manner for the preparation of α-drug. The active ingredient (s) may be formulated with customary carriers and excipients such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, dehydrating agents, / or preservatives.

The dosage of the active ingredient will vary depending on the severity of the disease, the particularities of the patient, and the route of administration. THE

The daily dose of the active ingredient shown in Examples 2, 4 and 6 varies between 0.250 g and 4 g when administered orally to an adult human, while the daily dose is 0.500 to 1 g three times a day when administered intramuscularly via calender or intravenous route.

The present invention makes it possible to prepare new compounds of the color configuration IV. In the formula, ΐ 2, R 1, E _a and A 'are as defined above.

The compounds of formula III used as starting materials are described in Belgian Patent No. 850,662.

Starting compounds of formula II wherein Rp is alkylthio are prepared as described in French Patent No. 2,282,895.

The starting compounds of formula II wherein R _a is R 1 -C 6 -NH are prepared as described in US Patent 2,555,912.

The latter compounds, wherein R _a is R 4 -CO-NH, may also be prepared by acylating a compound of formula B wherein R 1 represents an amine protecting group * and represents an easily removable ester forming group, and then removing the amino groups; and protecting groups on carboxylic groups. This latter process is also illustrated in our examples. Compounds of formula B are described in French Patent No. 2,501,260.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1

7- [2- (2-Tritylaminothiazol-4-yl) -2-methoxyimino-acetamido] -5-methoxy-cef-5-em-4-carboxylic acid diphenylmethyl ester, color isomer

1.02 g of the color isomer of 2- / 2-tritylaminothiazol-4-yl / -2-methoxyiminoacetic acid described in Belgian Patent 850,662 are mixed with 10 ml of methylene chloride and 5 ml of 2N hydrochloric acid. The reaction mixture was stirred for 5 minutes, decanted, washed with water, dried, filtered and evaporated in vacuo to give 0.980 g of the free acid.

-6182.738

The former 0.980 g of the free acid is dissolved in 20 ml of anhydrous methylene chloride. To the solution was added 0.232 g of dlcyclohexylcarbodiimide at room temperature. The reaction mixture was stirred for one hour and then filtered off with suction to remove 0.175 g of dicyclohexylurea. The filtrate was cooled to -10 ° C and a solution of 0.396 g of 7-hmino-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride was added at the same temperature. The reaction mixture is then allowed to warm to room temperature _? then decanted, washed with n hydrochloric acid and water, sealed, filtered and concentrated to dryness in vacuo. 1.2 g of a resin-like product are obtained. This was chromatographed on silica gel eluting with benzene-ethyl acetate (6: 4). 0.220 g of an ohmic product having an Rf of 0.3 are obtained.

UV spectrum / ethanol + 0.1 N aqueous hydrochloric acid / maximum: 275 nm E = 233 = 19130 infusion 290 nm = 202

Nuclear Magnetic Resonance Spectrum (CDCl ^), 60 MHz / ppm. = 3.69 (-O-CH2), (4.06) -N-OCH3, (6.8) proton of the thiazole ring, (6.9).

Example 2

7- (2H-Aminothiazol-4-yl / -2-methoxyiminoacetamido) -3-methoxy-cef-3-em-4-carboxylic acid, color isomer

7- / 2- / 2-tritylaminothiazol-thia zol-4-yl _r / -2-methoxyimino-acetamido7-3-methoxy-ceph-3-eni-; 4- carboxylic acid diphenylmethyl ester obtained in Example 1, 0.415 g- and under nitrogen atmosphere at 0 ° C was mixed with 2 ml of anisole followed by 20 ml of trifluoroacetic acid. The reaction mixture was stirred for 15 minutes at 0 ° C and then poured into 50 ml of water. After washing with methylene chloride, the aqueous phase is evaporated to dryness. The residue obtained is taken up several times with a few ml of ethyl acetate and then concentrated to dryness in vacuo. 0.267 g of trifluoroacetate of the desired product are obtained. This trifluoroacetate was dissolved in 10 volumes of acetone containing 20% water. To the solution is added 0 * 04 ml of pyridine. The solution is evaporated to dryness, 1 ml of acetone is added to the residue and the product is precipitated with ethyl ether. The solid was filtered off with suction and washed with ethyl acetate followed by ether. 0.126 g of the first product and 0.025 g of the second product are obtained. The two products were combined, 1.5 mL ethyl acetate was added and stirred for 30 min. It is then filtered off with suction, washed with ether and dried in vacuo overnight; 0.123 g of purified product are obtained, m.p. 170 ° C.

Nuclear Magnetic Resonance Spectrum (DMSO), 60 MHz (ppm): 3 x δ 5 (N-O-Me), 3. 76% (OMe), 6.86 (thiazole proton), 7. 16 (NH ₂ ).

3 · Example

7- (2- (2-Tritylaminothiazol-4-yl) -2-methoxyiminoacetamide) -7-3-chloro-cef-3-bulk-4-carboxylic acid, color Isomer

Sodium salt of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid (1 * 54-8 g) was suspended in methylene chloride (50 mL). Add 2 ml hydrochloric acid (G ml), stir, decant. wash with water and then dry to dryness. 1.4-77 g of the desired acid are obtained.

This acid was dissolved in anhydrous methylene chloride (25 mL) under argon. Dicyclohexylcarbodiimide (0.376 g) was added all at once and stirred at 20 ° C for 1 hour under argon and then dicyclohexylcarbamide was filtered off under argon. The methylene chloride solution, the anhydride solution, was cooled to -10 ° C.

0.390 g of 7-amino-3-chloro-cef-3-em-4-carboxylic acid are suspended in 5 ml of methylene chloride. 0.46 ml of triethylamine are added. A further 10 ml of methylene chloride was added and the solution was cooled and added at -10 ° C to the former anhydride solution.

The reaction mixture was stirred and 5 ml of anhydrous dimethyl sulfoxide was added to give a clear solution. Stirring was continued for 10 minutes at -10 ° C, then the reaction mixture was allowed to warm to 20 ° C. After stirring at 20 ° C for 2 hours, the organic solution was washed twice with 20 ml of 2N hydrochloric acid and three times with distilled water. The methylene chloride phase was evaporated to dryness below 30 ° C. 1.715 g of crude product are obtained. TLC (100:10 acetone-water) Rf = 0.4. This product was purified twice from silica gel eluting with 10% water in acetone. 0.485 g of the desired purified product is obtained.

UV spectrum 235 / ethanol / nm λ = 341 = 17800 λ 259 nm λ = 270 λ 264 nm λ / ethanol + maximum 273 nm

0.1 N HCl / E * = 277

7- = 18J00.

inflexion 290 nm E = 213 inflexion 300 nm E _p = 144 inflexion 300 nmE.

= 5600

Example 4

257

- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido / -3-chloro-cef-3-em-4-carboxylic acid, color isomer

0.385 g of the acid prepared according to Example 3 is pasteurized at 55 ° C with 4 ml of aqueous formic acid containing 50% water. After 10 minutes paste formation, the triphenylcarbinol formed is partially soluble and partially precipitated. Stirring is continued for 20 minutes at 55 [deg.] C., after which 4 ml of distilled water are added, the solid is filtered off with suction and washed three times with water to give 0.135 g of triphenylcarbinol.

The clear filtrate was evaporated to dryness in vacuo to give an azeotropic addition of ethyl acetate. The resulting powder product was slurried with 25 ml of ethyl ether, filtered off with suction, washed with ether and dried at 20 ° C. 0.265 g of product having an Rf of 100 are obtained:

chromatogram Q, 55, of a mixture of acetone / acetic acid: The resulting compound of formula V has a NMR (DMSO, 60 MHz) / a: two doublets at 3.42 and 3.9 p at J = 18 Hz / b /: singlet at 3.84 ppm (c): doublet at 5.12 ppm

-8182.738 (d/:) two doublets at 5.58 and 5.72 ppm J = 4.5 and 5.5 Hz (e): azinglet at 6.72 ppm (£): azinglet at 7.8 ppm- at / g /: doublet at 9.6 ppm J = 7.5 Hz

Example 5

7- (5- / 2-Amino-1-thiazol-4-yl) -2- (methoxy) -amino-7-methyl-thioceph-3-em-4-carboxylic acid, Azine Isomer

Step A: 7- [2- (2-Tritylaminothiazol-4-yl) -2'-methoxyiminoacetamido] -3-methyllo-cef-3-em-4-carboxylic acid, Azine Isomer 79O ~ mg 2- (72-tritylaminothiazol-4-yl) -2-methoxyimino7-

The isomer of the sodium salt of acetic acid is mixed with 8 ml of methylene chloride and 4 ml of 2N hydrochloric acid. The reaction mixture was stirred for 5 minutes, then decanted, washed with water, dried, filtered and evaporated to dryness under reduced pressure. 755 mg of the acid are obtained, which is dissolved in 3 ml of methylene chloride. 185 mg of dicyclohexylcarbodiimide are added at room temperature. After stirring for one hour at room temperature, the precipitated dicyclohexylurea (140 mg) was filtered off with suction. The filtrate was cooled to -10 ° C and 300 mg of 7-amino-3-methylthio-ceph-3-em-4-carboxylic acid trifluoroacetate in 3 ml of anhydrous methylene chloride and 0.6 ml of triethylamine were added at -10 ° C. solution. The reaction is maintained at -10 ^o C y e ^ h; then allow to warm to room temperature over one hour. The reaction mixture was washed with 2N hydrochloric acid and water, dried, filtered and evaporated. 1.02 g of the crude product is obtained, which is chromatographed on silica gel. The eluent was ethyl acetate / ethanol / water (70:20:10). 100 mg of pure product are obtained first and then combined with the further pure product, a total of 160 mg. having an Rf value of 0.35 on a thin-film cored with 70:20:10 ethyl acetate-ethanol-water.

Step B: 7- &lt; 2 &gt; -aminothiazol-4-yl / -2-methoxyiminoacetamido-3-methylthioceph-3-em-4-carboxylic acid, color isomer

260 mg of the product obtained in Step A are mixed with 4 ml of 50% aqueous formic acid. Stir at 55-60 ^D for 35 minutes.

The resulting precipitate was filtered off with suction, washed with aqueous formic acid and dried. 60 mg of triphenylcarbinol are obtained. The filtrate was concentrated to dryness under reduced pressure. The residue was taken up several times with a small amount of ethanol. Distill again, then add a small amount of ether. The resulting precipitate was filtered off with suction, washed with ether and dried. 122 mg of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (CDC3 / gSO) (a): (a): doublet at 2 ppm J = 11 Hz (b): azinglet at 5.83 ppm (c): azinglet at 6.75 at ppm / d: azinglet at 7.16 ppm / e at 5-5 to 6 ppm

Example 6

7- / 2- / 2-aminothiazol-4-yl / -2-methoxyiminoacetamido / -3-9182.738

-acetamido-cef-3-em-4-carboxylic acid, color isomer

Step A: 7- [2- (2-Tritylaminothiazol-4-yl) -2-methoxyimino-aoetamido] -3-acetamyclo-cef-3-em-4-carboxylic acid, Syn isomer 2.366 g of 2- [72- tritylaminothiazol-4-yl - [2-methoxymethyl] -no-acetic acid, the syn isomer is mixed with 45 ml of anhydrous methylene chloride. Dicyclohexylcarbodiimide (0.65 g) was added all at once and stirred at 20 ° C for 1 hour. It is rapidly filtered under an inert atmosphere to remove the dicyclohexylcarbamide formed. The filtrate containing the anhydride was cooled to -15 ° C.

0.92 g of 7-anino-3-aoethamido-cef-3-em-4-carboxylic acid, as trifluoroacetate, is suspended in 10 ml of methylene chloride. To the suspension was added 0.8 mL of triethylamine. After partial dissolution of the solid, the suspension is cooled to 0 ° C and added to the anhydride solution prepared above. After 5 min, 0.2 mL of triethylamine was added to the reaction mixture. After stirring for 30 minutes, 2 ml of dimethylformamide are added. The solids are then completely dissolved. The resulting solution was stirred for 1.5 hours at 20 ° C, then washed with dilute hydrochloric acid and water. The solution is evaporated to dryness under reduced pressure. 3.187 g of crude product are obtained. This was purified twice by chromatography on silica gel. The eluent was acetone containing 10% water. 0.789 g of pure product is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ·H) thiazole proton 6.2 ppm.

proton of the trityl group: 7.26 p.p.m.

Step B: 7- (2- / 2-Aminothiazol-4-yl / -2-methoxyiminoacetamido) -3-acetamido-cef-3-em-4-carboxylic acid, Syn isomer

0.68 g of the product obtained in Step A is dissolved in 8 ml of 50% aqueous formic acid under argon. The solution was heated to about 55 ° C and the resulting product was pulsed.

The resulting tetriphenylcarbinol precipitated as a white precipitate.

The system is stirred for 20 minutes, then 8 ml of distilled water is added and the triphenylcarbinol (0.26 g) is filtered off with suction. The formic acid solution was evaporated to dryness. Formic acid is azeotropically removed by adding ethanol and ethyl acetate to the mixture. 0.44 g of the crude product is obtained. This was slurried with 5 mL of ethyl ether at 20 ° C. After filtration under vacuum filtration and washing with ether, 0.425 g of product are obtained.

Elemental composition of 15 ° ^H 16 ^N 6 O 6 ^S 2 '· 2 ^H calculated ^hc0: 0 39.50%, H 3.72%, N 17.27% found: 0 39.48%, H 3.71% , N 16.90%

Nuclear Magnetic Resonance Spectrum (70 DJ) / ₂ 807 (Compound A illustrated by Formula VII) / (a): 2 ppm

/ b / slnglett: 3.83 p.p.m.

/ c / stlglett: 6.82 p.p.m.

/ d / doublet: 5.45 * - 5.55 p.p.m;

/ e / doublet: 5.04 - 5.1 p.p.m.

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7-Amino-3-acetamido-cef-3-em-4-carboxylic acid trifluoroacetate is prepared as follows:

N-Diphenyl-11- (triphenylmethylamino) -3-aminoceph-3-em-4-carboxylate

7.3 S 7- (triphenylmethylamino) -3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is added to 180 absolute ethanol under an inert atmosphere. 3.1 g of pure ammonium chloride and 7.1 g of pyridine are then added. The reaction mixture was stirred for 20 hours at 50 ° C. The reaction mixture was cooled, poured into 500 ml of distilled water and extracted with methylene chloride. The extract was washed and evaporated to dryness. 7.1 g of product are obtained which is chromatographed on silica gel. The eluent was 8: 2 benzene-ethyl acetate. The 0.35 Bf fraction gave 3.1 g of the purified product, m.p. 255 ° C.

B / 7- (triphenylmethylamino) -3-acetanido-cef-3-em-4-carboxylic acid diphenylmethyl ester

3.1 g of the ester prepared according to paragraph A is added to 100 ml of anhydrous benzene. 1.41 ml of acetyl chloride and 2.13 ml of diisopropylethylamine are then added. The reaction mixture was stirred at 50 ° C for 17 hours, then cooled. Wash the reaction mixture with aqueous sodium bicarbonate, then with water. The organic phase is evaporated to give 3.6 g of crude product. It contains a mixture of cef-3-em and cef-2-em isomers.

To prepare these products, the crude product obtained is chromatographed on silica gel. The eluent was 9: 1 benzene-ethyl acetate. 2.259 g of the desired cef-3-em compound are obtained. R _f is 0.4. Mp 180 ^° C.

O-7-amino-3-acetamido-cef-3-em-4-carboxylic acid

2.21 g of the product of paragraph B are dissolved in 17.5 ml of methylene chloride and 2.5 ml of anisole in an inert atmosphere. The solution is cooled to about 0 ° C and 17.5 ml of pure trifluoroacetate are added. The reaction mixture is stirred for 30 minutes, then 50 ml of distilled water are added. Extract with ethyl acetate and concentrate the extract to dryness. 0.953 g of the desired product is obtained in the form of trifluoroacetate. Rf value on a chromatogram prepared with 9: 1 acetone / acetic acid, m.p. 260 ° C. .

7 · example

We inject with the following composition:

7- (2- / 2-Amino-thiazol-4-yl) -2-methoxy-imino-acetamido] -3-chloro-cef-3-em-4-carboxylic acid, Syn isomer · 500 mg

Sterile aqueous vehicle q.s.ad 5 ml

Example 8

We inject with the following composition:

7- [2- (2-Amino-thiazol-4-yl) -2-methoxyimino-acetamido] -3-methoxy-cef-3-em-4-carboxyl, isomer 500 mg sterile aqueous excipient qsad 5 ml

-11182,738

9 · Example

A gelatin capsule is prepared with the following composition:

7- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-3-chloro-cef-3-em-4-carbonic acid, syn isomer 250 mg gelatin capsule carrier q.s.ad 400 mg

Example 10

A gelatin capsule is prepared with the following composition: 7- [2- / 2-Amino-thiazol-4-yl] -2-methoxyiminoacetamido] -3-methoxy-cef-3-em-4-carboxylic acid, Syn isomer 250 mg carrier for gelatin capsule qsad 400 mg

Example 11

Injection is prepared with the following composition: 7- (2- / 2-Aminothiazol-4-yl / -2-methoxyiminoacetamido) -3-methylthio-cef-3-em-4-carboxylic acid, silyl isomer 500 mg sterile aqueous vehicle qsad 5 ml

Example 12

Injection is prepared with the following composition: 7- (2- / 2-aminothiazol-4-yl / -2-methoxyiminoacetamido) -3-acetamido-cef-3-em-4-carboxylic acid, syn isomer 500 mg sterile aqueous vehicle qsad 5 ml

Example 13

A gelatin capsule is prepared with the following composition: 7- / 2- / 2-Amino-1-ol-4-yl / -2-methoxy-irino-ac e stored do7-3-methyl-11-cef-3- em-4-carboxylic acid, syn isomer 250g gelatin capsule carrier qsad 400 mg

Example 14

A gelatin capsule is prepared with the following composition:

7- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido) -3-3-acetamido-cef-3-em-4-carboxylic acid, syn isomer 250 mg gelatin capsule carrier q.s.ad 400 mg

15 · example

Sodium salt of the syn isomer of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-methoxy-cef-5-em-4-carboxylic acid mg mg 7- [2- / 2-amino- The syn isomer of 4-thiazolyl / -2-methoxyiminoacetamido-3-methoxy-cef-3-em-4-carboxylic acid is mixed with 0.07 ml of 0.1 N aqueous NaOH solution. The solid was dissolved with stirring and the solution was evaporated to dryness under vacuum at a temperature below 30 ° C. The title compound is obtained as a beige solid.

Example 16

7- (2- / 2-Amino-4-thiazolyl) -2-methoxyiminoacetamido7-312

-12182,738

sodium salt of the color isomer of -chloro-cef-3-em-4-carboxylic acid.

7 mg of the 7-Z5- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido [beta] -3-chloro-cef-3-em-4-carboxylic acid isomer is added to 0.085 ml of 0.1 N aqueous NaoH solution. The solid was dissolved with stirring and the solution was concentrated to dryness under vacuum at a temperature below 30 ° C. The title compound is obtained as a white solid.

Elemental composition; calculated Na 5.24% found Na 5.2%

Pharmacological Testing of Compounds of the Invention

Investigation of in vitro activity by liquid dilution method

An equal volume of sterile medium was inoculated into a series of tubes. An increasing amount of the test compound is placed in each test tube, then each tube is inoculated with a bacterial strain.

The tubes were kept in a 37 ° C incubator for 24 or 48 hours, and then the minimum inhibitory concentration / MIC7 · MIC value in micrograms / ml was determined by screening. The results are presented in the tables below.

-13182,738

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-14182,738

The products of Example 6

Microorganism strains MIC / yUg / ml / 24 H 48 H Staphylococcus aureus ATCC 6 538 penicyl-. linre sensitive 10 10 Staphylococcus aureus UC 1 128 penicillin resistant 10 10 Staphylococcus aureus exp. n ^c '54,146 10 10 Streptococcus pyogenes A 561 0.05 0.1 Streptococcus faecalis 5,432 5 40 Bacillus subtilis ATCG 6,633 10 Z '~ Escherichia Coli ATCC 9,637 tetracycline 9 sensitive 20 20 Escherichia Coli ATCC 11,303 tetracycline resistant 3 10 Excherichia Coli Exp. TOpgBg 20 20 Escherichia Coll gentamicin resistant Tobramycin R 55 123 D 10 10 Klebsiella pneumoniae Exp 52 : 145 2 2 Klebsiella pneumoniae 2,536 gentamicin-re- resistant 20 20 Proteus mirabilis / indol- / a 235 0.5 1 Salmonella typhimurium 420 20 20 Providencia Du 48 10 10 Serratia 2,532 gentamicin resistant 40 '-40

Patent claims

Claims (10)

Patent claims A process for the preparation of the oxime closure of 7-amino-thiazolylacetamido-3-substituted-cef-3-em-4-carboxylic acids and the pharmaceutically acceptable salts thereof at the 4-position of the Carboxyl group, wherein R 1 is C 1 -C 4 alkyl, R is chlorine, metoxicsojportot, C1-4 al'kiltiocsoportot or a radical of the formula R-CO-NH-STANDARD represents ^- wherein R _represents C1-4 alkyl group, and - OR ^ group is ^ azine position, wherein characterized in that a compound of formula II wherein R 'is as defined above and A * is a hydrogen atom or an leaving ester forming group which is easily removable by acid hydrolysis or hydrogenolysis, preferably a diphenylmethyl group, or a functional compound of formula III with a derivative thereof, wherein R ₂ is an acid hydrolysis cut; an easily removable leaving group, preferably a trityl group, by hydrogenolysis, and R '' is a C 1 -C 4 alkyl group, and the compound of formula IV is obtained in a color configuration wherein R _a , R * 1 * S ₂ and A 'are as defined above; * i, R ₂ and subject to a * meaning of reacting with an acidic hydrolyzing agent and / or hidrogenolizálószerrel and / or thiourea * and the resulting 1 ^ formula syn configuration compound wherein R and R, are as defined above, if desired the 4-position carboxyl group to a pharmaceutically acceptable salt. -15182,738 2. A process according to claim 1 wherein the starting material is a compound of formula II wherein R is chlorine or methoxy and A 'is the compound of claim I and the compound of formula I is obtained. to an alkaline salt, wherein R is as defined above and R 1 is as defined in claim 1. ^x The process of claim 1 for the preparation of a compound of formula I _A wherein R 1 C 1 -C 4 alkyl, and R _a is a methylthio acetamido group, characterized in that compounds of general formula II or III are used wherein R _a is methyl or acetamido; and A * is as defined in claim 1 or R? is C 1-4 alkyl, and R ₂ is 1 *. According to claim 1. 4. The process according to claim 2, which is a isomer of 7- [5- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-methoxy-cef-3-em-4-carboxylic acid. or 7- (2- / 2-aminothiazol-4-yl) -2-methoxyiminoacetamido-3-chloro-cef-3-em-4-carboxylic acid, characterized in that a compound of formula II or III starting with compounds wherein R _a is methoxy or chloro and A 'is as defined in claim 1 or R 1 is as defined in claim 1; R ₂ is methyl, and R ₂ is az According to claim 1. The method of claim 1 for the preparation of a color isomer of 7- [2- / 2-aminothiazol-4-yl] -2-methoxyliminoacetamido] -3-acetamido-cef-3-em-4-carboxylic acid, characterized in that it is based on compounds of formula II or III wherein R _a is acetamido 'and A * is as defined in claim 1 or R 1 is methyl and R _{2 is as} defined in claim 1. 6. A process for the preparation of a pharmaceutical composition, wherein at least one compound of formula I according to claim 1, wherein R n is C 1 -C 4 alkyl and R 1 is _a chlorine atom, _a methoxy group, a C 1 -C 4 alkylthio group or a R 1 is -CO-NH, where R 11 is C 1 -C 4 alkyl, mixed with customary pharmaceutical excipients, diluents and optionally other excipients. 7. A process according to claim 6 wherein the active ingredient is a compound of formula I as defined in claim 2, wherein R _a and R j are as defined in claim 2. according to claim 2. 8. A process according to claim 6 wherein the active ingredient is a compound of formula I as defined in claim 5, wherein R ₁ and R 4 are as defined in claim 3. 9. A process according to claim 6 wherein the active ingredient is a compound of general formula I as defined in claim 4, wherein R &lt; 1 &gt; and R &lt; 1 &gt; according to claim 4. -16182,738 10. A process according to claim 6 wherein the active ingredient is a compound of formula I as defined in claim 5, wherein R _a and is as defined in claim 5.