CS271730B1 - Cephalosporin derivatives and method of their preparation - Google Patents

Abstract

The solution concerns cephalosporin derivates of a general formula I, where R1 represents the group 2-aminothiazole-4-yl, 2 furyl, 5-nitro-2-furyl, 5-phenyl-2-furyl, 5-(2-chlorophenyl)-2-furyl, 5-(4-chlorophenyl)-2-furyl, 5-(2,6-dichlorphenyl-2-furyl, Y stands for -CH2- group or the group of the general formula II. R2 means hydrogen, acetoxy group or the group of the general formula III, where A is the atom of sulphur, atom of nitrogen substituted by the methyl group or -CH2-CO2R group, where R is hydrogen, ethyl or tertiary butyl and B is the atom of nitrogen or carbo substituted by the R' group, where R' is hydrogen atom, linear or ramified alkyl C1 to C4, cyclohexyl, 2-tienyl, 2-furyl, phenyl, phenyl substituted in the positions ortho, meta, para by the hydroxy group, -C02R group, where R means hydrogen atom or linear or ramified alkyl C1 to C4, -CH2-CO2R<IV> group, where R<IV> means the hydrogen atom or linear or ramified alkyl C1 to C4 and their non-toxic salts. Compounds I are prepared by acylation of derivates of 7-amino-cephalosporan acid.<IMAGE>

Description

The present invention relates to 7- (2-furylacetamido) or 7- (2-aminothiazoles) acetamidocephalosporane derivatives. Cephalosporin derivatives substituted with heterocyclic acetic acids at the 7-Д- »position, respectively. by heterocyclic thiols at the 3-cephem position are conventionally divided into three generations .alpha.-Callaghan, C., J. Antimicrob. Chemother. 5, 635 (1979)]. Derivatives with a 5-substituted-2-furyl acetate moiety are described in U.S. Patent 321,818, wherein methyl or halogen or carboxamido-Tinti, A. et al., J. Antibiotics 33, 1177 (1960) are mentioned as substituents.

The substitution of the 3-acetoxy group of 7-aminocephalosporanoic acid or its 7-acyl derivatives with sulfur nucleophiles is well known to those skilled in the art. in E. Flynn: Cephalosporins and Penicillins, Academic Press, New York. 1972. For example, 2-aminothiazol-4-yl- (Z) -methoxyimino cephalosporin derivatives disclose it. Blumbach (Blumbach et al., J. Antibiotics 40, 1, 29 (1987). Starting mercapto-triazoles can be prepared as disclosed in U.S. Patent 234,892).

2-Aminothiazol-4-ylacetamidocephalosporins form a large group of broad-spectrum antibiotics, including e.g. cefotaxime, cefotiam, ceftriaxone (Drickheimer, W., Symp., Trent. Pharmacol. 1, 3 (1982)).

The invention relates to cephalosporin derivatives of the formula I

CO ₂ H wherein R 1 is 2-aminothiazol-4-yl, 2-furyl, 5-nitro-2-furyl, 5-phenyl-2-furyl, 5- (2-Chlorophenyl) -2-furyl, 5- (4-chloro-phenyl-2-furyl, 5- (2,5-di-chlorophenyl) -2-furyl) represents a group -CH ₂ - or a group of formula II

I

N-OCH ₃

_R2 is hydrogen, acetoxy or a group of the formula III wherein A is a sulfur atom, a nitrogen atom substituted by a methyl or CH ₂ CO ₂ R _t wherein R is hydrogen, ethyl or tertiary butyl а В is N or a carbon atom substituted by R 'and R * is a hydrogen atom, straight or branched alkyl C 1 -C 4, cyclohexyl, 2-thienyl, 2-furyl, phenyl, phenyl substituted in the ortho, meta, para position by hydroxy-, the group -COgR, wherein R represents a hydrogen atom or a straight or branched alkyl of C 1 to C 6, a group wherein R ¹ represents a hydrogen atom or a straight or branched alkyl of C 1 to C 1, and pharmaceutically acceptable salts thereof; That is, 0.8 to 1.2 moles of the compound of formula IV

C0 ₂ M

CS 271 730 B1 is reacted at 0 to 80 ° C for 0.5 to 8 h with 0.8 to 1.2 mol of the reactive derivative derived from a group of formula III and _R2 and ^e acetoxy, and moreover, the substituents are as defined above above, or a reactive derivative V, wherein Y, R, and R ₂ represents that of the above formula I.

The compounds of formula I exhibit antimicrobial activity, therefore, the compounds and their physiologically acceptable salts can be used as medicaments for bacterial infections.

The compounds of the formula I according to the invention are prepared by acylation of 7-aminocephalosporanoic acid derivatives of the formula IV,

/ IV, wherein R ₂ stands for that of the above formula I and M is an alkali metal, an ammonium cation or a cation of the type R RGR ^ N, wherein R ^ R ^ R ^ is hydrogen, alkyl of C to C, or cycloalkyl of C C 1 to C 8 or readily hydrolyzable groups such as silyl esters with a reactive derivative such as the acid chloride or anhydride of formula V,

R _T -Y-CO ₂ H / V, wherein Y and R 6 are as in formula I above, in the presence of a basic agent at a temperature of -30 ° C to 50 ° C. However, in a compound of formula I, wherein Y and R indicate that the above formula I, and R ₂ represents an acetoxy group, acetoxy replaced by a nucleophilic group of the alkali or ammonium salts, e.g. 1-methyl-1,2,3,4-tetrazole-5-thole, 5-methyl-1,3,4-thiadiazole-2-thiol, i.e., thiols derived from formula III, in an aqueous or aqueous organic medium at pH from 5.0 to 9.5 at 50 ° C to 100 ° C. The compounds of the present invention with the meaning of Y is a group of formula (II) include, in the formula, the syn-isomers of a. anti-isomers of the methoxyimino group, as well as a mixture of these isomers.

The processes for the preparation of the compounds according to the invention are carried out by adding to 1 molar part of the salt of 7-aminocephalosporanoic acid or a derivative thereof, e.g. sodium, potassium, ammonium, triethylammonium salts prepared from 7-aminocephalosporanoic acid or a derivative thereof and a suitable base, e.g. sodium bicarbonate or triethylamine, but to its silyl ester prepared by conventional methods by reaction of 7-aminocephalosporanoic acid or a derivative thereof and halosilanes, e.g. trimethylchlorosilane or silazans, e.g. hexamethyldisilazane, 0.8 to 1.3 mol. of a reactive derivative of a substituted acetic acid of the formula IV.

An acid halide, in particular chloride or bromide, acid anhydride or mixed anhydride, acid azide or reactive acid ester can be used as the reactive derivative.

The term mixed acid anhydride may be used to denote e.g. mixed anhydride with substituted acetic acid or alkylcarbonic acid. The term reactive ester is designated e.g. cynomethyl ester, p-nitrophenyl ester, N-hydroxysuccinimide ester, hydroxybenzotriazole ester.

When working with acyl halides, it is preferable to use basic agents such as e.g. alkali metal carbonates or tertiary organic bases, in particular an excess of the base forms a cation of the salt of the 7-aminocephalosporanoic acid derivatives.

The acylation reaction may be carried out in an anhydrous or aqueous medium. How anhydrous

Suitable halogenated hydrocarbons such as dichloromethane or acid esters such as ethyl acetate are suitable.

A mixture of water and an organic solvent, such as e.g. acetone, acetonitrile, tetrahydrofuran. The mixing of the reaction components takes place at a temperature of -30 ° C to 60 ° C, preferably -10 ° C to 20 ° C. It takes 1 to 5 hours to react.

Upon completion of the reaction, the compounds of formula I are isolated by distilling off the organic solvent and, after acidifying the aqueous layer to a pH of 1.0 to 2.5, isolating the compound of formula I by filtration or extraction followed by distillation of the extractant.

The compound of formula I can also be isolated by distilling off the organic solvent after the acylation in an anhydrous medium and dissolving the distillation residue by adding an aqueous solution of an alkali metal salt. Suitable salts include carbonates, bicarbonates, hydroxides or salts of weak organic acids such as acetic acid. From such an aqueous solution, the compound of formula I can be obtained e.g. by acidification or lyophilization, preferably after prior purification of the aqueous solution of the salt of compound I on non-ionic resins such as e.g. XAD-2. An alternative process for obtaining derivatives of the formula I, which consists in substituting the acetoxy group acylated with 7-AGK, is usually carried out in an aqueous medium at a pH which can be neutrally acidic or ground alkaline, namely in the range of pH 5.0 to 9.5. Preferably, the pH of the reaction mixture is initially 6.5 to 9.0. the desired pH is adjusted by adding a buffering agent such as e.g. potassium tertiary phosphate or used to react the salts of the respective thiols, such as sodium, potassium, ammonium. The reaction is carried out by heating the reaction mixture to a temperature of 50 ° C to 100 ° C, preferably about 70 ° C. The reaction is complete in about 2 to 8 hours. The isolation is carried out by conventional methods such as extraction or filtration of the acidified reaction mixture. For the preparation of pharmacologically acceptable salts, known methods are used, e.g. reaction of the free acid with a mineral base or reaction with salts of weak organic acids. The reaction is carried out in polar solvents, such as e.g. water, ethanol or mixtures thereof ach.

A suitable pharmacologically acceptable salt of a compound of formula I of the invention is a conventional non-toxic salt, and a metal salt such as e.g. an alkali metal salt such as sodium, potassium or ammonium salt or substituted ammonium salt, trimethylammonium, dicyclohexylammonium.

The antibiotic of the invention can be administered in a conventional manner analogous to other beta-lactam compounds, as parental or in a suitable vehicle as suspensions or solutions in a suitable form for absorption by the gastrointestinal tract. The details of the various preparation methods are given in the following examples of conversion without being limited to these.

Example 1

7- (2-furylacetamido) -3- (5-methyl-1,2,4-triazol-4H-4-ylcarbethoxymethyl) thiomethyl-3-cephem-4-carboxylic acid

To a solution of 2.6 g (1 mmol) of 2-furylacetic acid in 20 ml of a mixture of dimethylacetamide and dichloromethane was added 4.14 g (1 mmol) of phosphorus pentachloride. After stirring for 20 minutes, a solution prepared from 7.1 g (1 mmol) of 7-amino-3- (5-methyl-1,2,4-triazol-4H-4-ylcarbethoxymethyl) thiomethyl-3- was added. of cephem-4-carboxylic acid and 15.7 g (6 mmol) of N, O-bis-trimethylsilylacetamide in 250 ml of dichloromethane. The reaction mixture was stirred at room temperature for 0.5 h. Dichloromethane was distilled off under reduced pressure, saturated sodium bicarbonate solution (200 ml) was added to the residue, and the reaction mixture was extracted with ethyl CS 271 730 B1 with acetate. The aqueous layer was acidified with 15% (w / w) hydrochloric acid. The precipitated product was filtered off and dried over phosphorus pentoxide. There were obtained 6.8 g of 7- (2-furylacetamido) -3- (5-methyl-1,2,4-triazol-4-yl-carethoxymethyl) -thiomethyl-3-cepham-4-carboxylic acid, m.p. Mp 135-138 ° C.

IR = 1775 cm ^-1 (beta-lactam).

Examples 2 to 12

Analogously to the procedure of Example 1, the following derivatives of formula A * were obtained; and are listed in Table 1

⁰⁰ 2 ^H CHg-COgB

Table no. 1

Example У R ' R ^z * MP: (° C) 2 -CH ₂ - 2-Fu H 135 to 138 3 -CH ₂ - 4-OH-Ph H 126 to 130 4 -CH ₂ - co ₂ h H 140 to 144 '5 -CH ₂ - ch ₂ every ₂ h H 132 to 135 6 -CH ₂ - ch ₃ . ^C 2 ^H 5 155 to 159 7 C (N = _OCH3) 4-0HPh H 142 to 148 8 C (N = _OCH3) ch ₃ H 132 to 135 9 C (N = _OCH3) ch ₂ every ₂ h H 155 to 158 10 C (N = _OCH3) co ₂ h H 148 to 152 11 -ch ₂ - cyclohexyl ^C 2 ^H 5 129 to 135 12 -CH ₂ - CH ₂ -CO ₂ tBu Bu 115 to 118

Examples 13 to 26

In analogy to the procedure of Example 1, with the use of various substituted 7-amino-3- (heteroarylthiomethyl or acetoxymethyl) -3-alpha-carboxylic acid, the following derivatives are obtained and are listed in Table 1. Second

CS 271 730 B1

Table no. 2

Example ^E 3 r ₂ MP: . (° c) 13 ph OAc 151 until 153 14 ph H 80 until 83 15 X.H1 wz 176 until 179 16 ph ММТБ 109 until 112 17 2-ClPh OAc 95 until 98 18 4-ClPh OAc 120 until 123 19 4-ClPh H 120 until 123 20 4-ClPh . MMTZ 120 until 123 21 4-ClPh MMTH 102 until 105 22 2,6-Cl ₂ -Ph OAc 126 until 130 23 2,6-Cl ₂ Ph H 118 until 122 24 2,6-Gl ₂ Ph MMTD 109 until 111 25 no ₂ OAc 144 until 147 26 no ₂ H 165 until 168 for R ₂ used shortcuts

OAc = -OCOCH ₃

Example 27

7- [2- (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetamide] -3- [5- (4-hydroxyphenyl) -1,2,4-triazol-4H-4-yl- carbetoxymethyl] -thiomethyl-3-cephem-4-carboxylic acid

2.8 g of ethyl 5- (4-hydroxy-phenyl) -3-mercapto-1,2,4-triazol-4-yloctane and 4.5 g of cefotaxime were dissolved in 50 ml of deionized water and stirred at 65 ° C for 3.5 hours. The reaction mixture was cooled and the pH was adjusted to 2.5. The precipitate was filtered off and crystallized from dimethylformamide-ethanol (1:10). 5.1 g of 7- 2- (2-aminotriazol-4-yl) - (Z) -methoxyiminoacetamido-3- [5- / 4] were obtained. -hydroxy-phenyl] -1,2,4-triazol-4H-4-ylcarbethoxymethyl] -thiomethyl-3-cephem-4-carboxylic acid with m.p. Mp 167-169 ° C.

CS 271 730 Bl

Examples 28 to 38

OONH

In analogy to the procedure of Example 20, the following derivatives of the formula V * were obtained and are shown in Table 2. Third

TabuTka č. 3

Example R ' R MP: (° C) 28 ch ₃ H 171 to 175 29 tBu ~ c ₂ h ₅ 129 to 133 30 H c ₂ h ₅ 111 to 118 31 -CH ₂ CO ₂ C ₂ H ₅ H 149 to 152 32 -CH ₂ -CO ₂ H H 181 to 183 33 -CH ₂ CO ₂ C ₂ H ₅ ^C 2 ^H 5 172 to 180 34 -co ₂ c ₂ h ₅ ^C 2 ^H 5 168 to 172 35 2-furyl c ₂ h ₅ 179 to 182 36 -co ₂ c ₂ h ₅ H 169 to 173 37 4-OH-Ph H 180 to 184 38 4-OH-Ph H 172 to 176

In the examples of conversion, the products obtained were tested in vitro against Gram-positive and Gram-negative bacterial strains. The results compared to cefazoline and cefotaxime are shown in Table 2. 4 ·

Table no. 4

Example Minimum growth inhibition amount, µg / ml E.coli E.C. 67/59 S. lutea IRM sar S. pyogenes IM A1 / 49 S. aureus IM 78/71 13 0.06 0.06 0.25 0.03 22 0.03 0.12 0.06 0.03 15 0.03 0.12 0.50 0.06 5 0.12 0.50 0.25 0.03 6 0.12 0.50 0.25 0.06 27 0.03 0,001 0,001 0.03 34 0.03 0,001 0.06 0.01 36 0.12 0.12 0.12 0.06 37 0.25 0.12 0.12 0.12 35 0.03 0.12 0.25 0.50 23 0.03 0.03 0.03 0.06 13 0.06 0.06 0.25 0.03 16 0.03 0.12 0.03 0.50

CS 271 730 B1

Table no. 4

Example Smallest amount to prevent growth / Ug / ml E.coli E.C. 67/59 S. lutea IEM sar. 5/58 S. pyogenes IEM Al / 49 S. aureus IEM 78/71 19 0.25 0.06 0.06 0.03 20 0.03 0,125 0.06 0.03 21 0.06 0,125 0.06 0.03 22 0.03 0,125 0.25 0.03 24 0.03 0,125 0.06 0.03 4 0.25 0.50 0.25 29 0.06 0,125 0.06 0.06 cefazolin 1.00 0.50 0.50 0.50 cefotaxime 0,125 0,125 0,125 0,125

MC were determined by dilution method in liquid medium (Mueller-Hinton broth) with addition of methylene red *

Claims (3)

OF THE INVENTION Cephalosporin derivatives of the general formula I (I) wherein R 1 represents 2-aminothiazol-4-yl, 2-furyl, 5-nitro-2-furyl, 5-phenyl-2-furyl, 5- (2-chlorophenyl) -2-furyl, 5- (4-chlorophenyl) -2-furyl, 5- (2,6-dichlorophenyl) -2-furyl, Y is -CH ₂ - ^{or a} group of formula II, - C o N - OCH ₃ wherein R 1 represents hydrogen, an acetoxy group or a group of formula III, K — N where A is a sulfur atom, a nitrogen atom substituted by a methyl group or -CH2-CO2R ^{Z /} , where R ^z * is hydrogen, ethyl or tertiary butyl and V is a nitrogen atom or a carbon atom substituted by R ', where R * is a hydrogen atom, straight or branched alkyl to C 1-4, cyclohexyl, 2-thienyl, 2-furyl, phenyl, phenyl substituted in ortho, meta, para hydroxy, a -CO ₂ R group, wherein R represents a hydrogen atom or straight or branched alkyl CS 271 730 B1 And the pharmaceutically acceptable salts thereof. 2. A process for the preparation of cephalosporin derivatives of the formula I according to claim 1, characterized in that from 0.6 to 1.2 molar parts of the compound of the formula TV S as ₂ m wherein M is an alkali metal, ammonium or a cation _R-ft h ^ ^N-R _0, wherein R _a, R _b, R _Q is independently hydrogen, alkyl, and 0 to ^ Og, or cycloalkyl, and 0? to C 8, or represents readily hydrolyzable groups such as a silyl ester group and R 8 is as defined above, reacts with 0.8 to 1.2 molar parts of a reactive derivative of a compound of formula V, even ₂ h where R 6 and Y are as defined above, at -30 ° C to 60 ° C for 0.5 to 5 hours. 3. A process for preparing cephalosporin derivatives of the formula I to be cut down to claim 1, characterized in that 0.8 to 1.2 mole parts of a compound of formula I with R ₂ meaning as acetoxy group, is treated with 0.8 to 1.2 molar parts of a compound of formula IIIa! SH where A and V are as defined above, at 0 to 80 ° C, for 0.5 to 8 iodine.