CS199671B2 - Method of producing derivatives of 7beta-/p-acyloxyphenylmalonamido/-3-substituted thiomethyl-1-oxadethia-3-cephem-4-carboxylic acids - Google Patents

Description

The present invention relates to a process for the preparation of 1-oxadethiationphalosporins, namely derivatives of N - (? - acyloxyphenylmalonamido) -3-substituted-thiomethyl-1-oxadethia-3-cephem-4-carboxylic acids of the general formula I

in which . R is C 1 -C 4 alkyl, amino, methylamino or carbamoylamino; and

COB ¹ and COB ^{2 each} independently represent a carboxyl group, optionally protected in the form of an ester, for example phenyl (f) ester, xylyl ester, indanyl ester, phenacyl ester, acetoxymethyl ester or phthalidyl ester, and their pharmaceutically acceptable base salts.

In accordance with the invention, the compounds of formula (I) above are prepared by producing a compound of formula (II)

() in which

COB ¹ and COB ² , as defined above, are acylated by the action of an acylating agent of formula

RCOX in which

X represents a halogen atom or an alkanoyloxy group having 1 to 3 carbon atoms in the alkyl moiety; and

R is as defined above, and the compound of formula I obtained is optionally converted by treatment with a base into its pharmaceutically acceptable salt.

Cephalosporin analogs containing an oxygen atom in the nucleus instead of sulfur are already described in the Journal of Heterocyclic Chemistry, Vol. 5, p. 779 (1968) (JC Sheehan and M. Dadic), in DOS No. 2 219 601 (1972), in the Canadian Journal of Chemistry, vol 52, p. 3996 (1974) (Saul Wolfe et al. and in the Journal of the American Chemical Society, vol. 96, p. 7582 (1974) (BG Christensen et al.).

In accordance with the invention, various 1-oxadethiacephalosporins closely related to known (1-thia) cephalosporins are prepared. In contrast to the data published by BG Christensen et al., Whose racemic 1-oxacephalosporins showed only about half the activity of (1-thia) cef alosporins, the optically active products produced by the method of the invention are about four to eight times more antibacterially effective than the corresponding. (thia) cephalosporins. However, the β-lactam ring of 1-oxacephalosporins is less stable (for use in clinical medicines) than the corresponding (1-thia) cef alosporin ring.

The compounds of formula (I) selected from the optically active substances prepared according to the invention do not have the aforementioned deficiency of 1-oxadethiacephalosporins.

Further, the compounds of formula I are characterized by the following properties:

1) higher antibacterial activity against gram-negative organisms,

2) higher stability of the β-lactam ring,

(3) a narrower range of minimum inhibitory concentrations in relation to β-lactamase-producing and non-β-lactamase-producing bacteria;

4) less dependence on inoculum size,

5) higher efficacy against bacteria resistant to certain other cephalosporins (eg Enterobacterla, Serratia, indolpositive Proteus),

6) higher bactericidal character; and

7) higher blood levels.

In addition, the compounds of the formula I have the following advantageous properties:

(a) a wider spectrum of antibacterial activity (eg 3,6 χ / ml or more against Pseudomonas sp. and anaerobic bacteria such as Bacteroides fragilis),

b) higher activity against β-lactamase producing organisms,

(c) increased blood stability; and

(d) lower blood protein binding.

The COB ¹ and COB ² moieties may be carboxyl or protected carboxyl groups common in the chemistry of penicillins and cephalosporins, usually containing up to 15 carbon atoms. Individual carboxyl groups in a molecule may be protected with the same or different protecting groups. The protecting groups are usually cleaved to give the free carboxylic acids or salts thereof, so that the structure of the carboxyl protecting groups can vary within wide limits without departing from the scope of the invention. In other words, the structures of protecting groups of carboxyl functions have no other specific meaning and mission than to allow protection of carboxyl functions, cleavage of protecting groups and, where appropriate, carboxyl groups. salt formation. Preferred protecting groups are ester moieties.

Thus, specific examples of the aforementioned protecting groups include esters including optionally substituted alkyl esters, for example tert-butyl, monohydroxy-tert-butyl or 2,2,2-trichloroethyl, acyloxymethyl, aralkyl esters, for example benzyl, p-tolylmethyl, p-nitrobenzyl. , p-methoxybenzyl tester, phthalidyl ester, diphenylmethyl ester, trityl and phenacyl ester, metal esters, e.g. .

The compounds of formula I may also be in the form of pharmaceutically acceptable salts, including alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium, calcium and acyloxy calcium salts, and organic base salts such as procaine, triethylamine and dicyclohexylamine. The individual carboxyl groups in the molecule may be free or in the form of salts or may be protected by the same or different groups.

The COB ¹ and COB ² moieties may preferably be free carboxyl groups or pharmaceutically acceptable salts thereof. Other preferred COB ¹ moieties are 5-indanyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

However, some carboxyl-protecting groups are useful for altering the nature of the products as pharmaceuticals. In such cases, such protecting groups may be specific known groups commonly used in drugs in the art. These groups include the following pharmaceutically acceptable groups:

phthalidyl ester, acyloxymethyl ester, indanyl ester, phenyl ester, tolylester, dimethylphenyl ester and ethoxycarbonylmethyl ester groups.

Specific examples of acyl radicals in the meaning of the RCO moiety are formyl, acetyl, propionyl, butyryl, isobutyryl, carbamoyl, N-methylcarbamoyl and carbamoylcarbamoyl radicals.

For application in human or veterinary medicine, the compounds of the formula I are usually used in the form of salts. The most preferred salts are sodium or potassium salts, or salts with certain organic bases. These salts are selected with regard to their safety, solubility, stability and the like.

Compounds of formula I containing p-acetoxyphenylmalonamido, p-carbamoyloxyphenylmalonamido, pN-methylcarbamoyloxyphenylmalonamido or p-ureidocarbonyloxyphenylmalonamido at the 7-position are potent antibacterial agents, less inactivated in blood due to their nutrient levels ) than the corresponding unsubstituted aryl malonamide derivatives. They also have a very high potency against Pseudomonas strains, including relevant carbenicillin-resistant strains.

The compounds of formula (I) are very potent antibacterial agents against Gram-negative organisms and their effect is associated with a small decrease in efficacy at larger inoculum size.

The results of the potency assays of representative compounds of the invention are shown in Table A below. Table B shows the results obtained in analogous assays with comparative, closely related substances.

In vitro assays are performed using the following microorganisms.

(1) = Escherichia coli JC-2 (2) = Enterobacter cloacae 233 (3) - Proteus vulgaris CN-329 (inoculum size 10 ⁸ , 5% horse blood added for esters). Antibacterial activity values in this case are given in µg / ml.

In vivo tests are performed in mice (intraperitoneal administration) using the following microorganisms:

(4) = 'Pseudomoonas aeruginosa PS-24' (5) = Escherichia coli EC-14

Antibacterial activity values in this case are given in mg / kg.

Table A

Antibacterial activity of the compounds of the invention in vitro (g g / kg) and in vivo (mg / kg)

Ar *

B ‘(1) (2) (3) m-vivo (4) (5)

^{CH3 ^ CHCOO

-H

-H

λ //

-H

0.2

0.2

0.2

0.2

0.4

0.4

0.4

0.4

0.4

0.4

0.4

0.4

0.19

Test substance Ar ‘B‘ in vitro (1) (2) Efficiency (3) (4) in vivo (5) c ^ c ^ oo-Q- -h 0.2 0.2 0.4 - - -h 0.2 0.2 0.2 7.1 0.12 C ^ - COO - 0.4 0.8 0.2 - 0.22 H _Z N CONH CO O —— H 0.2 0.2 0.2 19 Dec 0.16

Table Β

Antibacterial potency of reference compounds in vitro (^ g / ml)

In vitro potency (1) (2) (3)

> 100> 100> 100> 100

COOH CH, > 100 > 100 > 100 > 100

> 100> 100> 100> 100

All of the compounds of formula I are novel substances with high antibacterial activity, and are useful as medicaments in human and veterinary medicine, and as disinfectants. For example, the compounds are conveniently administered orally or parenterally to humans or animals in a daily dosage of, for example, 0.05 to 50 mg per kilogram of body weight.

The compounds of formula (I) are usually supplied in ampoules containing sterilized microcrystals or lyophilisate, and are administered in the form of solutions prepared before use. Further, an effective amount of a compound of the invention may conveniently be administered orally or parenterally together with pharmaceutically acceptable carriers, excipients, diluents or stabilizers in the form of pharmaceutical compositions, for example, ampoules, injections, ointments, solutions, tablets, powders and capsules. These compositions may be in unit dosage form. For parenteral administration, the abovementioned salts, including alkali metal salts, are predominantly used. Acyloxymethyl, indanyl, phenyl, phthalidyl and the like esters are also suitable for oral administration. The compounds of formula I may also serve as intermediates for the preparation of other useful compounds, whether or not within the scope of formula I.

The preparation of the starting materials of the general formula II is described in our related Czechoslovak patents Nos. 199 669 and 199 670.

The acylating agents used in the process of the invention and the reaction conditions of these acylation reactions are generally known in the art.

The compounds of the formula I obtained can be converted into salts in the customary manner or the carboxyl protecting groups present therein can be cleaved to give free carboxyl groups, or the free carboxyl groups present can be modified by introducing protecting groups or substituents.

For example, if a carboxyl group at the 4-position or a side chain carboxyl at the 7-position or a carboxyl group at the Het residue is protected, the appropriate protecting groups can be cleaved in the conventional manner to give the desired compounds of formula I. for example, one of the following:

1) highly reactive esters, amides and anhydrides are readily hydrolyzed by treatment with acid or base;

2) 2-haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters can be cleaved by slight reduction, for example with tin, zinc or divalent chromium salts in the presence of acids, sodium dithionite or catalytic hydrogenation with hydrogen in the presence of a catalyst such as platinum, palladium or ;

3) benzyl-, methoxybenzyl-, p-methylbenzyl-, dimethoxybenzyl-, t-alkyl-, trityl-, diarylmethyl- and cyclopropylmethyl esters can be cleaved by treatment with acids or solvolytically (for example by treatment with mineral acids such as hydrochloric acid, Lewis acids, for example aluminum chloride, sulfonic acids such as p-toluenesulfonic acid or strongly acidic carboxylic acids such as trifluoroacetic acid or formic acid);

4) phenylacyl-, ethynyl-, p-hydroxy-3,5-di-tert-butylbenzyl esters can be cleaved by treatment with a base (e.g., alkali metal thiophenoxides, inorganic bases or basic salts), and the like.

As mentioned above, compounds of formula I containing one or more free carboxyl groups can be converted to the corresponding derivatives on the carboxyl group by introducing protecting groups or substituents in a manner known per se, such as for preparing esters by treatment with the corresponding alcohols together with conventional condensation reagents, diazo compounds, haloformates and the like, for the preparation of salts by treatment with alkali metal hydroxides or alkali acid salts with alkali metals, or by treatment with organic bases or by using ion exchangers.

The invention is illustrated by the following non-limiting examples. The results of elemental analyzes and the physical constants of the products in all these examples are nowhere in conflict with the stated structure. The products in these examples usually contain practically equal amounts of isomers at the asymmetric carbon at the position and the amide side chain. Both of these isomers are within the scope of the invention and can be separated, if necessary, by chromatography or other conventional means. The nomenclature of the compounds is in accordance with the nomenclature disclosed in Japanese Patent Application Publication No. 49133 594.

Example 1

To a solution of 286 mg of diphenylmethyl 7β- (ω-p-hydroxyphenyl-α-diphenylmethoxycarbonylacetamido) -7'-methoxy-3- (1-methyltetrazol-5-yl) thlomethyl-1-oxadethia-3-cep-4- of carboxylate in 2 ml of methylene chloride was added 0.5 ml of trichloroacetyl isocyanate while cooling to -78 ° C. The reaction mixture was stirred at -78 ° C for 30 min and then at 0 ° C for 1 h. The reaction was diluted with 20 mL of benzene and 20 mL of ethyl acetate, washed with water, dried and concentrated. The residue is chromatographed on 30 g of silica gel containing 10% water, eluting with a 1: 1 mixture of benzene and ethyl acetate. There was obtained diphenylmethyl-N- (p-carbamoyloxyphenyl-α-diphenylmethoxycarbonylacetamido) -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate, which resulted in yield 179.9 mg as a colorless foam, 59.5%.

i O. in m & x

3530, 3425, 3325, 1790, 1750, 1728, 1700 cm ^-1 ;

NMR: δ ^{CDCl 3} (3.42 singlet + 3.45 singlet) 3H

3.73 singlet 3H

4.22 singlet 2H

4.42 singlet 2Ή

4.80 singlet 1H

5.03 singlet 1H

5.33 singlet 2H

Example 2

In analogy to Example 1, 100 mg of diphenylmethyl-7β- (? -Hydroxyphenyl-ar-diphenylmethoxycarbonylacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia- are treated. 3-cep-4-carboxylate with a solution of 0.2 methylisocyanate in 1 ml tetrahydrofuran in the presence of 1,5-diazabicyclo [3.5.0] undecene,

4.5 hours at 0 ° C. 52 mg of diphenylmethyl-7 H- (α-β-N-methylcarbamoyloxyphenyl-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cefem-4 are obtained. Yield: 49%.

Example 3

In analogy to Example 1, 175 mg of diphenylmethyl-7β- (p-carbamoyloxyphenyl-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3 The ε-4-carboxylate in 2 ml of methylene chloride is treated with 0.4 ml of trichloroacetyl isocyanate under cooling at 0 DEG C. After a reaction for 15 hours at room temperature, the N ³ -trichloroacetylureidocarbonyloxyphenyl derivative is obtained. at room temperature. There were obtained 145 mg (79%) of diphenylmethyl _7-1S- (AP-ureidokarbonyloxyfenyl-and-difenylmethoxykarbonylacetamidoj-7a-methoxy-3- (l-methyl-tetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem m-4-carboxylate as a colorless foam.

Tp. cucb

V max

3500, 1790, 1758, 1725, 1700 (shoulder) cm ¹

NMR: δ ^{CDCl 3}

3.43 singlet 3H

3.68 singlet 3H

4.21 wide singlet 2H

4.43 wide singlet 2H

4.83 broad singlet 1H

5.03 singlet 1H

5.80 - 6.70 multiplet 2H

6.95 singlet 2H

8.2.3 broad singlet 1H

9.20 broad singlet 1H

6.95 singlet 2H

EXAMPLE 4 (1) To an ice-cooled solution of 170 mg of diphenylmethyl ethyl 7, β- (α-ρ-hydroxyphenyl-α-phthalidyloxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl of 1-oxadethia-3-cephem-4-carboxylic acid in 2 ml of dichloromethane was added with stirring 180 µl of acetic anhydride and 90 µl of pyridine. After 2 hours, the reaction mixture was poured into ethyl acetate / water / ice, the organic layer was separated, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. 144 mg (yield 80.4% of diphenylmethyl 7β- (α-p-acetoxyphenyl-α-phthalidyloxycarbonylacetamido) -7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl) -1-oxadethia-3-cefem-4 are obtained. -carboxylic acids in the form of an amorphous material.

(2) To a solution of 600 mg of 7β- (α-p-hydroxyphenyl-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-caroxylo diphenylmethyl ester Acetic acid in 10 ml of dichloromethane was added 280 µl of pyridine and 304 µl of protpionyl chloride with stirring and ice-cooling, followed by stirring for 40 minutes under ice-cooling, the reaction mixture was poured into water and extracted with ethyl acetate. hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure, and the residue chromatographed on silica gel using a 9: 1 mixture of benzene and ethyl acetate as the eluent to give 600 mg (94% yield). 7-3- (ap-propionyloxyphenyl- N -diphenylimethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -methyl-1-oxadethia-3-cephem-4-carboxylic acid foamed diphenylmethyl ester.

(3) The reactions summarized in the following Table 1 were also carried out in an analogous manner to give the products listed in Table 2.

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Example 5

To a solution of 1.0 g 7 / 3- (wp-hydroxy - «- karboxyacetaniido 7a-methoxy-3- ^{1 i} (l-metlhyltetrazol-5-yl) thiomethyl-l-oxadethia-3-cephem-carboxylic acid ethyl ester in 6 ml of N, N-dimethylformamide, 832 mg of phthalidyl bromide are added under stirring and ice-cooling, the reaction mixture is stirred at room temperature for 1 hour and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The residue (1.39 g) is chromatographed on 42 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1). 06 g of the powdered product (II COB COB = ^{1 2} = ftalidyloxyíkarbonyl) containing 282 mg isoberu A (less polar fraction] 164 mg of isomer B, the more polar fraction), differing in the configuration of the side chain. These isomers may be isolated by preparative thin layer chromatography, using ethyl acetate as solvent system.

(3.20 singlet + 3.23 singlet) 3H,

3.37, singlet, 3H,

4.40, broad singlet, 2H,

4.63, broad singlet, 2H,

5.05, wide singlet, 2Ή,

6.8-8.0, multiplet.

Company ID:

⁰¹ max 1790, 1750 (shoulder], 1770 ^cm-1 (isomer Bj

NMR: δ cd3cocd3

3.17, wide singlet, 3H,

4.00, singlet, 3H,

4.20 - 4.65, multiplet, 4H,

5.03, broad singlet, 1H,

1H, 6.7-8.4, multiplet.

Company ID:

rt max ¹ 1790, 1750 (arm), 1700 cm ¹ Example 6 (isomer A)

NMR: .delta

• ->

CH _from Stetr sodium

Ph - phenyl

Tetr = 1-methyltetrazol-5-yl

To a solution of 2.3 g 7 /? - (N-PN-valeryloxyfenyl-and-fenoxykarbonylacetamldo) -7a-methoxy-3- (l-methyl-tetrazol-5-yl thiomethyl j-1-oxadethia-3-cephem-4 ^j carboxylic acid in 5 ml of ethyl acetate at 0 ° C was added 3.38 ml of a 2.0 M solution of sodium-and-ethylhexanoate in isopropanol, the reaction mixture was stirred for 10 minutes at 0 ^q C and then diluted with ether. the precipitate was filtered and washed with ether to give 1.72 g (yield 73%) of .alpha .- [beta] - [beta] - [beta] -n-valeryloxyphenyl-1H-phenoxycarbonyl-lacetamido-7 [alpha] -methoxy-3- (1-methyltetrazole); 5-ylthiomethyl-1-oxadethia-3-cephem-4-carboxylic acid.

NMR: δ CD 3 COCD 3

0.93, multiplet, 3H,

1.58, multiplet, 4H,

2.55, braid (7 Hzj 2H, (3.33 singlet + 3.40 singlet) 3H,

3.80 singlet, 3H,

4.14, wide multiplet, 4H,

4.99, singlet, 1H,

5.40, singlet, 1H,

7.02-7.70, multiplet, 9H.

Example 7 (11

To a solution of 550 mg of N - (N-p-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethla-3icephem-4-carboxylic acid in N, N-dimethylforimamide (3 ml), with stirring and ice-cooling, 0.2 ml of aicetoxymethyl bromide was added, the mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, water and The residue is chromatographed on 25 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1) to give 285 mg of acetoxymethyl ethyl ester 7β powder. - (β-hydroxyphenyl-α-acetoxymethoxycarbonyl lacetamido) -7, α-methoxy199671

-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-clarboxylic acid.

NMR: δ cdscocds (2.05 singlet + 3.32 singlet + 3.47 singlet) 3H, (3.97 singlet + 3.98 singlet) 3H,

4.33, short singlet, 2H,

4.62, AB-quartet,

4.83, broad singlet, 1H,

5.03, singlet, 1H,

4.07, singlet, 2H,

4.23, AB-quartet (7 Hz),

7.03, AzB'2, 4H.

Company ID:

in S 1790 (shoulder), 1760, 1690 cm ^-1 .

(2)

A small amount of (side chain) monoacetoxymethyl ester was treated with the alkaline wash liquors and treated with diphenyldiazomeethane to form diphenylmethyl ester of N- (α-p-hydroxy-phenyl-α-cetoxymethoxycarbonylacetamido) -7'-methoxy-3- (1- (methyltetrazole)). -5-yl) thlomethyl-1-oxadethia-3-cephem-4-carboxylic acid.

NMR: δ ^{CDCl 3}

2.00, singlet, 3H,

3.47, singlet, 3H, (3.73 singlet + 3.77 singlet) 3H,

4.17, singlet, 2H,

4.47, broad singlet, 2H,

4.53, broad singlet, 1H,

5.00, singlet, 1H,

5.73 singlet, 2H,

6.5-7.0, multiplet.

Company ID:

in mix ”1790, 1730, 1705 (shoulder) cm ^-1 .

Claims (1)

A process for the preparation of 7β-3- (p-acyloxyphenylmalonamido) -3-substituted-thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid derivatives of the general formula I in which: R is C 1 -C 4 alkyl, amino, methylamino or carbamoylamino; and COB ¹ and COB ^{2 each} independently represent a carboxyl group, optionally protected (t) in the form of an ester, for example, a phenyl ester, a xylyl ester, an indanyl ester, a phenacyl ester, an acetoxymethyl ester or a phthalidyl ester, and their pharmaceutically acceptable base salts; the compound of formula II W in which in which QOB ¹ and COB ² , as defined above, are acylated by treatment with an acylating agent of formula X is a halogen atom or a (C 1 -C 3) alkanoyloxy group in the alkyl moiety; and RCOX R is as defined above, and the compound of formula I obtained is optionally converted by treatment with a base into its pharmaceutically acceptable salt. MVMOgritta, n., Ilvod 7, Mott