WO1993013109A1

WO1993013109A1 - Cephalosporin derivative

Info

Publication number: WO1993013109A1
Application number: PCT/JP1992/001660
Authority: WO
Inventors: Akira Onodera; Tomoki Miyazawa; Shigeo Morimoto; Katsuo Hatayama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1991-12-24
Filing date: 1992-12-18
Publication date: 1993-07-08
Also published as: AU3171593A

Abstract

To provide a medicine with an excellent effect on both Gram-positive and negative bacteria. A cephalosporin derivative represented by general formula (I) and a nontoxic salt thereof, wherein R1 represents hydrogen or a protective group; R2 represents hydrogen, lower alkyl or a protective group; R3 represents hydrogen or a protective group; and X, Y and Z represent each hydrogen, halogen, lower alkyl, phenyl or lower alkoxycarbonyl provided that at least one of X, Y and Z represents halogen, lower alkyl, phenyl or lower alkoxycarbonyl.

Description

Description Cephalosporin derivative

Technical field

The present invention relates to a novel cephalosporin derivative having a substituted thiocyanate group at the 3-position. More specifically, the present invention relates to an oral cephalosporin derivative and a non-toxic salt thereof, which are novel compounds and exhibit strong antibacterial activity. Background art

Cephalosporins are extremely effective drugs for treating bacterial infections because of their excellent antibacterial activity and high safety. In recent years, a number of research and development have been carried out on cefm derivatives having an aminothiazolyl group on the substituent of the 7-amino group, in particular, because they have strong antibacterial activity and a broad antibacterial spectrum.

Many cephalosporin-based antimicrobial substances useful as pharmaceuticals are known, but many of them are administered parenterally due to poor oral absorption. Currently, among oral cephalosporins used in clinical practice, cephalexin and cefaclor have a phenylglycylamino group at the 7-position and exhibit high oral absorption, but their antibacterial activity is high. Is significantly inferior to Gram-negative bacteria compared to cephalosporins for injection

Recently, oral cephalosporins have been developed that have esterified the 4-potassium ruponic acid to enhance oral absorption as a so-called prodrug. The introduction of an aminothiazolyl group at the 7-position enhanced the antibacterial activity against gram-negative bacteria compared to cephalexin, etc., but rather reduced the antibacterial activity against gram-positive bacteria, and oral absorption The disadvantages are that the properties are not so good. Disclosure of Invention

The present inventors have conducted intensive studies to solve the above problems, and as a result, have strong antibacterial activity and high We succeeded in synthesizing a novel cephalosporin derivative that also has oral absorbability and completed the present invention.

That is, Honkiaki is of the formula (I)

Η, s Ν

(Wherein, R ¹ represents a hydrogen atom or an amino protecting group, R ² represents a hydrogen atom, a lower alkyl group or a hydroxyl protecting group, and R ³ represents a hydrogen atom or a carboxyl protecting group. X , Υ, and Ζ represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, or a lower alkoxycarbonyl group, and at least one of X, Υ, and Ζ is a halogen atom, a lower alkyl group, A phenyl group or a lower alkoxy carboxy group.) A cephalosporin derivative represented by the formula: and a non-toxic salt thereof. The functional groups in the present invention have the following meanings. That is, the protecting group for an amino group, the protecting group for a hydroxyl group, and the protecting group for a hydroxyl group mean a protecting group that is commonly used in the field of β-lactamylamide.

For example, the protecting group for the amino group represented by R ¹ includes a monochloroacetyl group, a formyl group, a benzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, t —Butoxycarbonyl group, trimethylsilyl group, etc.

The protecting group for the hydroxyl group represented by R ² includes formyl group, acetyl group, propyl group, methoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, benzoyl group, toluoyl group, benzenesulfinyl group, Tosyl group, phenyl group, 4-methoxybenzyl group, 2,4-dimethylbenzyl group, trityl group, tetrahydroviranyl group and the like.Lower alkyl group means methyl group, ethyl group, propyl group and the like. is there.

The carboxyl-protecting group represented by R ³ includes methyl, ethyl, and propyl Group, isopropyl group, t-butyl group, vinyl group, aryl group, ethynyl group, methoxymethyl group, ethoxymethyl group, 1-methoxethyl group, methylthiomethyl group, carboxymethyl group, carboxyl group, t-butyl group Butoxycarbonylmethyl group, 2- (t-butoxycarbonyl) ethyl group, benzyl group, paranitrobenzyl group, bis- (4-methoxyphenyl) methyl group, 3,4-dimethoxybenzyl group, trityl group, phenethyl group, Prodrugs of phenacyl group, 2,2,2-trichloroethyl group, trimethylsilyl group, 4-hydroxy-3,5-di (t-butyl) benzyl group, phenyl group, trilyl group, xyl group and β-lactam 5-Methyl-1,3-Dimethyl Kissak Mouth Pentoe 4-One-2-On-4-Ilme Group, acetooxymethyl group, bivaloyloxymethyl group, 1-bivalyloxyshethyl group, 1-cyclohexylmethylcarboxyloxyshethyl group, 1-acetoxicetyl group, 3-furidylidyl And cyclohexyloxycarbonyl groups, and 11- (isopropoxycarbonyl) ethyl groups.

The lower alkyl group represented by X, Υ, or を represents a methyl group, an ethyl group, or a propyl group, and the lower alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, or the like. It is.

On the other hand, the non-toxic salt of the compound represented by the formula (I) of the present invention means a pharmacologically acceptable salt, for example, an inorganic base containing sodium, potassium, magnesium, ammonium and the like. Salts with organic bases such as triethylamine and cyclohexylamine, salts with basic amino acids such as arginine and lysine, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, or acetic acid, lactic acid, tartaric acid, fumaral Examples thereof include salts with organic acids such as acid, maleic acid, trifluoroacetic acid, and methyl sulfonic acid.

In the formula (I), a preferred example of R ¹ is a hydrogen atom, a preferred example of R ² is a hydrogen atom, or it is known in the art of prodruging a β-lactam agent such as a bivaloyloxymethyl group. also there group, R ³ can be exemplified hydrogen atom, respectively, to the compound represented by the formula of the present MizunotoAkira (I) may exist as geometric isomers derived from Okishiimino group 7-position side chain '(E body and Ζ The present invention encompasses any one of the above, and is preferably an isomer. Compound represented by the general formula of the present Mizunoto ^March (〖), for example, it can be obtained by the production method shown in the reaction经路shown in the following synthetic g path. m

C v)

_RlN ^N rCO ₂ H

Step c H s (VI) or its reactive derivative

H

Η

[Wherein R ¹ R ³ is X. Y and Z are as defined above, and R ⁴ is phenylacetyl, phenoxyacetyl, trityl, fluoryl, formyl, benzoyl] And a protecting group for an amino group such as a group.

R ⁵ represents a lower alkyl group or a hydroxyl group shown by the R ^2, R ⁶ represents a hydrogen atom or a lower alkyl group shown above. R is a group that can be hydrolyzed in vivo, which is known from the β-lactam agent prodrug-forming technology shown in R ³ above, and W, A, and B are each a halogen atom (eg, a chlorine atom, a bromine Atom, iodine Atoms), leaving groups such as methanesulfonyloxy, trifluoromethylsulfonyloxy, diphenylsulfonyloxy, and toluenesulfonyloxy. Step a: dissolving a known compound of the formula (II) in an organic solvent which does not participate in the reaction and stirring with 1.0 to 1.2 molar equivalents of sodium hydrosulfide in the presence of a base to obtain a 3-mercapto compound . The reaction temperature is from 150 to 100 ° C, preferably from -40 to 5 ° C. The reaction time is {0 minutes} to 4 hours, preferably 10 minutes to 1 hour.

Next, without isolating the 3-mercapto compound obtained by the above operation, 1.0 to 2.0 molar equivalents of the compound of the formula (iI1) were added in the presence of a base in the same system, and the reaction temperature was reduced to 50. ~ 100. C, preferably <25 ° C. and stirring at 25-50 ° C. to obtain a 3-thio replacement of formula (IV).

The reaction time varies depending on the kind of the base used, the kind of the compound of the formula (III) and the reaction temperature, but is 10 minutes to 5 hours, usually 10 minutes to 2 hours. In the above, preferred organic solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, acetate nitrile, tetrahydrofuran, dichloromethane and the like. They can be used alone or in combination.

Preferred bases include organic bases such as diisoprovirethylamine, N, N-dimethylaminopyridine, N, N-dimethylaniline, triethylamine, and the like. The concentration is 1.0 to 2.0 moles per compound.

Further, the 3-mercapto form obtained by the above operation can be used for the next reaction after isolation. That is, a 3-mercapto compound is reacted with a compound of the formula (II) in the presence of the same base and organic solvent as described above to obtain a 3-thio-substituted compound of the formula (IV). The same applies to the reaction conditions.

Step b: Next, the protecting group for the 7-amino group of the compound of the formula (IV) obtained in the above step a is removed by a method commonly used in the field of β-lactam chemistry to obtain a compound of the formula (V) is obtained. For example, the protecting group R ⁴ of the compound of formula (IV) may be substituted with a quinoxyacetyl group, In the case of a phenylacetyl group or a benzoyl group, the compound of formula (IV) is dissolved in dichloromethane or benzene, and 1.5 to 2.0 molar equivalents of phosphorus pentachloride and pyridin 2.0 to 3.0. Add 0 molar equivalent and stir at 40-40 ° C for 30 minutes to 3 hours. Then add a large excess of methanol or isobutyl alcohol at 50-20 ° C, stir for 30 minutes to 2 hours, add a large excess of water, and stir at 50-20 for 30 minutes to 1 hour. To give the compound of formula (V).

When the protecting group R ⁴ of the compound of the formula (IV) is a trityl group, the compound of the formula (IV) is dissolved in a solvent that does not participate in the reaction (eg, ethyl acetate), and the solution is cooled under ice-cooling. By adding 1.0 to 1.5 molar equivalents of ruenesulfonic acid monohydrate and stirring for 1 to 5 hours, a paratoluenesulfonic acid salt of the compound of the formula (V) can be obtained. This paratoluenesulfonate can be treated with a base, if necessary, to give a free compound of the formula (V).

Step c: In order to obtain a compound of the formula (VII) from a compound of the formula (V), a compound of the formula (V) is reacted with a 2-aminothiazolacetic acid derivative of the formula (VI) in the presence of a condensing agent. Or reacting a compound of formula (V) with a reactive derivative of a compound of formula (VI). Here, the condensing agent is N, N-dicyclohexylcarpoimidide, 1-ethoxydiphenyl-1,2-ethoxy-1,2-dihydroquinoline, carbonyldiimidazole, diphenylphosphoric azide, Vilsmeier reagent And so on.

The reactive derivative of the compound of the formula (VI) includes an acid halide (for example, an acid chloride or an acid bromide of the formula (VI)), an acid anhydride (for example, a symmetrical acid anhydride of the compound of the formula (VI) or Mixed acid anhydrides with chlorocarbonate, diphenylphosphoric acid, methanesulfonic acid, etc.), and activated esters (for example, esters with paranitrophenol, titanium phenol, N-hydroxysuccinimide, etc.) .

As an example of the reactive derivative of the compound of the formula (VI), a mixed acid anhydride of the compound of the formula (VI) with methanesulfonate is described. The compound of the formula (VI) is dissolved in a solvent which does not participate in the reaction. In the presence of a base at a temperature of from 70 to 130 ° C, 1.0 to 1.1 molar equivalents of methanesulfonic acid chloride are added, and the mixture is stirred for 20 to 40 minutes and mixed acid anhydride of the compound of the formula (VI) Is prepared. In the presence of a base, 0.5-0.7 mol equivalent of the compound of the formula (V) is added within a range of 170--30, and stirred for 20-40 minutes. / Image

-8- to give the compound of formula (VII). Preferred solvents in the present step include N, N-dimethylmethylammonium, tetrahydrofuran, acetonitrile, dichloromethanyl chloride form and the like.

Suitable bases are diisopropylethylamine, triethylamine, N, N-dimethylaniline, N.N-dimethylamino pyridine, pyridine and the like, and the amount of the base used is 1.0 to 1 with respect to the compound of the formula (V). 0 to 2.2 molar equivalents.

When acid chloride is used as a reactive derivative of the compound of the formula (VI), the compound of the formula (V ()) is dissolved in a solvent that does not participate in the reaction, and is dissolved in the presence of a base at 30 to 110. Then, 1.0 to 1.1 molar equivalents of phosphorus pentachloride are added, and the mixture is stirred for 10 to 30 minutes to prepare an acid chloride of the compound of the formula (VI). A solution in which ~ 1.0 molar equivalent is dissolved in a solvent which does not participate in the same reaction as described above is added within a range of 130 to 0 ° C, and stirred for 10 to 30 minutes to obtain a compound of the formula (VII). the preferred solvent for the step is dichloromethane, black hole Holm, Asetonitori Le, _r N-dimethyl formamidine de, etc.. Further, suitable bases are pyridine, Toryechiruamin, N, N-dimethylamino pyridine, N, N-Jimechiruaniri And diisoprovirethylamine, etc. It is from 4.0 to 5.5 molar equivalents against the compound of formula (V).

Further, as an example of the reactive derivative of the compound of the formula (VI), a mixed acid anhydride of the compound of the formula (VI) with phosphorus oxychloride is explained. Dissolve 3 molar equivalents of a compound of formula (V) in a solvent that does not participate in the same reaction as described above. To this is added 20-4.0 moles of base and 1.0-3.0 mole equivalents of phosphorus oxychloride at 20--5 ° C, and within 1-20-0, After stirring for 10 to 30 minutes, the compound of the formula (VII) is obtained. Preferred solvents in this step include ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform and the like. Suitable bases include pyridine, triethylamine, diisopropylethylamine and the like.

Step d: Next, in order to obtain a compound of the formula (VIII) from the compound of the formula (VII) obtained in the above step c, the protecting group of the compound of the formula (VIi) is converted to β-lactam chemical Elimination is carried out by hydrolysis and reduction methods commonly used in the field. (1) Hydrolysis

Usually, the hydrolysis is preferably carried out in the presence of an acid. Examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, formic acid, acetic acid, acetic acid with triflic acid, methanesulfonic acid, and benzene. Organic acids such as sulfonic acid and para-toluenesulfonic acid are exemplified. In place of the above acids, Lewis acids and acid ions such as boron trifluoride, boron trifluoride etherate, aluminum trichloride, antimony pentachloride, ferric chloride, tin chloride, titanium tetrachloride, zinc chloride, etc. An exchange resin or the like may be used.

When the above-mentioned organic acid or Lewis acid is used, it is desirable to carry out the reaction in the presence of a scavenger such as anisol. Preferred solvents for the hydrolysis are, for example, water, methanol, ethanol, tetrahydrofuran, N, N

—Dimethylformamide, dioxane, dichloromethane, nitromethane, etc. When the acid is a liquid, the acid itself can be used as a solvent.

(2) Reduction

The reduction is performed by a chemical reduction or a catalytic reduction method. Examples of the reducing agent used in the chemical reduction include a combination of a metal such as zinc and iron with an organic or inorganic acid such as formic acid, acetic acid, trifluroic acid, hydrochloric acid, and hydrobromic acid. . Examples of the catalyst used in the catalytic reduction include platinum black, platinum oxide, palladium black, palladium carbon, Raney nickel and the like.

The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, vinegar, tetrahydrofuran, N, N-dimethylformamide, dioxane, or a mixture thereof. It takes place inside.

The reaction temperature of the above-mentioned hydrolysis and reduction is not particularly limited, but it is usually carried out under cooling or under heating.

D) The compound of the formula (X) is prepared by reacting the compound of the formula (VIII) with the compound of the formula (IX) in the presence of a base or reacting the compound of the formula (IX) with a salt of the compound of the formula (VIII) Can be obtained. Suitable bases in this reaction include triethylamine, diisoprovirethylamine, N, N-dimethyl Organic bases such as aminoviridine or inorganic bases such as sodium bicarbonate, sodium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide. The salt of the compound of the formula (VI [I]) is a salt with a metal such as silver, sodium, potassium, calcium, and magnesium. This reaction will be described by taking a sodium salt as an example of the salt of the compound of the formula (VIII). The sodium salt of the compound of the formula (VIII) is dissolved or suspended in a solvent that does not participate in the reaction, and is used in an amount of 1.0 to 2.0 molar equivalents. Is added, and the mixture is stirred at 50 to 50, preferably -30 to 20 ° C for 5 minutes to 2 hours, preferably 10 minutes to 1 hour. Suitable solvents for this reaction are acetone, chloroform, dichloromethane, tetrahydrofuran, acetoneonitrile, getyl ether, methanol, ethanol, benzene, N, N-dimethyl wood amide, N, N-dimethyl acetate. Evening dimethyl, dimethyl sulfoxide, hexamethyl thiocyanate, water, etc. The best form for carrying out KIKI

Next, the production method of the present compound will be described in more detail with reference to Examples.

Example 1

(a) 7β-phenylacetamide 3-methanesulfuryl 3-cyphene 4-paramethoxybenzyl ester of rurubic acid 2.5 g (4.7 mM) in N, N-dimethylformamide 29. Dissolve in 5 ml and add 10. C, 70% sodium bisulfide (13 mg, 5.2 mM) in 17 ml of N, N-dimethylformamide and 91 mg of diisoprovirethylamine (7.1.1) mM). After stirring at the same temperature for 30 minutes, 1.03 g (9.5 mM) of 2,3-dichloropropene was added, and the mixture was further stirred under ice cooling for 2 hours.

After the reaction, 100 ml of 0.5% hydrochloric acid was added, extracted with 200 ml of ethyl acetate, washed with 100 ml of saturated saline [(X 2), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: dichloromethane = 1: 2) to give 7β-phenylacetamide 13- (2-port 2-pro- ぺ). Nil) Chisaichi 3-Sefmu 4 One-handed rubonic acid paramethoxyl benzyl ester 1.8 1 g was obtained. NMR (DMS 0-d ₆ ) δ (ppm);

3.48 and 3.56 (2 H, AB q, J = 1 H z), 3.75 (3 H, S), 3.77 (2 H, bs), 3.80 and 3.88 (2 H, AB q. J = 15 Hz), 5.11 and 5.23 (2 H, AB q, J = 12 Hz), 5.13 (1 H, d, J = 4. 5 Hz), 5.33 (1 H, d, J = 1.5 Hz), 5.53 (1 H, d, J = 1 Hz), 5.65 (1 H, dd, J = 4. 5, 8 H 2), 6.92 (2 H, d, J = 8.5 H z), 7.20 to 7.33 (5 H, m) 7.34 (2 H, d, J = 8.5 Hz), 9.13 (1H, d, J = 8Hz)

^{_{^{IR KBr v ma xc m "1}}} ; 3269, 3030, 1 770, 1 705, 1 654, 1 6 1, 1 537, 1 5 1 6, 1 455, 1 388, 1 358, 1 287, 1 249, 1 228, 1 1 74, 1 1 2 1, 1 033

(b) 7 β-phenylacetamide obtained in (a) above 3- (2-chloro-1-2-propionyl) thi-1,3-cefmu 4 (3.3 mM) in 20 ml of anhydrous dichloromethane, add 0.52 g (6.6 mM) of pyridine and 1.02 g (4.9 mM) of phosphorus pentachloride under ice-cooling, and add at room temperature. The mixture was stirred for 1.5 hours. With, under ice cooling, isobutyl alcohol

1.8 g (24.3 mM) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 5 mL of water was further added, and the mixture was stirred for 30 minutes. After the reaction, the organic layer of the reaction solution was washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated (approximately 5 ml), the residue was added dropwise to 80 ml of diisopropyl ether, and the precipitated powder was collected by filtration to give 7β-amino-3- (2-cyclo-2-propyl). Nyl) Thi-Shiichi 1.41 g of the hydrochloride salt of 3-cef-4-carboxylate paramethoxybenzyl ester was obtained.

NMR (DM S 0-d ₆ ) δ (ppm)

3.40 (3 Η, b s), 3.75 (3 Η, s), 3.79 a n d 3.87

(2 Η, AB q, J = 15 Η ζ), 3.98 (2 Η, bs) 5.09 (1 Η, d, J = 5 Η ζ), 5.18 (2 Η.s) , 5.25 (1 Η d, J = 5 Η ζ), 5.40 (1 Η, d, J = 1.5 Η ζ), 5.60 (1 Η d, J = 1 Hz) 6.92 (2 H, d, J = 8.5 Hz), 7.34 (2 H.d.J = 8.5 Hz)

IR ^KBr v _{ra3x cm} - ¹ ; 343 1, 2 9 0 6, 1 78 0, 1 7 0 2, 1 6 1 3,

I 5 1 5, 1 464, 1 3 9 5, 1 2 9 9, 1 249, 1 2 1 4, 1 1 7 6,

I I 2 3, 1 0 3 3

(c) The hydrochloride of β-amino-3— (2-c □□ -2-propidinyl) thiophene-3-cefmue 4-carponic acid paramethoxybenzyl ester obtained in (b) above 1.38 g (3.0 mM) and 2- (tritylaminothiazoyl 4-yl) 1 2 1 [(Z) -trityloxyimino] acetic acid sodium salt 2.06 g (3.0 m) was dissolved in 50 ml of tetrahydrofuran and cooled to 120 ° G. To this, 0.71 g (9.0 mM) of pyridine and 0.91 g (5.9 mM) of phosphorus oxychloride were added, and the mixture was stirred at 115 to 15 ° C for 20 minutes. After the reaction, 50 ml of water was added, extracted with 100 ml of ethyl acetate, washed with 50 ml of a saturated saline solution, and dried with anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate: π-hexane = 1: 1) to give 7β- {2- (2-tritylaminothiazole). 4-yl) 1 2— 〖(Ζ) —trityloxyimino] acetamide} -3 -— (2-chloro-2-propionyl) thio 3—cef-m 2.52 g of the benzyl ester were obtained.

NM R (DMS O-d _e ) δ (ppm)

3.75 (3 H, s), 3.75 (2 H, bs), 3.88 (2 H, bs), 5.19 (2 H, bs), 5.24 (1 H, d , J = 4.5 Hz), 5.35 (lH, d, J = 1.5Hz), 5.55C1H, d, J = 1Hz), 5.78 (1H, d, J = 4.5, 8Hz), 6.63 (1H, s), 6.93 (2H.d, J = 8.5Hz), 7.06 ~ 7.40 (3 2 H, m), 8.76 (1 H, s), 9.86 (1 H, d, J = 8 Hz)

IR ^k ' ^Br v _raax cm "¹; 3 3 8 2, 3 0 52, 2 9 5 7, 1 78 9, 1 73 1, 1 688, 1 6 1 3, 1 5 1 6, 1 49 3, 1 48, 1 3 6 0, 1 2 5 0, 1 2 1 8, 1 1 7 5, 1 1 1 4, 1 0 3 4 (d) 7β- {2- (2-tri.tylaminothiazol-4-yl) obtained in (c) above 2-[(Ζ) -tritylaminoxyimino] asemid}} — 3- (2-c 2-D-propenyl) 3-cefem-4 4-paramethoxybenzyl rubonate 2.39 g (2.2 mM) in 4.5 ml of trifluoroacetic acid To a mixture of 0.9 ml of anisol and 0.9 ml of dichloromethane and 4.5 ml of dichloromethane, and the mixture was stirred for 1.5 hours. The reaction solution was dropped into 100 ml of isopropyl ether, and the precipitated crystals were collected by filtration. Next, the crystals were dissolved in 9.0 ml of formic acid and stirred at room temperature for 1 hour. The insolubles were removed by filtration, and the filtrate was added dropwise to 120 ml of isopropyl ether.

The precipitated crystals are collected by filtration, and 7β- {2- (2-aminothiazo-l- 4-yl) -l 2-{[(Ζ) -hydroxyimino] ase-mido} -l 3-(2-chloro- 2-Propenyl) Chi-shi 3-Sefume 4 One-strength formic acid of rubonic acid 800 mg was obtained. This formate was suspended in 10 ml of water, dissolved in 464 mg (5.5 mM) of sodium hydrogen carbonate, and then subjected to column chromatography on Toyopearl (HW-40F) (elution solvent: water). 7 β- {2- (2-aminothiazol-41-yl) -1-2-[(Ζ) -hydroxyimino] ase-mid} 1-3- (2-ku-low-2-pro Benzyl) Thio-3-Sefm-4 500 mg of sodium salt of rubonic acid was obtained. NR (DMS 0-d ₆ ) δ (ppm);

3.33 and 3.57 (2 H, AB q, J = 17 Hz), 3.60 and 3.70 (2 H, AB q, J = 15 Hz), 4.97 (1 H , D, J = 4.5 Hz), 5.27 (1 H, d, J = 1.5 Hz), 5.58 (1 H, dd, J = 4.5, 8 Hz), 5.6 1 (1 H, d, J = 1 H z), 6.64 (1 H, S), 7-. 1 2 (2 H, b S), 9.1 (1 H, d, J = 8 H z), 1 1. 3 2 (1 H, S)

^{_{^{IR KBr v ma xcm _1; 3326}}} , 1 762, 1 6 07, 1 532, 1 3 92. 1 352, 1 1 84, 1 1 1 8, 1 046 Example 2 '

300 mg (0.6 mM) of the sodium salt obtained in Example 1 (d) was The solution was dissolved in 4.5 ml of dimethylformamide, added with 204 mg (0.8 mM) of bivaloyloxymethyl iodide under ice cooling, and stirred for 1 hour. After the reaction, 30 ml of water was added, extracted with 50 ml of ethyl acetate, washed with 30 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was Sephadex, and subjected to H-20 column chromatography (elution solvent: Acetone) to give 7β- {2- (2-aminothiazoyl 4-yl) 12- [( Ζ) -Hydroxyimino] acetamide} 3- (2-c- □ --2-propionyl) thio 3-cef-m-4 4-hydroxyrubonate bivaloyloxymethyl ester 125 mg Obtained.

N R (DMS O-de) δ (ppm);

1.15 (9 H, S), 3.79 (2 H, bs), 3.89 and 3.95 (2 H, AB q, J = 15 Hz), 5.2 1 (1H, d, J = 4.5Hz), 5.38 (TH, d, J = 1.5Hz), 5.57 (1H, d, J = 1Hz), 5 77 (1 H, dd, J = 4.5, 8 Hz), 5.80 and 5.88 (2 H, AB q, J = 6 Hz). 6.68 (1 H, S ), 7.17 (2H, bS), 9.48 (1H, d, J = 8Hz), 11.3 (1H, s)

IR ^KBr v _raax cm ^_1 _t -343 5, 2 6 75, 1 78 1, 1 7 5 7, 1 67 2, 1 628, 1 5 3 1, 1 48 1, 1 3 7 1, 1 2 8 1, 1 2 1 6, 1 1 5 8, 1 1 0 9, 1 0 28Example 3

(a) 7 β-Amino-3- (2- (1-)-2-probenyl) thio-3-Sefmue 4 obtained in Example 1 (b) Hydrochloride of paramethoxybenzyl ester of 1-ketone ruponic acid 1 0.5 g (2.3 mM) and 1.0 g (2.3 mM) of 2- (tritylaminothiazole-41-yl) -1-2-[(Z) -methoximino] acetic acid The solution was dissolved in 25 ml of Rahid's mouth furan and cooled to 20 ° C. To this was added 0.59 g (7.5 mM) of pyridine and 0.45 g (2.9 mM) of phosphorus oxychloride, and the mixture was stirred at 115 to 15 ° G for 20 minutes.

After the reaction, 50 m of water was added, and the mixture was extracted with 100 ml of ethyl acetate, washed with 50 m of saturated saline, and dried over anhydrous magnesium sulfate. Evaporate the solvent and remove the residue After subjecting to silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1), 7 β- {2- (2-tritylaminothiazo-1-yl 4-yl) 1-2- (Ζ) —Methoxyimino] asemid}} — 3— (2-Cro——Propenyl) 3-Cefem-4

00 g was obtained.

NMR (DS 0 -d ₆ ) δ (ppm);

3.73 (2H, bs), 3.75 (3H, s), 3.81 (3H, s), 3.80 and 3.89 (2H, AB q, J = 1 5 H z), 5. 1 7 and

5.2 1 (2 H, AB q, J = 12 Hz), 5.16 (1 H, d, J = 4.5 Hz), 5.33 (1 H, d, J = 1 5Hz), 5.53 (1H, d, J = 1Hz), 5.65 (1H, dd, J = 4.5, 8Hz), 6.72 (1H, s ),

6.92 (2H, d, J = 8.5Hz), 7.16-7.42 (17H, m), 8.82 (1H, s), 9.56 ( 1 H, d, J = 8 H z)

1 R ^KBr vmaxc m ^_1 ; 3306, 2937, 1 785, 1 730, 1 683, 1 6 1 3, 1 5 1 6, 1 448, 1 385, 1 36 1, 1 284, 1 249, 1 2 1 9 , 1 1 7 5, 1 1 1 5, 1 036

(b) 7 β- {2- (2-tritylaminothiazol-4-yl) -1 2-[(Ζ) -methoxyimino] ase obtained from above (a)} 1-3— ( 2—c □□ —2—propionyl) thi--3-cef-m- 4-carboxylate paramethoxybenzyl ester 950 mg (1.1 mM) was added to trifluro-chloroacetic acid (2.9 mL) and anisol A mixture of 0.58 mI / l and 2.9 mI of dichlormene was added under ice-cooling, and the mixture was stirred for 1 hour and further at room temperature for 20 minutes.

After the reaction, the reaction mixture was added dropwise to 50 ml of isopropyl ether, and the precipitated crystals were collected by filtration and filtered to obtain 7 (3- (2- (2-aminothiazoyl-41-yl) —2 — [(Z) -Methoxyimino] acetamide} 1-3-(2-□ □ □ 1-2-propionyl) thisai 3-cefm-4 tritolutrilic acid acetic acid 600 mg was obtained. Fluoroacetate was suspended in 5 ml of water, dissolved by adding 234 mg (2.8 m) of sodium hydrogen carbonate, and then subjected to Toyopearl (HW-40F) column chromatography. 1 (eluting solvent; water), then 7 β- {2- (2-aminothiazo-1-yl 4-yl) —2— [CZ) -methoximino] asemid} 1 3 -— (2— □□ — 2-Prodenyl) Thio 3-cefum-4-carboxylic acid sodium salt 478 mg was obtained.

NMR (DMS 0- d ₆ ) δ (ppm);

3.35 and 3.58 (2 H, AB q, J = 17 Hz), 3.6 1 and 3.70 (2 H, AB q, J = 15 Hz), 3.83 (3 H, s), 4.97 (1H, d, J = 4.5Hz), 5.28 (1H, d, J = 1.5Hz), 5.56 (1H.dd , J = 4.5, 8 Hz), 5.62 (1H, d, J = 1Hz), 6.72 (1H, s), 7.22 (2H, bs), 9. 55 (1 H, d, J = 8 Hz)

IR ^KBr v _max C m ^_I ; 341 2, 1 766, 1 662, 1 607, 1 534, 1 392, 1 353, 1 1 82, 1 1 20, 1 040 Example 4

330 mg (0.6 mM) of the sodium salt obtained in Example 3 (b) above was dissolved in 4.5 ml of N, N-dimethylformamide, and 219 mg of bivaloyloxymethyl iodide was added under ice cooling. CO. 9 mM) and stirred for 1 hour.

After the reaction, 30 ml of water was added, extracted with 50 ml of ethyl acetate, washed with 30 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to SEPH ADEX LH-20 column chromatography (extracted solvent; Aceton) to give 7β- {2- (2-aminothiazo-1-yl 4-yl) 1-2— [( Ζ) —Methoxyimino] asemid} 1-3- (2-chloro □ -2-propionyl) thio-13-cefume-4-carboxylate bivaloyloxymethyl ester 265 mg was obtained. .

NMR (DMSO-de) δ (p p m);

1.16 (9 H, s), 3.8 1 (2 H, bs), 3.84 (3 H, s), 3.89 and 3.96 (2 H, AB q, J = 15 H z), 5.22 (1 H, d, J = 4.5 H z), 5.38 (1 H, d, J = 1.5 H z), 5.57 (1 H, d, J = 1 H z), 5.76 (1 H ₍ dd, J = 4.5, 8 H z), 5. 8 0 and 5.88 (2 H, AB q, J = 6 H 2), 6.66 (1 H, s) 7.2 2 (2 H, bs) .9 '62 (1 H, d, J = 8 Hz)

1 R ^KBr v _max cm ^_1 ; 3436, 297 6, 1 780, 1 757, 1 673, 1 628, 1 537, 1 48 1, 1 463, 1 37 2, 1 28 1, 1 2 1 7, 1 1 58, 1 1 09, 1 0 35 Example 5 (a :) to 9 (a)

• The compounds shown in Table 1 below were obtained according to the procedures and reaction conditions disclosed in Example I (a).

Hereinafter, in each table, G indicates a phenylasemid group, Tr indicates a trityl group, PMB 'indicates a paramethoxybenzyl group, and nd indicates unmeasured.

HN · iOH

_: :) 2 ^ 02 Sat, 嗨 ^^} ¾ ί¾: α: τ: ^^^ ¾ :) (q) ι rnmrn

(q) 6 ~ (q) 9

-61

099I0 / r6df / JOd 60ΐει / εβ O Examples 5 (c) to 9 (c) _ Based on the operation and reaction conditions disclosed in Example 1 (c), the compounds shown in Table 3 below were obtained.

Example 5 (d) to 9 (d)

The compounds shown in Table 4 below were obtained according to the procedures and reaction conditions disclosed in Example I (d).

Table 4

*; Measurement solvent; D ₂₀

Examples 10 to 13

According to the procedures and reaction conditions shown in Example 4, the compounds shown in Table 5 below were obtained. (s "Hi) OS 'TT ^, (ZH8 = f' P i sa

'111) 3 "6' (sq ΉΖ) ΤΤ

'(ZHS' 5 = Γ "δ ES 'HT) S8

2L "9" (s "HT) i9 -9 '(ZH9' ZHS Ή

'PP i ss * HT) 8i' SPUE i -g '(in

Ηΐ) Τ9 5 to 55 'S "(ZH2 = f' P ^ BS

OOOT "9iOT '9Πΐ HT) 6S' S '(ZHS" f = f "P t

L9TT 'λΙΖΤ Ό9ΖΤ' HT) TZ-S UE6T'S '("i'HT) Z9

6i £ T '6' TEST ~ OS · "(m ΉΖ) 00 ~ 98 · £ '(sq ¾0

8Z9T 'Zi9T' Ζ9Π t {B9 'HZ) 61-g uB8i-8 "(ZHS * S ^:

T98Z '6 £ 6Z6εεε' P ΉΕ) 6 T '(' Η0τ) ΐ6-Τ〜9Τ "ΐ

(s ΉΤ) OS TT '(ZHS "8 = f' P

i es 'HT)' 6PUE3 6 '(sq "HZ) h OOOOHO- TT' L '(2HS' 9 = Γ 'b ES' HT) S8" 9

puE8i -g '(s q es' es) s -9 PUE99

• 9 '(ZHS' 8 'S "f = f" PP Ήΐ) 6

L -SPue "s-(m · ΗΤ) 29 'S〜SS" S (

S '(ZHS = f' P t ES

OT 0TT 'i9TT 61' S '(m' HOS8 ^ ~ Si '' ('ΗΖ)

8ΤΠ '692T Ίΐ £ Ίΐ OCT G i8'S' (sq ¾OBa-HZ) 6i'S -HO

TEST '8Z9T' ZI9T p

Z9LT '8868' 6288 6 ^S («HO) HOOOOOHO- ZT

HS

"(

89 "9PUBi9" 9 "(ZHS" 8 S ^ = f 'PP

i ss' HI) U 'SPUE5' (m'HT)

09 'S〜9S -S "(ZHZ = f' P ¾3B3 ΉΤ

690T '80TT) 6 £' SPUBSE "S '(ZHS'? = F 'P'HT)

89TT '9ΤΠ' 98ZT OZ5 '(ω'ΗΖ) 00 ^ ~ 58

6AST '8' OSST δ8 · ΗΖ) 6λ 'ε "Ε9λ' ε '(ΖΗ5" 9 = Γ' Ρ

L29T 'Si9T' Τ8Π MOBS 'ΗΖ) 0Ζ' ΖΡ "δ6Τ 'I' (ZHS 'S = f

T982 'S262 "OS? £' Ρ 'HS) 9f · ΐ' 'ΗΤΐ) · Τ〜 WO

(s · ΉΤ) Τ8 "TT '(2Η8

= Γ Ρ 'ΗΤ) 6' 6pue "6 '(sq monument ² H3030H0- IT

Ή2) 9Τ · £ '(ZHS' S = f 6 q.es ΉΤ '

HT) T6 "Θ υΒί'δ" 9 * (s qoB3 ΉΤ) 89

• 9PUB99 -9 '(ZH8 "9' Τ = Γ 'PP ^ ES

690T "ΟΟΐΐ" HT) 6i 'SPUBSi "S' (q. ΉΤ) 6

SS TT 7221 Ί2Ζ 2 'SPUEiS "S' (ZHS '-f P es Ή

08ST "ZSST" S ^ 02 ''('ΗΖ) 66 ~ ^ ^S H3

8Z9T "0i9T 'SSiT S' (sq Ή2) 08 'iP ^ LL" £' (1

08LT '5i62' 2ZZZ ZHS 'S = f "P' HS) 'T' (s Ή6) Η 'Τ ^Ε ( ^Ε Η3) Ο000Η3-01

(ui d d)

i-i UI o (a p— o s w a)

(J 8 i) H I H W N

.11-I0 / Z6df / JDd 60I £ I / £ 6 OAV Industrial applicability

The compound of formula (I) and the non-toxic salt thereof of the present invention not only have a strong antibacterial activity against various pathogenic bacteria including gram-positive bacteria and negative bacteria, but also have an excellent oral absorbability. As an antibacterial agent for oral administration Useful.

For this purpose, the compound of the present invention can be orally administered in the form of tablets, pills, capsules, granules, etc., manufactured according to conventional formulation techniques. In each of the above-mentioned preparations, usual additives such as a bulking agent, a binder, a pH adjusting agent, and a solvent can be used.

The dosage of the compound of the present invention for a treated patient may vary depending on the age of the patient, the type and condition of the disease, and the like, but usually, 10 to 300 mg per day is divided into 1 to several doses. can do. Next, the antibacterial activity of the compound of the present invention is shown.

Test example

By the agar plate dilution method performs antibacterial tests against various bacteria (inoculum ^{volume: 1 0 s eel I s /} m I), to obtain a Yui杲the following Table 6.

3 ^ 6

[MI C value (y gZm l) j., (Note)

• A: The compound obtained in Example 1 (d) is shown.

B ': Shows cefaclor (known compound).

C: Cefixime (sodium salt, known compound) K Experiment 2

Hi The change in blood concentration Hi by CR administration to CR strain Si'fe mice (4 weeks old, 1113 animals) was examined.

Drug dosage: 20mgZkg (5% gum arabic suspension)

Quantitative S: Bioassay method (Test bacterium: Bacillus cellureus S〗 101) 3 cloud 7 to 7 "

(Note)

D: Indicates the compound obtained in the real signal order 2.

B: indicates cefaclor.

Claims

Expression

H — z

(Wherein, R ¹ represents a protecting group for a hydrogen atom or an amino group, R ² represents a protecting group for a hydrogen atom, a lower alkyl group or a hydroxyl group, and R ³ represents a protecting group for a hydrogen atom or a propyloxyl group. X, Υ, and 、 represent a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, or a lower alkoxyl group, and at least one of X, Υ, and Ζ is a halogen atom or a lower alkyl group. And a cephalosporin derivative represented by L or a lower alkoxycarbonyl group and a non-toxic salt thereof.