KR830000344B1 - Preparation of Cephalosporin Derivatives - Google Patents

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Description

Preparation of Cephalosporin Derivatives

The present invention relates to the preparation of cephalosporin derivatives having a broad antimicrobial spectrum and active against many strains of gram positive and gram negative bacteria. The present invention relates to a method for producing cephalosporin derivatives represented by the following general formula (I) and salts thereof.

Where

Y represents a hydrogen atom or a protecting group,

R ₁ represents a hydrogen atom or a lower alkyl group,

R ₂ represents a hydrogen atom or a hydroxyl group,

R ₃ represents a two or three hydroxyl group or a lower alkanoyloxy group present to at least two adjacent, substitution of R ₃ above, and R ₁ is a lower alkyl group, and the 3-5 position when the R ₃ is a hydroxyl group In other cases, it is selected in 2 ~ 6 positions.

R <_4> represents a hydrogen atom or a methoxy group, R <_6> represents the 5-membered heterocycle which contains 1 or 2 or more nitrogen atoms, and optionally 1 sulfur atom, and may be substituted by the lower alkyl group.

Cephalosporin derivatives having a benzoylureido group in the α-position of the 7-acylamide side chain have already been reported.

For example, US Pat. Ho. However, as a substituent of these corresponding benzoyl groups, neither of a hydroxyl group nor a lower alkanoyl group is mentioned.

U.S. Pat.

Furthermore, all of these prior documents only list “lower alkanoyloxy groups” along with several other substituents, as for 2 to 3 lower alkanoyloxy groups and at least two adjacent ones. There is no mention, and there is no mention of specific compounds.

That is, the cephalosporin derivative of the present invention represented by the general formula (I) is a novel compound. The compound of the present invention has a strong antibacterial activity against gram positive bacteria and gram negative bacteria. In particular, Pseudomonas genus and Ceracia genus have a remarkable effect compared to cephalosporins, cephalosidines and other cephalosporin-based antimicrobial agents widely used in the past. In addition, the substance is excellent in the body action such as absorption, excretion, distribution, metabolism after administration of the animal, and also shows excellent infection defense effect. Thus, the compounds of the present invention are useful as antibacterial agents.

Among the compounds of the present invention, in the general formula (I), R ₃ is a lower alkanoyloxy group, which is useful as an intermediate because a compound in which R ₃ is a hydroxyl group can be obtained by desorbing the lower alkanoyl group.

In general formula (I), the lower alkyl group represented by R < ₁ > group is C1-C4 linear or branched alkyl, for example, a methyl group, an alkyl group, n-propyl group, isopropyl group, n-butyl group, and iso Butyl, t-butyl, and the like, and preferably methyl and ethyl. The lower alkanoyl group in the lower alkanoyloxy group in R ₃ is a C 2-4 straight or branched alkanoyl group, for example. It is the same as an acetyl group, a propionyl group, a butyloyl group, and an isobutyloyl group, Preferably it is an acetyl group. In the case where R ₁ is a lower alkyl group and R ₃ is a hydroxyl group, when the hydroxyl group is present at the 2 or 6 position on the benzoyl ring, the ureido group becomes unstable, and in such a case, the substitution position of R ₃ is limited. . That is, when R ₁ is a lower alkyl group and R ₃ is a hydroxyl group, the substitution position of R ₃ is selected from 3 and 4 positions or 3, 4 and 5 positions. Except for the combination of R ₁ and R ₃ described above, the substitution positions of R ₃ are 2 and 3 positions, 3 and 4 positions, 2, 3 and 4 positions, 2, 4 and 5 positions, 2, 3 and 5 Position or 2, 3 and 6 positions can be selected, preferably 2 and 3 positions, 3 and 4 positions or 3, 4 and 5 positions.

The 5-membered heterocyclic ring defined in R ₆ is the same as 1,3,4-thiothiazole, triazole, tetrazole, and these may be substituted with lower alkyl groups. As a lower alkyl group, it is a C1-C3 side chain or linear alkyl group, For example, it is a methyl group, an ethyl group, n-propyl group, isopropyl group, Preferably it is a methyl group.

Examples of salts of the compounds of the present invention include inorganic bases, for example salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and salts of organic bases such as procaine and dibenzylethylenediamine salts. Can be mentioned. These salts are prepared by a conventional method, that is, by treating the above-mentioned inorganic or organic base with the free carboxyl group of the cephalosporin derivative.

Among the compounds of the present invention, DL-, D- and L-optical isomers exist because of the sub-carbon atoms in the 7-acetamide group. All of these are included in the scope of the present invention.

The present invention is characterized by reacting a 3-acetoxy methylcephalosporin derivative represented by the following general formula (II) with thiols represented by the following general formula (III) or salts thereof and converting Y into a hydrogen atom as necessary. It relates to a method for producing the cephalosporin derivative of the general formula (I).

Where

R ₁ , R ₂ , R ₃ , R ₄ and R ₆ are as described above and Y represents a hydrogen atom or a protecting group.

Thiols are generally used in the form of, for example, sodium salts, potassium salts and the like. In addition, the thiols in the form of glass may be reacted in the presence of an inorganic base such as alkali hydroxide, alkali carbonate, alkali hydrogen carbonate and organic base such as trialkylamine. The reaction is usually carried out in a solvent, and acetone, methanol, ethanol, tetrahydrofuran, etc. are frequently used as the solvent, and in some cases, may be mixed with water. The reaction is usually carried out at room temperature to warm. That is, it is 20-70 degreeC normally, Preferably it is 45-55 degreeC. The reaction time is 5 to 60 hours, preferably 15 to 30 hours.

Isolation of the desired product from the reaction mixture can be easily accomplished according to the conventional method as described above.

The preparation of the optically active substance (D- or L-isomer) which is one of the objective compounds of the present invention represented by the general formula (I) is conventional in the step of α-aminophenyl acetate or substituted ureido phenylacetic acid. Optical powder techniques, eg "amino acid chemistry" [JP Greenstein, M. Winitz, “Chemistry of the Amino Acids” Vol. 1.P715-760, John Wiley & Sons, N. Y. (1961)] can be used by using the optically active raw material compound obtained by applying the technology described in.

The target compound of the present invention can be prescribed in a form suitable for various administration methods as in the case of other cephalosporin-based compounds. Accordingly, embodiments of the present invention include various pharmaceutical compositions suitable for human or animal medicinal use. Their compositions are provided by conventional methods using the required pharmaceutical carriers or excipients.

That is, when provided as an injectable composition, it is possible to take a formulation (formulation) such as a suspension, a solution, an emulsion in an oily or aqueous carrier. Suppositories are available, and conventional suppository substrates such as cocoa butter or other glycerides may also be used.

These compositions may contain 0.1% or more, for example 5 to 99%, preferably 10 to 60% active material, depending on the method of administration. The dosage for humans is selected in the range of 100-3000 mg for adults. For example, depending on the route of administration, frequency or weight, age, symptoms, 500-2000mg daily dose is an example. The manufacturing method of the compound of this invention is demonstrated to a specific example below.

In addition, thin-layer analysis by chromatography of the product, using silica gel 60F ₂₅₄ <Merck Co. free kooh lead plate> as a carrier, and as the developing solvent, was used in the following composition.

(I) ethyl acetate-ethanol-acetic acid (25: 5: 1 volume part)

(II) ethyl acetate-ethanol-acetic acid-water (10: 4: 2: 1 volume part)

Example 1

7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3-acetoxymethyl-3- 0.57 g of cefem-4-carboxylic acid (Compound A) is suspended in 10 ml of phosphate buffer at pH 6.3, and 0.07 g of sodium hydrogen carbonate is added thereto to dissolve. Subsequently, 0.13 g of 5-methyl-2-mercapto-1,3,4-thiadiazole is added to dissolve, and the reaction is carried out at 45 to 55 ° C. for 24 hours while maintaining the pH at 6.0 to 6.5 using dihydrochloric acid and sodium hydrogencarbonate. Let's do it. The reaction solution is cooled, sufficiently washed with ethyl acetate, and the water layer is separated. The water layer is adjusted to pH about 1.0 with dilute hydrochloric acid, and the insoluble matter precipitated is collected by filtration. After washing with 50 ml of water, the insolubles are dissolved in 20 ml of acetone, treated with activated charcoal and evaporated to dryness at room temperature under reduced pressure. The residue was treated with 10 ml of ether to give 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] 3- (5-Methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound C) is obtained as an off-white amorphous solid.

TLC: Rf 0.40, Developing Solvent (II).

(㎝^-1)3700~2300, 1775, 1680, 1515.IR:

(Cm ^-1 ) 3700-2300, 1775, 1680, 1515.

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 2.69 (3H, s), 3.19 (3H, s), 3.68 (2H, brs), 4.4 (2H, br), 5.04 (1H, d, J = 5 Hz), 5.6-6.1 (2H, m), 6.9-7.7 (8H, m).

UV: (EtOH) λ _max (nm) 272.

(a) Similarly, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetami FIG. 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido from 3-cefe-4-carboxylic acid (compound B) {-α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid ( Hereinafter referred to as Compound D) as an off-white amorphous solid.

(c) Likewise in compound B, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl ) Acetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound E) is obtained as an off-white amorphous solid.

TLC: Rf 0.39, Developing Solvent (II).

(㎝-1)3700~2300, 1770, 1675, 1510IR:

(Cm-1) 3700-2300, 1770, 1675, 1510

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 3.11 (3H, s), 3.6 (2H, br), 3.95 (3H, s), 4.31 (2H, brs), 5.1 (1H, d, J = 5 μs), 5.3-5.9 (2H, m), 6.5-7.5 (7H, m).

UV: (EtOH) λ _max (nm) 265, 280 (shoulder), 290 (shoulder).

Ferric chloride color reaction, positive (dark green)

(d) Similarly, in compound A, 7- [D (-)-α- {3- (3,4-hydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3 -(1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound G) is obtained as an off-white amorphous solid.

TLC: Rf 0.40, Developing Solvent (II).

(㎝-1)3700~2300, 1770, 1680, 1520IR:

(Cm-1) 3700-2300, 1770, 1680, 1520

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 3.17 (3H, s), 3.7 (2H, br), 5.04 (1H, d, J = 5 Hz), 5.6 to 6.0 (2H, m), 6.9-7.7 (8H, m). 9.36 (1 H, s)

UV: (EtOH) λ _max (nm) 268

Ferric chloride color reaction, positive (dark green)

(e) Similarly, in compound B, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl ) Acetamido] -3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound H) is obtained as an off-white amorphous solid.

TLC: Rf 0.39, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1510IR:

(Cm-1) 3700-2300, 1775, 1680, 1510

NMR: (DMSC-d ₆ , 60 MHz) δ (ppm) 3.18 (3H, s), 3.7 (2H, brs), 4.5 (2H, br), 5.05 (1H, d, J = 5 Hz), 5.5 to 6.0 (2H, m), 6.7-7.5 (7H, m), 9.37 (1H, s),

UV: (EtOH) λ _max (nm) 270, 280 (shoulder)

Ferric chloride color reaction, positive (dark green)

(f) Similarly, from compound B, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl ) Acetamido] -3- (1,2,3-triazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound I) is obtained as an off-white powder.

TLC: Rf 0.39, Developing Solvent (II).

(㎝-1)3700~2300, 1770, 1680, 1515.IR:

(Cm-1) 3700-2300, 1770, 1680, 1515.

NMR: (DMSO-d ₆ , 60 MHz) δ (ppm) 3.11 (3H, s), 3.6 (2H, brs), 5.03 (1H, d, J 5 ′), 5.4 to 5.9 (2H, m), 6.6 ˜7.5 (7H, m), 7.95 (1H, s).

UV: (EtOH) λ _max (nm) 272, 280 (shoulder).

Ferric chloride color reaction, positive (dark green)

(g) Similarly, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -1-ureido} -α-phenylacetamido] -3-acetoxymethyl-3 7- [D (-)-α- {3- (2,3-dihydroxybenzoyl) -1-ureido in 1-methyl-5-mercapto-1H-tetrazole with cefem-4-carboxylic acid } -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound K) Obtained as a powder.

TLC: Rf 0.38, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1530, 1490.IR:

(Cm-1) 3700-2300, 1775, 1680, 1530, 1490.

NMR: (acetone-d ₆ , 60 MHz) δ (ppm) 3.7 (2H, br), 3.96 (3H, s), 4.37 (2H, brs), 5.05 (1H, d, J = 5 Hz), 5.6- 6.0 (2H, m), 6.8-7.7 (8H, m).

UV: (EtOH) λ _max (nm) 256, 280 (shoulder), 310 (shoulder).

Ferric chloride color reaction, positive (dark green)

(h) Similarly, 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -1-ureido} -α-phenylacetamido] -3-acetoxymethyl-3 7- [D (-)-α-} 3- (3,4-dihydroxybenzoyl) in cefem-4-carboxylic acid and 5-methyl-2-mercapto-1,3,4-thiadiazole 1-ureido} -α-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter compound Also referred to as L), is obtained as an off-white powder.

TLC: Rf 0.36, Developing Solvent (II).

(㎝-1)3700~2200, 1770, 1675, 1525.IR:

(Cm-1) 3700-2200, 1770, 1675, 1525.

NMR: (acetone-d ₆ , 60 MHz) δ (ppm) 2.69 (3H, s), 3.72 (2H, brs), 4.4 (2H, br), 5.13 (1H, d, J = 5 Hz), 5.5 to 5.9 (2H, m), 6.8-7.7 (8H, m).

UV: (EtOH) λ _max (nm) 268, 290 (shoulder), 310 (shoulder).

Ferric chloride color reaction, positive (dark green)

(i) Similarly, 7β- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-meth Treatment with ethoxy-3-acetoxymethyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound AB) and 1-methyl-5-mercapto-1H-tetrazole with 7β- [D (-) -α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (1-methyl-1H-tetra An off-white powder of sol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound T) is obtained.

TLC: Rf 0.51, developing solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1515.IR:

(Cm-1) 3700-2300, 1775, 1680, 1515.

NMR: (acetone-d ₆ , 60 MHz) δ (ppm) 3.18 (3H, s), 3.49 (3H, s), 3.5 (2H, brs), 3.94 (3H, s), 4.37 (2H, ABq), 5.03 (1H, s), 5.70 (1H, d, J = 7 Hz), 6.9-7.7 (8H, m), 8.6 (1H, s), 9.90 (1H, d, J = 7 Hz).

UV: (EtOH) λ _max (nm) 272, 290 (shoulder).

Ferric chloride color reaction, positive (dark green)

(j) Similarly, in compound AB and 5-methyl-2-mercapto-1,3,4-thiadiazole, 7β-[[D (-)-α- {3- (3,4-dihydroxybenzoyl ) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3 An off-white powder of cefem-4-carboxylic acid (hereinafter also referred to as compound U) is obtained.

TLC: Rf 0.52, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1515.IR:

(Cm-1) 3700-2300, 1775, 1680, 1515.

Ferric chloride color reaction, positive (dark green)

(k) 7β- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl in the same manner as Compound AB and 2-mercapto-1,3,4-thiadiazole -1-ureido} -α-phenylacetamido] -7α-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4- An yellowish-white powder of carboxylic acid (hereinafter also referred to as compound V) is obtained.

TLC: Rf 0.52, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1520.IR:

(Cm-1) 3700-2300, 1775, 1680, 1520.

Ferric chloride color reaction, positive (dark green)

(l) Similarly, 7β- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-4-hydroxyphenyl) acetamido ] -7α-methoxy-3-acetoxymethyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound AC) and 1-methyl-5-mercapto-1H-tetrazole, 7β- [D ( -)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -7α-methoxy-3- An off-white powder of (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid (hereinafter also referred to as compound W) is obtained.

TLC: Rf 0.49, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1675, 1510.IR:

(Cm-1) 3700-2300, 1775, 1675, 1510.

Ferric chloride color reaction, positive (dark green)

(m) 7β- [D (-)-α- {3- (3,4-dihydroxybenzoyl) in the same manner with compound AC and 5-methyl-2-mercapto-1,3,4-thiadiazole -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -7α-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-yl An off-white powder of thiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound x) is obtained.

TLC: Rf 0.50, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1510.IR:

(Cm-1) 3700-2300, 1775, 1680, 1510.

Ferric chloride color reaction, positive (dark green)

(n) Similarly, in compound AC and 2-mercapto-1,3,4-thiadiazole, 7β- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3- Methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -7α-methoxy-3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem An yellowish-white powder of -4-carboxylic acid (hereinafter also referred to as compound Y) is obtained.

TLC: Rf 0.52, Developing Solvent (II).

(㎝-1)3700~2300, 1775, 1680, 1510.IR:

(Cm-1) 3700-2300, 1775, 1680, 1510.

Ferric chloride color reaction, positive (dark green)

For some of the compounds of the invention prepared by the method of Example 1, the minimum growth inhibitory concentrations (MIC) for various bacteria are shown in the following table. The bacteria used in the following table can be represented by the following numbers.

① Bacillus subtilis PCI-219 ⑪ pseudomonas erginoza J-272

② Staphylococcus Ereus 209P ⑫ Pseudomonas erginoza J-169

③ Staphylococcus Ereus JU-5 ⑬ Pseudomonas erginoza J-169-CM-222

④ Sarsina Lutea B ⑭ Pseudomonas erginoza GNB-75

⑤ Escherichia coli NIHJ ⑮ pseudomonas erginoza GNB-75-M5 7740

슈도모나스·에르기노자 KAN-2⑥ ShigellaFlexinelli 2b

Pseudomonas erginoza KAN-2

슈도모나스·에르기노자 Ps-6⑦ Salmonella and Paratyfipe A

Pse-6 Monus elginosa Ps-6

세라시아·마르세센스Ser-25b⑧ 15C to Krebsila & Pneumoniae

Ceracia marse sense Ser-25b

세라시아·마르세센스 FU-104⑨ Proteus and Mirabiris 1287

Cerasia Marsense FU-104

⑩ Proreus organga JU-244 ⑪ Enterobacter croca FU-250

Claims (1)

Three-acetoxy methyl cephalosporin derivative represented by the following general formula (II) is reacted with thiols represented by the following general formula (III) or salts thereof. Preparation of a palosporin derivative or its salt.

Where R ₁ represents a hydrogen atom or a lower alkyl group, R ₂ represents a hydrogen atom or a hydroxyl group, R ₃ represents a 2 to 3 hydroxyl groups or a lower alkanoyloxy group present to at least two adjacent, the substitution position of R ₃ is and R ₁ is a lower alkyl group, and the 3-5 position when the R ₃ is a hydroxyl group In other cases, it is selected in 2 ~ 6 positions. R ₄ represents a hydrogen atom or a methoxy group, R ₆ represents a 5-membered heterocycle which contains 1 or 2 or more nitrogen atoms and optionally 1 sulfur atom and may be substituted with a lower alkyl group, Y represents a hydrogen atom or a protecting group.