CS240387B1

CS240387B1 - Cephaelosporine derivatives

Info

Publication number: CS240387B1
Application number: CS846771A
Authority: CS
Inventors: Miroslav Veverka; Marta Muckova
Original assignee: Miroslav Veverka; Marta Muckova
Priority date: 1984-09-07
Filing date: 1984-09-07
Publication date: 1986-02-13
Also published as: CS677184A1

Description

SOCIALIST REPUBLIC OF CZECHOSLOVAKIA (19) DESCRIPTION FIXED TO COPYRIGHT βΠΒ & Ν 240387 (11) (Bl) Ø (22) Enrolled 07 09 84 (21) (PV 6771-84) (40) 13 08 85 (51) Int, Cl .4 C 07 D 501/36 C 07 D 501/28 C 07 D 501/34 // A 61 K 31/545 OFFICE AND DISCOVERY OFFICE (45) Published 15 08 87 (75)

Author of the Invention VEVERKA MIROSLAV ing., BRATISLAVA; MUCKOVA MARTA ing., MODRA (54) Cephalosporin derivatives

The invention relates to novel cephalosporin derivatives of the general formula I

wherein X is sulfur or oxygen, Y is methylene or methoxyimino, R 1 is hydrogen or bromo, nitro, phenyl, ortho-chlorophenyl, para-chlorophenyl, 2,6-dichlorophenyl, R 2 is hydrogen, acetoxy-5 -methyl-1,3,4-thiadiazol-2-yl-thio-, 1-methyl-1H-tetrazol-5-yl-thio, or a group of the general formula II

wherein R 3 is phenyl, para-chlorophenyl, ortho-chlorophenyl, 2,6-dichlorophenyl, and pharmaceutically acceptable salts thereof, as well as the preparation thereof,

The compounds of formula (I) exhibit antimicrobial activity, therefore, these compounds and their physiologically innocuous substances are used as drugs for bacterial infections.

The compounds of formula I are prepared according to the invention by acylation of 7-aminocephalosporanic acid derivatives of the formula III 240387 240387

wherein R 2 is as in the above formula Ia M is an alkali metal cation, an ammonium cation or a R 1 R 2 R + N + cation wherein R 1 R 2 R 3 is hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl or 1 easy hydrolysable groups such as silyl esters, with a reactive derivative such as the chloride or anhydride of the formula IV

(IV) wherein X, Y and R 1 are as in formula I above, in the presence of a basic agent at a temperature of -30 ° C to 50 ° C. Alternatively, in a compound of formula I wherein X, Y and R 1 are as defined above in formula I and R 2, acetoxy is replaced by 1-methyl-1,2,3,4 by the action of alkali or ammonium salts. -tetrazole-5-thiol, 5-methyl-1,3,4-thiadiazole-2-thiol or thiols of formula II wherein R 3 is, as in formula I above, in an aqueous or aqueous organic medium at a pH of 5.0 to 9.5 priteplote 50 ° C to 100 ° C.

The compounds of the present invention include the syn isomers and the anti-isomers of methoxyimino as well as a mixture of these isomers in the general formula.

The processes for the preparation of the compounds of the invention are carried out by bringing them to 1 mol. of diisodium, potassium, ammonium, triethylammonium and the like. 7-aminocephalosporanic acid salts (prepared from 7-aminocephalosporanic acid and a suitable base, for example sodium bicarbonate, triethylamine and the like) or its silyl esters prepared by conventional methods by reacting 7-amino-cephalosporanic acid and halosilanes, for example trimethylchlorosilane or silazanes, for example hexamethyldisilazane 0.8 to 1.3 mol. of a reactive derivative of substituted acetic acid of Formula IV.

As the reactive derivative, the acid halide or chloride, the acid anhydride or the mixed anhydride, the acid azide or the reactive ester of the acid may be used as described, for example, by E. Flynn (ed) Cephalosporins and penicillins AcademiePress. N. York, 1972. The mixed acid anhydride may be, for example, a mixed anhydride substituted with acetic acid or an alkyl carbonate. By reactive ester is meant, for example, cyanomethyl ester, p-nitrophenyl ester, N-hydroxysuccinimidoester, hydroxybenzotriazole ester. When working with an acyl halide, it is preferable to use basic agents and, for example, alkali metal carbonates or tertiary organic bases, and it is particularly preferred to use an excess of base forming the salt of 7-aminocephaloate acid derivatives.

The acylation reaction may be carried out with anhydrous or aqueous media. Halogenated hydrocarbons such as dichloromethane or acid esters such as ethyl acetate are suitable as the inert medium. The reaction mixture may be a mixture of water with an organic solvent such as acetone, acetonitrile, tetrahydrofuran. The mixing of the reaction components takes place at a temperature of -30 ° C to 60 ° C, preferably -10 ° C to 25 ° C. It takes 1 to 5 hours to react.

After completion of the reaction, the compounds of formula (I) are isolated by distilling off the organic solvent and subsequently acidifying the aqueous layer to a pH of 1.0-2.5, isolating the compound of formula (I) by filtration or extraction followed by distillation. extraction agent.

The compound of formula (I) may also be isolated by distilling off the organic solvent after acylation in an anhydrous medium and dissolving the residue by addition of carbonates such as carbonates, hydrogen carbonates, hydroxides or solisol acids such as acetic acid from the aqueous solution, e.g. or by lyophilization, preferably after prior purification of the aqueous solution of Compound I salt and non-ionic resins such as XAD-2. The alternative procedure for obtaining derivatives of the formula I, which consists of the substitution of the ethoxy group, is generally known, for example, as described by E. Flynn (ed) in. Ce-phalosporins and penicillis. Academic Press N. York 1972. The replacement of the acetoxy group is usually carried out in an aqueous pH-setting which can be neutral, slightly acidic or slightly basic, namely in the pH range of 5.0 to 9.5. Preferably, the pH of the reaction mixture is initially about 6.5 to about 9.0. Although the pH is adjusted by the addition of a buffering medium such as phosphorous potassium tertiary. Alternatively, salts of the corresponding thiols, such as potassium or ammonium, are used to react. The reaction is carried out by heating the reaction mixture to a temperature of about 50 ° C to about 100 ° C, preferably 70 ° C. The reaction is carried out in about 2 to 8 hours. The isolation is carried out by conventional methods such as extraction or filtration of the acidic reaction mixture. For the preparation of pharmacologically acceptable methods, methods are used as well. for example, MS. Patent 154 6'46. It can be carried out, for example, by reacting the free acid with a minor base or by reacting it with weak organic acids. The reaction is carried out in solvents such as water, ethanol or mixtures thereof.

A suitable pharmaceutically acceptable salt of formula (I) prepared by the process of the invention is a conventional non-toxic salt, wherein a metal salt such as an alkali metal salt such as sodium, potassium, ammonium salt is included in the group of such compounds or a substituted ammonium salt of triethylammonium, dicyclohexyl-ammonium.

Antibiotics of the invention may be administered by conventional means analogous to other beta-lactam compounds, either parenterally or in a suitable vehicle such as suspensions or solutions in a suitable form for absorption by the gastrointestinal tract.

The details of the individual methods are set forth in the following examples without being limited thereto. Example 1 7-beta-k2- (5-trifluoro-2-furyl) thiazole [3,2-b] -s-triazol-5-yl) acetamidoj-3-acetoxymethyl-3-cephem-4-carboxylic acid 0.29 g of 2- (5-nitro-2-furyl) thiazolo [3,2-b] triazol-5-yl acetic acid and 0.29 g of phosphorus pentachloride are mixed in 15 ml of dichloromethane and 0.9 ml of Μ, β-dimethyiacetamide for 20 minutes. To the resulting solution was added 0.3 g of 7-aminocalphosporanate and 0.29 ml of triethylamine in 15 ml of dichloromethane at 0 DEG C. for 3 hours. Dichloromethane: Vacuum Partitioning and Saturated Sodium bicarbonate solution are added to the reaction. The resulting solution is extracted with 2 x 10 mL of ethyl acetate. The resulting layer is subsequently acidified to pH 2.2 and extracted with 3 x 10 mL of acetic acetate. The combined organic extracts are washed with water, dried and concentrated to a 1/5 volume of the original volume in vacuo. The syrup solution is added to 60 ml of diethyl ether with stirring, the precipitated product is filtered off and dried in a desiccator over P2O5 to give 0.31 g of product, mp 189-140 ° C (decomposition). No spectrum (KBr = max = 1786 cm -1 (beta-lactam. Example 2 7-beta-j (2- (5-phenyl-2-furyl) thiazolo [3,2-b] - s) -triazol-5-yl) acetamido} -3 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl-3-acetic acid 4-carboxylic acid 6 R solution G / 31 g of 2- (5-phenyl-2-fluoro) thiazolo [3,2-b] thiazol-5-yl acetic acid in 5 ml of dichloromethane and 3 ml of N, N-dimethyl acetamide are added 0.29. g of phosphorus trichloride, Real mixture was stirred for 20 min at t, ° C and cooled to -30 ° C with add a solution of 7-amino-3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-ene-4-carboxylic acid and 1.1 ml of N, O-bis- dimethylsilylacetamide in 20 ml of dichloromethane. The reaction temperature is maintained at CC5 ° C for 3 hours.

Dichloromethane is distilled off under vacuum and 25 ml of saturated bicarbonate solution are added to the reaction mixture. sodium. The solution is extracted with 2 x 10 ml of ethyl acetate and the aqueous layer is subsequently acidified with the addition of hydrochloric acid to a pH of 2.2. The precipitated material is filtered off and dried over P2O5 in a desiccator. 0.35 g of product is obtained. Mp 139-142 ° C (dec.). I.I spectrum (KBr) .nu.max = 1783 cm @ -1 (.beta.-lactam). Example 3 7-beta- {2- (2-tert-butyl-thiazolo (3,2-b) -s-triol-5-yl) -2- (Z) -methoxyimino-acetamide-3- 0.25 g of 2- [2-furyltiazolo [3,2-b] -s-triazol-5-yl) -2- (2) -methoxyiminoacetic acid and 0.29 g g of phosphorus pentachloride are stirred at a temperature of C ° C and 0.92 ml of N, N-dimethylacetamide in 15 ml of dichloromethane for 1 hour. The solution is cooled to 1010 ° C and 0.3 g of 7-aminocephalosporane and 0.31 are added. ml of triethylamine in 10 ml of dichloromethane and the reaction mixture was stirred at room temperature for 3 hours. The dichloromethane was distilled off under vacuum and 20 ml of saturated sodium bicarbonate solution was added to the reaction solution. The resulting solution is extracted with 2 x 10 mL of ethyl acetate. The aqueous layer is layered with 20 ml of ethyl acetate and acidified with 10% phosphoric acid to pH 2.2. The extract is vacuum concentrated to 1/5 of the original volume and 30 ml of diethyl ether is added. The precipitate is filtered off and dried in a desiccator over P2O5. 0.33 g of product is obtained. Mp 146-148 ° C (solution). IC spectrum (KBr) pmax = 1790cm-1 (beta-lactam). Example 4 7-beta - {(2- (5-bromo-2-furyl) thiazolo [3,2-b] -s-triazol-5-yl) acetamido} -3-acetoxy-methyl-3-cephem -4-carboxylic acid To a solution of 0.33 g of 2- (5-bromo-2-fluoro) thiazolo [3,2-b] -s-triazol-5-yl acetic acid and 0.15 ml of triethylamine in 20 ml of tetrahydrofuran, a solution of 240387 0.12 ml of pivaloyl chloride in 5 ml of tetrahydrofuran is added at -5 ° C. The reaction mixture is stirred at -5 ° C for 0.5 hours and after filtration is added to a mixture of 0.3 g of 7-aminocephalo-sporate and 0.1 g of sodium bicarbonate in 10 ml of tetrahydrofuran. The solution is stirred for a further 3 hours at 0 ° C and 20 minutes at room temperature. The tetrahydrofuran is distilled off under vacuum and the aqueous solution is extracted with 2 x 10 ml of ethyl acetate. The aqueous layer was acidified to pH2.2 with hydrochloric acid and extracted with 2 x 10 mL of ethyl acetate. The extracts were washed with water and concentrated in vacuo. Crystallization. 0.4 g of product is obtained from the isopropanol-ether mixture. Mp 162-165 ° C (dec.). IC spectrum (KBr), max = 1785 cm -1 (beta-lactam). Example 5 7-beta- «2- (5-bromo-2-furyl) -thiazolo [3,2- b] -s-triazol-5-yl-acetamidoj-3- [(1-methyl-1H- tetrazol-5-yl) thio] methyl 3-chloro-4-carboxylic acid 200 mg of the product of Example 4 was heated with 70 mg of sodium bicarbonate and 40 mg of 1-methyl-1H. -tetrazole-5-thiol for 3 hours at 65 ° C in 5 ml of water. After cooling to 5 ° C, the reaction mixture was acidified to pH 2.0 and stirred for 15 minutes. The precipitated product is filtered off and washed with water. 0.15 g of product is obtained. mp 136-139 ° C (dec.). IC spectrum (KBr) max = 1789 cm -1 (beta-lactam). Example 6 7-beta- [2- (5- (2,6-dichlorophenyl) -2-furyl) -thiazolo [3,2 -b] -s-triazol-5-yl) acetamido {3 - {[5- (5-phenyl-2-furyl) -4-amino-s-triazol-3-yl] thiomethyl} -3-Cephem-4-carboxylic acid A solution of 0.5 g of 7-amino-3- [5- (5-phenyl-2-furyl) -4-amino-s] was added to the chloride solution prepared analogously to Example 2. - triazol-3-yl-thio] methyl-3-cephem-4-carboxylic acid and 1.1 ml of N, O-bis-trimethylsilyl acetamide in 20 ml of dichloromethane. 10 [deg.] C. for 3 hours and treated as in Example 2. 0.4 g of product is obtained T.I.151-153CC (decomposition) I.I spectrum (KBr) max = 1775 cm < -1 > Example 7 7-beta- {(2-2-fluorothiazolo [3,2-b] -s-triazol-5-yl) acetamidoj-3- [5- (5-phenyl-2- furyl) - 4-amino-s-triazol-3-yl] thiomethyl-3-cephem-4-carboxylic acid -5-acetacetamide] -3- ((5- (5-phenyl-2- f uryl Ι- 49, 49 g 7-beta - ((2-2-furyltiazolo [3,2-b] -s - t of the riazol-5-ylacetamido-cephalosporane acid obtained analogously to Example 1 was heated with 0.29 g of 5- (5-phenyl-2-furyl) -4-amino-3-mercapto-s-triazole in 10 ml pH 6.8 phosphate-buffered buffer at 55 eC for 2 hours. The reaction mixture is filtered through a pad of alumina and acidified with cooling to pH 2.2. The precipitate is filtered off and dried over P2O5 in a desiccator. 0.32 g of product T is obtained. mp 181-184 ° C (dec.). I. spectrum No (KBr) vmax = 1778 cm -1 "(beta-lactam). Example 8

7-beta- (2- (2-2-furylthiazolo [3,2-b] s-triazol-5-yl) -2- (Z) -methoxyiminoacetamidoj-3-acetoxymethyl acid sodium salt -3-Cephem-4-carboxylic acid 0.25 g of the compound of Example 3 was dissolved in 5 ml of methanol and the resulting solution was adjusted to pH 7 with a methanolic solution of 2-ethylhexanoate. Add 20 ml of diethyl ether and discard after 15 minutes The precipitate was filtered off and chromatographed on Amberlite XAD-2. Elution with water followed by lyophilization yielded 0.11 g of product T. mp 220 ° C No spectrum (KBr) m / l = 1790 cm -1 (beta-lactam) Examples 9 to 25

The following cephalosporin derivatives were prepared analogously to Example 2 and set forth in Table 1. R-1

Y-CONH

O

9 240337 10 Example Ri R2 T abu 1 'ka no 1 X T. t. (Beta-lactam) No. (° C) »co (cm-1) 9 H OAc 0 10 HH 0 11 H MMTZ 0 12 H MMTD 0 13 H OAc S 14 HHS 15 H MMTZ S 16 H MMTD S 17 Ph OAc 0 18 Ph MMTZ 0 19 2-Cl — Ph OAc 0 20 4-Cl — Ph OAc, 0 21 4-Cl-Ph H 0 22 4-C1 — Ph MMTZ 0 23 2,6-Cl — Ph OAc 0 24 2,6-Cl — Ph MMTZ 0 Abbreviations are used for Rz where: OAc = —O — COCH3 152—153 1788 162—164 1775 106—109 1782 121—124 1779 141—144 1786 163—166 1775 155—158 1775 171—174 1774 169—171 1782 176-179 1780 132—134 1779 162—164 1783 158—160 1780 167—170 1792 138— 140 1788 172-175 1775 In the exemplary embodiments obtained in vitro tested against gram positive and gram negative bacterial strains, the results compared to cefazoline sodium salt are shown in Table 2.

MMTD -s ch3

MMTZ

Table 2 Example Minimum Growth Prevention Amount (µg / ml) E.coli IEM S.lutea IEM S.pyogenes S.aureus IEM P. pneumoniaeEck 67/59 Sar 5/58 IEM A1 / 49 Mau 78/71 CCM 1848 1 0.25 0.25 0.5 0.125 0.125 2 0.125 0.125 0.125 0.125 0.125 23 0.125 0.125. 0.125 0.125 0.125 24 0.25 0.125 0.125 0.125 32 15 0.125 0.125 0.125 0.125 0.125 16 0.125, 0.125 0.25 0.125 0.125 6 0.125 0.125 0.125 0.125 - Cefazoline-Na 1.0 0.5 128 0.5 - i in> MIC were determined by the dilution method in liquid medium (Mueller-Hinton broth) with addition of methylene red. i 1

Claims

11 24036? The subject of the invention is the Cefalosporin derivatives of the general formula

Y-CONH

Wherein X is sulfur or oxygen, Y is methylene or methoxyimino, R 1 is hydrogen or bromine, nitro, ortho-chlorophenyl, para-chlorophenyl, 2,6-dichlorophenyl, phenyl , and R 2 represents a hydrogen atom, an acetoxy-, 5-methyl-1,3,4-thiadiazol-2-yl-thio, 1-methyl-1H-tetrazol-5-ylthio group, or a general group of formula II wherein R 3 is phenyl, para-chlorophenoyl, ortho-chlorophenyl and 2,6-dichlorophenyl and non-toxic salts thereof.