HU184788B - Process for the preparation of 7alfa-methoxy-ceph-3-em-4-carboxylic acid derivatives - Google Patents

Abstract

PURPOSE:Cephalosporin derivative I (A is (substituted) isothiazolyl; B is H, methoxy; R is H, lower alkyl).

Description

The present invention relates to a novel process of formula (I)

7a-methoxy-cef-3-ene-4-carboxylic acid derivatives wherein Y is a group of formula (a) or (b) wherein

R is hydroxy, C 1-4 alkoxy or amino,

R ¹ is hydrogen or C 1-4 alkyl optionally substituted with hydroxy,

R ² is hydrogen, C 1-4 alkyl optionally substituted with hydroxy, phenyl, carboxyl, carbazoyl, cyano, carbamoyl, mono or di (C 1-4 alkyl) carbamoyl, amino or C 1-4 alkoxycarbonylamino

R ³ is tetrazolyl substituted with C 1 -C 4 alkyl and pharmaceutically acceptable salts thereof.

The compositions of the present invention have antibacterial activity.

R '

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The present invention relates to a novel α-methoxy-cef-3-em4-carboxylic acid derivative of formula (I) wherein Y is a group of formula (a) or (b) wherein

R is hydroxy, C 14 alkoxy or amino,

R ¹ is hydrogen or C 14 alkyl optionally substituted with hydroxy,

R ² is hydrogen, C 14 alkyl optionally substituted with hydroxy, phenyl, carboxyl, carbazoyl, cyano, carbamoyl, mono or di (C 14 alkyl) carbamoyl, amino or (14). C 1-4 alkoxy) carbonylamino

R ³ is tetrazolyl substituted with C 14 alkyl

The novel compounds of formula I possess antibacterial activity. In addition, they are useful as intermediates in the preparation of other pharmaceutically useful derivatives of cef-3-em4-carboxylic acid.

Over the past few decades, various antibiotics have been studied and applied to treat infectious diseases in humans and animals. However, given that in many cases resistant bacteria appear, known antibiotics are not suitable for treating some infectious diseases. Therefore, research is constantly focused on producing newer and newer antibiotics to supplement the arsenal of doctors, especially when it comes to combating infectious diseases that have become pathogen-resistant to currently known and used chemotherapeutic agents.

No. 2,356,388. German Patent Application Publication No. 2,966,151 discloses cephalosponn derivatives containing heterocyclic acyl groups, but no compounds of formula I have been described.

No. 3,464,999. U.S. Pat. No. 4,198,195 discloses compounds containing an isothiazolylacetamido group at the 7-position. However, new cef-3-em4-carboxylic acid derivatives carrying an isothiazolylthioacetamido group in the 7-position which can be converted to a 1,3-dithiethanecarboxamido group are new.

The cef-3-em4-carboxylic acid derivatives of the formula (I) have outstanding antibacterial activity, particularly against gram-negative bacteria.

When R ² is a functional derivative of a carboxyl group in the formula (I), the mono- or di (C 14 alkyl) carbamoyl group, carbamoyl group, carbazoyl group (NH ₂ NHCO-), cyano group may be used. .

In the formula (I), the alkyl group is a straight or branched C 14 alkyl group such as methyl, ethyl, isopropyl, n-butyl, tert-butyl and the like.

In the formula (I), R ³ is a tetrazolyl group substituted as above with C 4 alkyl. Examples of the tetrazolyl group are 1H-tetrazol-5-yl, 2H-tetrazol-5-yl and the like.

The compounds of formula (I) are among the 7-methoxy-cef-3-em4-carboxylic acid derivatives as read from the formula. The compounds are characterized by having an isothiazolylthioacetamido group at the 7/3 position.

Compounds of formula (I) are prepared by reacting a compound of formula (II) wherein A is -NH ₂ or X-CH ₂ CONH, wherein X is halogen, R ³ is as defined above, a compound of formula (III). or (III) 'ALTRA ^ nos compound wherein D is -CH ₂ COOH or a reactive derivative thereof, when A is -NH ₂ group, or a hydrogen atom when X is CONH-CH, R, R ¹ and R ² is as defined above.

When a compound of formula (II) wherein A is an amino group by reaction with a formula (III) or (III) 'a compound of formula wherein D is -CH ₂ COOH or a reactive derivative, the reaction is usually an inert solvent - such as preferably acetone, chloroform, dichloromethane, ethyl chloride, tetrahydrofuran, dimethylformamide, acetonitrile, ethyl acetate, ethyl formate and the like. - in the presence of heat or cooling. Not only a single solvent, but also mixtures of solvents may be used, or, if the organic solvent is a mixture with water, an aqueous mixture may be used provided that the reaction is not detrimental.

The reactive derivative of the carboxyl group in the compound of formula (III) or (III) ', preferably the acid halide, mixed acid anhydride, active ester, active amide, acid anhydride, acid azide and the like. For the reagent containing the free carboxyl group, a condensing agent such as,, Ν'-dicyclohexylcarbodiimide, N, N'-diethylcarbodiimide and the like is preferred. use.

When R ¹ and / or R ^{2 in} the compound of formula (III) or (III) 'represent a reactive group which may inhibit the reaction, for example a carboxyl group or a hydroxymethyl group, the protecting group is preferably first and then reacting the reagent of formula (III) or (III) with the compound of formula (II). After the reaction, the protecting group is removed.

If A is a compound of formula (II) in which _X-CH2 CONH group is reacted with a compound represented by D = H (III) or 'formula (III), usually in the presence of a solvent, at room temperature or under cooling. Without limitation, any solvent which is not involved in the reaction may be used, but generally water, methanol, acetone, tetrahydrofuran, dimethylformamide or mixtures thereof are used. The compound of formula (III) or (III) 'can be used in most cases in the form of its alkali metal salt at the mercapto group. However, when the compound is used in the form of formula (III) or (III), the reaction is carried out on an aliphatic, aromatic or heterocyclic base such as triethylamine,,, Ν-dimethylaniline, N-ethylmorpholine, pyridine, collidine , 2,64utidine, etc. or an alkali metal carbonate or an alkali metal bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. in his presence.

The compounds of formula (I) can also be prepared by reacting the compound (IV) a compound of formula wherein R ⁵ is an acetyl group or a carbamoyl group, A is as defined above, (III) or (III) 'reagent of formula is reacted with and then reacting the resulting thermal with a compound of formula (V).

184,788

The reaction of the compound of formula (IV) with the reagent of formula (III) or (III) 'is carried out as described above. The product obtained can also be reacted with the alkali metal salt of the compound of formula V at room temperature or under heating, usually in the presence of an inert solvent. The inert solvent is, for example, acetone, dimethylformamide, methanol, ethanol, water, phosphate buffer or mixtures thereof.

When the compound of formula (V) is used in its free form not in the form of a salt, the reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, a trialkylamine, pyridine or dimethylaniline.

The cef-3-em-4-carboxylic acid derivatives of formula (I) have outstanding antibacterial activity, particularly against gram-negative bacteria, as shown in Table I.

Table I

Minimum inhibitory concentration of compounds in gamma / ml

Compound (example- number) Esche- richia coli NIHJ Klebsiella pneu- moniae ATCC 10031 Proteus vulgar OXKUS Proteus morganü Kono Serratia marces- CENS First 0.2 02 156 156 3.13 Second 0.78 156 3.13 12.5 6.25 4th 0.78 0.78 3.13 6.25 6.25 5th 0.78 0.78 0.39 125 25 10th 156 156 0.78 50 50 11th 0.78 0.78 156 25 50 12th 0.2 0.78 156 6.25 12.5 13th 0.78 0.78 3.13 125 25

Cef-3-em-4-carboxylic acid derivatives of formula (I) wherein R ^{2 at the} 4-position and -S-5 may be used as intermediates for other valuable cephalosporin compounds, e.g. 7a-methoxy-7- [3- (1,3-dithiethane-2-carboxamido) -ceph-3-em-4-carboxylic acid derivatives wherein R ¹ , R ² and R ³ are as defined above.

The compounds of formula (VI) have antibacterial activity. They may be prepared by treating the compound of formula (I) at room temperature or with cooling with a weak base such as sodium bicarbonate, potassium bicarbonate or sodium carbonate in water or a water-miscible organic solvent such as methanol, acetone, tetrahydrofuran or dimethylformamide.

The compounds of formula I according to the invention may be converted into a pharmaceutically acceptable salt thereof. For example, alkali metal salts such as sodium or potassium salts such as 2-ethylhexanoic acid or potassium salts, ammonium salts or organic amines such as procaine or ethanolamine may be prepared. The salts are prepared in a manner known per se.

The cef-3-em-4-carboxylic acid derivatives of formula (I) may be converted into the pharmaceutical composition using conventional excipients known in the art. For example, the compounds of formula (I) may be used as pharmaceutical compositions for oral, rectal, subcutaneous, intramuscular or intravenous administration.

For the treatment of patients, a sterile solution or suspension containing an effective but non-toxic amount of a compound of formula (I) is preferably injected. In the course of treatment, the compounds of the formula I are usually administered to adults in a daily dose of 250-3000 mg. The dose used will depend on the disease and on the age, weight and condition of the patient.

The invention is illustrated in detail by the following examples.

Example 7 270 mg of 4-carboxy-5-ethylthio-3-hydroxyisothiazole are suspended in 1 ml of liquid ammonia. The suspension is cooled to -50 ° C, 100 mg of sodium metal are added and the reaction mixture is stirred for 30 minutes at -50 to -35 ° C.

Liquid ammonia was evaporated and the residue was dissolved in methanol (20 mL) and treated dropwise with ice-cooling with 600 mg of 7a-methoxy-7H-bromoacetamido-3- (1-methyltetrazol-5,4) -thiomethyl-cef-3-em- 4-carboxylic acid in 10 ml of methanol. The reaction mixture was stirred for 30 minutes under ice-cooling and stirred for an additional 30 minutes at room temperature. After completion of the reaction, the reaction mixture was adjusted to pH 4 with 4N hydrochloric acid and the solvent was evaporated under reduced pressure.

Water was added to the residue, the pH was adjusted to 1 with 4N hydrochloric acid, and the product was extracted with 50 ml of a 1: 1 mixture of butanol and ethyl acetate. The organic layer was washed twice with water, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ether (30 mL), and the resulting precipitate was filtered, washed with 3 x 20 mL of food and dried in vacuo.

560 mg of 7α-methoxy-7β- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-3- (1-methyltetrazol-5-yl) thiomethyl-cef-3-em-4 -carboxylic acid is obtained in the form of a powder. NMR ^- (deuterated dimethyl sulfoxide) δ value:

3.41 (3H), 358 (2H), 3.93 (3H), 3.99 (2H), 4.28 (2H),

5.10 (1H).

Example 2

Preparation of Formula VII Liquid ammonia in ml was cooled to -70 ° C and 183 mg of 4-amino-5-ethylthio-3-hydroxyisothiazole was added followed by 55 mg of sodium. The reaction mixture was stirred at this temperature for 10 minutes, after which time the liquid ammonia was evaporated. To the residue was added methanol (15 mL) and cooled to 2 ° C. A solution of 300 mg of 7a-methoxy-7/3-bromoacetamido-3- (1-methyltetrazol-5-yl) -thiomethyl-cef-3-em-4-carboxylic acid in 15 ml of methanol is added dropwise over 30 seconds. and stir for 10 minutes at this temperature. The solvent was evaporated under reduced pressure, water (15 ml) was added and the mixture was adjusted to pH 25 with 5% hydrochloric acid. The precipitate formed was 1: 1 with n-butanol and ethyl acetate

After extraction with 100 ml of a mixture of 184,788 meshes, the extract was washed with water and then with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a silica gel column. Elution was carried out with a mixture of chloroform, methanol and formic acid (8: 2: 0.2 by volume).

In this way, 180 mg of 7α-methoxy-7β- (4-amino-3-hydroxyisothiazol-5-yl) -thioacetamido-3- (1-methyltetrazol-5-yl) -thiomethyl-cef-3 are obtained. -em-4-carboxylic acid is obtained.

MMR spectrum; (deutero-dimethylsulfoxide) δ values: 3.36 (3H), 354 (2H), 358 (2H), 3.94 (2H), 4.30 (2H), 5.09 (1H).

Example 3

Preparation of Formula VIII The procedure of Example 2 was followed. 300 mg

4- (ethoxycarbonylamino) -5-ethylthio-3-hydroxy-thiazole and 300 mg of 7a-methoxy-7- (3-bromoacetamido-3- (1-methyltetrazol-5-yl) thiomethyl- of cef-3-em-4-carboxylic acid 50 mg of 7a-methoxy-7- (5- (4-ethoxycarbonylamino) -3-hydroxyisothiazol-5-yl) thioacetamido-3- (1-methyl Trazol-5-yl) -thiomethyl-cef-3-em-4-carboxylic acid is prepared.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values: 1.14 (3H), 3.38 (3H), 3.60 (2H), 3.81 (2H), 3.92 (3H), 4.06 (2H), 4.29 (2H), 5.11 (1H).

Example 4

Preparation of Compound (IX) Example 2. 220 mg of 4-carbazoyl-5-ethylthio-3-hydroxyisothiazole and 400 mg of 7o-methoxy-7H-bromoacetamido-3- (1-methyltetrazol-5-yl) -thiomethyl-cef-3- of em-4-carboxylic acid 100 mg of 7a-methoxy-7- [3- (4-carbazoyl-3-hydroxyisothiazol-5-yl) thioacetamido-3- (1-methyltetrazol-5-yl) thiomethyl] -cef-3-em-4-carboxylic acid is obtained.

MMR Spectrum ^- (deutero-dimethylsulfoxide) δ values:

3.39 (3H), 3.63 (2H), 3.90 (2H), 3.93 (3H), 4.30 (2H), 5.13 (1H)

Following the procedure of Example 1, the following compounds were prepared:

Example 5

7a _6-methoxy-7 - (4-cyano-3-hydroxy-isothiazol-5-yl) thioacetamidate-3- (l-methyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid .

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.39 (3H), 3.59 (2H), 3 £ 2 (3H), 4.11 (2H), 4.28 (2H),

5.10 (1H).

Yield: 55.1% (250 mg).

Example 6

7a-Methoxy-7- [3- (3-hydroxy-4-phenylisothiazol-5-yl) thioacetamido-3- (1-methyltetrazol-5-yl) thiomethyl] ceph-3-em4-carboxylic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.40 (3H), 356 (2H), 3.87 (2H), 3.92 (3H), 4.27 (2H), 5.05 (1H).

Yield: 53.6% (250 mg)

Example 7

7a-Methoxy-70- (3-amino-4-cyano-isothiazol-5-yl) -thioacetamido-3- (1-methyl-tetrazole-5,4) -thiomethyl-cef-3-em4-carboxylic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.40 (3H) 3.60 (2H), 3.95 (3H), 4.08 (2H), 4.31 (2H),

5.11 (1H).

Yield: 44.9% (250 mg)

Example 8

7a-Methoxy-7- [3- (4-dimethylcarbamoyl-3-hydroxyisothiazol-5-yl) -thioacetamido-3- (1-methyl-tetrazol-5-yl) -thiomethyl-cef-3-em- 4-carboxylic acid.

MMR (deutero-dimethylsulfoxide) δ values: 2.88 (6H), 358 (3H), 356 (2H), 3.90 (5H), 4.26 (2H), 5.04 (1H).

Yield: 35.8% (300 mg)

Example 9

7a-methoxy-7 / 3- (3-hydroxy-izotiazol4-yl) thioacetamidate-3- (l-methyl-tetrazol-5-yl) thiomethyl-ceph-3-em-4-carboxylic acid. MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.39 (3H), 3.48 (2H), 3.66 (2H), 394 (3H), 4.26 (2H),

5.11 (1H), 759 (1H).

Yield: 42.1% (450 mg).

Example 10

7a-methoxy-7 / 3- (4-cyano-2-methyl-3-oxo-2,3-dihydroisothiazole-5-yl) thioacetamidate-3- (l-methyl-tetrazol-5-yl) -tiometil- ceph-3-em-4-carboxylic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.40 (3H), 3.64 (2H), 3.92 (8H), 4.30 (2H), 5.16 (1H). Yield: 35.0% (300 mg)

Example 11

7a-Methoxy-70- [4-cyano-2- (2-hydroxyethyl) -3-oxo-2,3-dihydroisothiazol-5-yl] thioacetamido -3- (1-methyltetrazol-5-yl) thiomethyl ceph-3-em-4-carboxylic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

3.40 (3H), 35-3.6 (3H), 3.76 (2H), 35.3 (3H), 4.16 (2H), 4.32 (2H), 5.14 (1H) .

Yield 31.4% (300 mg)

Example 12

7α-Methoxy-7β- (4-carbamoyl-3-hydroxyisothiazol-5-yl- (thioacetamido-3- (1-methyltetrazol-5-yl) thiomethyl-cef-3-em-4-) kar bonic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values: 3.39 (3H), 3.49 (2H), 3.64 (2H), 393 (3H), 4.28 (2H), 5.07 (1H ).

Yield: 75.1% (300 mg).

Example 13

7a-methoxy-7- (3- (hydroxymethyl-34iidroxi4 metil4zotiazoI-541) thioacetamidate-3- (l-methyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values:

184,788

3.40 (3Η), 3.58 (2Η), 3.83 (2Η), 3.92 (3Η), 4.12 (2Η), 4.30 (2Η), 5.10 (1Η).

Yield: 62.0% (230 mg)

Example 14 300 mg of 7a-methoxy-7/3-amino-3- (1-methyltetrazol-5-yl) -thiomethyl-cef-3-em4-carboxylic acid benzhydryl in 300 ml of dichloromethane are dissolved in -30 ° C. After cooling to 460 mg, pyridine is added.

A solution of potassium salt of (4-cyano-3-methoxyisothiazol-5-yl) thioacetic acid (240 mg) in dichloromethane (10 mL), oxalyl chloride (170 mg) and dimethylformamide (one drop) was added dropwise to the above solution. 30 to -20 ° C, and the reaction mixture is stirred at the same temperature for 1 hour. Chloroform (30 ml) was added, washed twice with 2% hydrochloric acid and twice with saturated aqueous sodium bicarbonate solution, and the organic phase was separated and dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was chromatographed on a silica gel column (eluent: chloroform / isopropanol = 10: 1).

190 mg of 7a-methoxy-70- (4-cyano-3-methoxy-isothiazol-5-yl) -thioacetamido-3- (1-methyl-tetrazol-5-yl) -thiomethyl-cef-3-em- 4-Carboxylic acid benzhydryl ester is obtained.

The above product is dissolved in 2 ml of dichloromethane, dropwise at -15 to -5 ° C, 1.6 ml of a 3: 1 mixture of trifluoroacetic acid and anisole and stirred at the same temperature for 40 minutes. The solvent was evaporated under reduced pressure, the residue was treated with ether (10 ml), filtered and dried under reduced pressure.

120 mg 7a-Methoxy-70- (4-cyano-3-methoxy-isothiazol-5-yl) -thioacetamido-3- (1-methyl-tetrazol-5-yl) -thiomethyl-cef-3-em-4 - Carboxylic acid is obtained.

MMR spectrum; (δ-values of deutero-dimethylsulfoxide);

3.40 (3H), 3.58 (2H), 3.92 (3H), 3.99 (3H), 4.15 (2H), 4.18 (2H), 5.12 (1H).

Example 15

Preparation of Compound (X) (a) In a 60 ml methanol was dissolved 6.1 g of 7a-methoxy-70-bromoacetamido-3-acetoxymethyl-cef-3-em-4-carboxylic acid. A solution of 4.3 g of 4-carboxy-3-hydroxy-5-mercaptoisothiazole trisodium salt (trihydrate) in ice-cooled water (15 ml) was added dropwise at 0-5 ° C. The reaction mixture was stirred at this temperature for 30 minutes and the methanol was evaporated under reduced pressure. The residue was taken up in water (40 mL), adjusted to pH 3 with 2N hydrochloric acid, and washed with ethyl acetate. The aqueous phase was acidified to pH = 1 with 2N hydrochloric acid and extracted twice with 1: 1 n-butanol / ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting powdery crude product was dissolved in a small amount of methanol and the solution was cooled with ice to aid crystallization. The crystalline material is filtered off.

4.8 g (64.2%) of 7a-methoxy-7- [3- (4-carboxy-3-hydroxyisothiazol-5-yl) -thioacetamido-3-acetoxymethyl-cef-3-em4-carboxylic acid are obtained. white, in the form of purified crystals.

Δ-values: 5.20 (1H, singlet), 4.84 (2H, quartet), 4.02 (2H, singlet), 3.52 (2H, quartet), 3, 44 (3H, singlet); 2.04 (3H, singlet).

(b) 7a-methoxy-7- [3- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-3-acetoxymethyl-cef-3-em-4-carboxylic acid and 5-mercapto-1 7-Methoxy-70- (4-carboxy-3-hydroxy-isothiazol-5-yl) -thioacetamido-3- (1-methyl-tetrazol-5-yl) -thiomethyl-cef-3-em4 using methyl-tetrazole -carboxylic acid.

Example 16

Preparation of compound of formula XI

123 mg of 3-hydroxy-5-mercaptoisothiazole are dissolved in 6 ml of methanol. To the solution was added, under ice-cooling, 250 mg of 7a-methoxy-70-bromoacetamido-3- (1-methyltetrazol-5-yl) thiomethyl-cef-3-em4-carboxylic acid in 4 ml of methanol. After stirring for 2 hours at room temperature, the reaction mixture was evaporated under reduced pressure. The residue is mixed with a little water and adjusted to pH 1 with 5% hydrochloric acid. The product was extracted with a 1: 1 by volume mixture of n-butanol and ethyl acetate. The organic layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: formic acid = 80: 20: 3).

120 mg of 7a-methoxy-7- [3- (3-hydroxyisothiazol-5-yl) thioacetamido-3- (1-methyltetrazol-5-yl) thiomethyl] cef-3-em4-carboxylic acid are obtained.

MMR Spectrum: (deutero-dimethylsulfoxide) δ values: 3.38 (3H), 3.60 (2H), 3.90 (3H), 3.94 (3H), 4.30 (2H),

5.10 (1H), 6.61 (1H).

EXAMPLE 17 Powdered 7- [3- (4-Carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl] -3-em4-carboxylic acid is suspended in 15 ml of water. The resulting suspension was cooled to 5 ° C and a solution of 0.44 g of sodium bicarbonate in 5.5 ml of water was added over 5 minutes. The reaction mixture was stirred for 30 minutes under ice-cooling and then lyophilized. 1.62 g of powdered disodium-7) 3- (4-carboxylato-3-hydroxyisothiazol-5-yl) -thioacetamido-7a-methoxy-3- (1-methyl-tetrazol-5-yl) -thiomethyl-cef-3 -em4-carboxylate is obtained. NMR spectrum (deutero-DMSO) δ values: 3.25 (2H, -CH ₂ -), 3.43 (3H, _OCH3), 3.90 (2H, -SCH ₂ CO-) 3 , 92 (3H, N-N), 4.33 (2H.A)

II II 1 Λ / \ N fCH ₂ -SI

CH ₃

IR spectrum (KBr, cm ^-1 ): 1750 (lactum)

Claims (2)

Patent claims A process for the preparation of a novel 7a-methoxy-cef-3-em4-carboxylic acid derivative of formula (I) wherein 184,788 Y is a group of formula (a) or (b) wherein R is hydroxy, C 14 alkoxy or amino, R ¹ is hydrogen or C 14 alkyl optionally substituted with hydroxy, R ² is hydrogen, C 14 alkyl optionally substituted with hydroxy, phenyl, carboxy-1, carbazoyl, dano, carbamoyl, mono- or di (C 14 alkyl) -carbamoyl, amino or (C14-C4 alkoxy) carbonylamino R ³ is a tetrazolyl group substituted with C 14 alkyl and pharmaceutically acceptable salts thereof, characterized in that: a) a compound of formula (II) wherein A is -NH ₂ or X-CH ₂ -CONH-, wherein X is halogen R ³ is as defined in the preamble, with a compound of formula (III) or (III) ' , wherein D is -CH ₂ COOH or a reactive derivative thereof, when A is -NH ₂ , or hydrogen, when AX-CH _{2 is} CONH, R, R ¹ and R ² are as defined or protected with a compound of formula (III) or (III) '; obsession b) a compound of formula IV wherein R ⁵ is acetyl or a carbamoyl tube powder; A is -NH ² or X-CH ₂ CONH - wherein X is halogen; ) 'compound wherein D is -CH ₂ COOH or a derivative reakdóképes when A is -NH ₂ group, or a hydrogen atom when X is -CH ₂ CONH10 moiety, R, ^R1 and ^R2 are reacting a compound of formula (III) or (III) 'as defined or protected, and then reacting the product with a compound of formula (V) wherein R ³ is as defined above: deprotecting if necessary, and optionally converting the resulting product of formula I into a salt. A process for the preparation of a pharmaceutical composition having an antibacterial effect, comprising the preparation of a compound of formula I according to claim 1 a) or b), wherein Y and R ³ are as defined in the scope of claim 1, or a pharmaceutically acceptable salt thereof. Suitable salts thereof are formulated into pharmaceutical compositions using conventional excipients. Figure 14 Published by the National Office of Inventions Responsible for publishing: Zoltán Himer Head of Department Published by Technical Publisher 88-003 YEARS Reproduction plant, Budapest VIII., Szörény u. 5-7. Responsible leader: Árpád Szeli -6ch ₂ conh 184,788 NGO ₃ : C 07 D 501/40