JPH0676415B2 - Novel cephalosporins and their salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to cephalosporins, and more specifically to the following general formula: [Wherein R ¹ is a hydrogen atom, an amino-protecting group or an acyl group, R ² is an optionally substituted thiazolyl group which forms a carbon-carbon bond with the 3-position exomethylene group, and R ³ is optionally protected. It represents a good carboxyl group or carboxylato group. ] Relates to a novel cephalosporin and its salt.

[Prior Art] Conventionally, various groups have been introduced into the 3-position of cephalosporins,
Studies have been carried out to develop excellent compounds having a broad antibacterial spectrum, but no such compounds having an optionally substituted thiazolyl group which forms a carbon-carbon bond with the 3-position exomethylene group are known. .

[Problems to be Solved by the Invention] An object of the present invention is to provide a broad antibacterial spectrum, that is,
It has an excellent antibacterial activity against Gram-positive and Gram-negative bacteria, and in particular, it exhibits excellent antibacterial activity against penicillin- and cephalosporin-resistant bacteria and has low toxicity, and is a general formula useful as a drug for humans and animals [ I] to provide a novel compound and a salt thereof.

[Means for Solving Problems] As a result of intensive studies to solve the above problems, the present inventors have an optionally substituted thiazolyl group that forms a carbon-carbon bond with the 3-position exomethylene group. It was found that the compound of the general formula [I] and a salt thereof, which have the structural characteristics described above, meet the object of the present invention, and have completed the present invention.

Hereinafter, the present invention will be described in detail.

In addition, unless otherwise specified in this specification, the term alkyl is used. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.
-Butyl, pentyl, hexyl, heptyl, octyl,
A linear or branched C ₁ ~ ₁₄ alkyl and dodecyl;
Cycloalkyl for example, cyclopropyl, cyclobutyl, cyclopentyl, C ₃ ~ ₆ cycloalkyl cyclohexyl; The Ariru, for example, phenyl, naphthyl, indanyl and the like; and and halogen atoms,
Fluorine, chlorine, bromine, iodine atom and the like are each meant, and lower means one having 1 to 5 carbon atoms. In addition, even when a term such as lower alkyl is included in various terms, the above-mentioned meanings are shown unless otherwise specified.

Hereinafter, the compound of the formula [I] will be described in detail.

Examples of the protecting group for the amino protecting group for R ^{1 and} the optionally protected carboxyl group for R ³ include protecting groups known in the art, specifically, Protective Groups in Organic Synthesis [Protective Groups in Organic Synthesis] (Theodora W.Green [Theodora.W.Green]; John Wiley & Sons, Inc.] and Japanese Patent Publication 60-52755
Each protecting group described in, for example, No.

In addition, examples of the acyl group for R ¹ include an acyl group commonly used in the field of monolactam, penicillin and cephalosporin, and examples thereof include α-amino-α-phenylacetyl, α-phenylacetyl and α-phenoxy. Acetyl, α- (2-thienyl) acetyl, α-carboxy-α-phenylacetyl, α- (1-tetrazolyl) acetyl, α-cyanomethylthioacetyl, α-
(2-Carboxyethyl) thioacetyl, α-hydroxy-α-phenylacetyl, α- (4-ethyl-2,3-
Dioxo-1-piperazinocarbonylamino) -α-
(4-hydroxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -αphenylacetyl, α- (4-ethyl-2,3-
Dioxo-1-piperazinocarbonylamino) -α-
(3,4-dihydroloxyphenyl) acetyl, α (4-
Ethyl-2,3-dioxo-1-piperazinocarbonylamino) -α- (3,4-diacetoxyphenyl) acetyl, α-difluoromethylthioacetyl, α- (cis-
2-chlorovinyl) thioacetyl, α- (trans-2-
Carbamoyl-2-fluorovinyl) thioacetyl,
(Z) -2- (2-aminothiazol-4-yl) -4
-Carboxy-2-butenoyl, (Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2-butenoyl and formula [In the formula, R ⁴ represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, and ˜ represents a syn or anti isomer or a mixture thereof. In addition, as a substituent of R ⁴ , there is disclosed in
Examples of the substituent include those described in JP-A No. 53-137988, JP-A No. 54-1325933, and the like. ] The group etc. which are represented by these are mentioned.

The substituent of the optionally substituted thiazolyl group which forms a carbon-carbon bond with the 3-position exomethylene group of R ² includes an alkyl group, an aryl group, an optionally protected hydroxyl and amino group, and a quaternized group. And a thiazolyl group may be one of the above-mentioned one or two.
It may be substituted with one substituent.

Here, as the protecting group for the hydroxyl and amino groups which may be protected, there are mentioned protecting groups known in the art, and specifically, Protective Groups in Organic Synthesis [Protective Groups in
Organic Synthesis] (Theodora W Green); John Willie &
Sands Incorporated [John Wiley & Sons, I
nc.]) and various protecting groups described in JP-B-60-52755 and the like.

Further, examples of the heterocyclic group include a heterocyclic group containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms such as pyridyl, thienyl and furyl.

Further, as the quaternized heterocyclic group, for example,
Examples include quaternized nitrogen-containing heterocyclic groups such as pyridyl quaternized with a lower alkyl group.

Further, the above substituents may be substituted with a halogen atom, an aryl group, a cycloalkyl group, a carboxyl group, a carbamoyl group, an amino group, a hydroxyl group, a sulfo group or the like.

In addition, as the salt of the compound of the general formula [I], a salt in a basic group or an acidic group can be mentioned. Examples of the salt of the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, trichloroacetic acid and trifluoroacetic acid, methanesulfonic acid and benzesulfonic acid. , Toluene-4-sulfonic acid, mesitylenesulfonic acid, naphthalene-2-sulfonic acid, salts with sulfonic acids such as naphthalene-1,5-disulfonic acid, as the salt in the acidic group, for example, sodium, potassium Examples thereof include salts with alkali metals such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

Further, when having an onium group such as a pyridinio group in the molecule, the onium group may usually form an inner salt with the carboxylato group in R ³ described above, a halogen anion, a lower alkanesulfonyloxy group. A salt may be formed with an anion or an arenesulfonyloxy anion which may be substituted with a lower alkyl group or a halogen atom.

The present invention also includes isomers (optical isomers, geometric isomers, tautomers, etc.), hydrates and various crystal forms of the compound of the general formula [I] or a salt thereof.

Next, a method for producing the compound of the present invention will be described.

The compound of the present invention can be produced, for example, according to the following production route.

[Wherein R ³ has the same meaning as described above; R ^3a represents an ^optionally protected carboxyl group of R ³ ; R ^2a represents alkyl, aryl,
A thiazolyl group optionally substituted with an optionally protected hydroxyl or amino or a heterocyclic group; R
^2b represents a thiazolyl group substituted with a quaternized heterocyclic group; R ⁵ represents an amino protecting group or an acyl group of R ¹ ; R ⁶
Is an acyl group of R ¹ ; R ⁷ is an optionally substituted lower alkyl group; R ^8a , R ^8b and R ^8c are the same or differently substituted alkyl or aryl groups; Leaving group is a △ ² , a △ ³ , or a mixture of △ ² and △ ³ . ] General formulas [Ia], [Ib], [Ic], [Id], [II], [II
I], [IV], [V], [VI], [VII], [VIII],
Examples of the salt of the compound of [IX] and [XII] include the same salts as those described as the salt of the compound of general formula [I].

(1) Introduction of thiazolyl group By reacting a compound of the general formula [II] or a salt thereof with a compound of the general formula [X] or [XI] in the presence of a solvent, a compound of the general formula [III] or The salt can be obtained.

The solvent used in this reaction can be used without particular limitation as long as it is a solvent inert to the reaction, for example,
Water; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethyl ether; aromatic hydrocarbons such as benzene and toluene; amides such as N, N-dimethylformamide; alcohols such as methanol and ethanol; Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; dimethylsulfoxide; and sulfolane, and these solvents may be used as a mixture of two or more kinds.

In this reaction, when the compound of the general formula [X] is used, it is preferable to react in the presence of a base, and as the base to be used, pyridine, dimethylaminopyridine,
Organic bases such as triethylamine, dimethylaniline, diethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene and sodium acetate; inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate and sodium hydroxide Examples thereof include organic metal bases such as n-butyllithium.

The amount of the compound of the general formula [X] or [XI] used is usually equimolar or more based on the compound of the general formula [II] or a salt thereof.

This reaction is usually 10 to 180 ℃, preferably 50 to 100 ℃
Then, it may be carried out for 5 minutes to 30 hours.

(2) Oxidation and reduction By subjecting a compound of the general formula [III], [VI] or [VIII] or a salt thereof to an oxidation reaction usually used in the field of cephalosporins, the general formulas [IV] and [VII] are respectively obtained.
Alternatively, a compound of [IX] or a salt thereof is obtained, and then subjected to a reduction reaction usually used in the field of cephalosporins, to give a compound of the general formula [Ia], [Ic] or [Id], respectively.
Alternatively, their salts can be obtained. These reactions are based on Journal of the Organic Chemistry (J.Org.Chem.) Vol. 34, page 2430 (1970), Journal of the Chemical Society (J. Chem.So.
c.) The method described in page 1142 (1966), JP-A-52-48683 or the like or a method analogous thereto can be used.

(3) Deacylation, elimination of amino protecting group By deacylating a compound of the general formula [III] or [Ia] in which R ⁵ is an acyl group or a salt thereof, a compound of the general formula [V] or Ib] compounds or their salts can be obtained. Specifically, a compound of the general formula [III] or [Ia] or a salt thereof in which R ⁵ is an acyl group is reacted with a halogenating agent such as phosphorus pentachloride to form an iminohalide, and then an alcohol is formed. By reacting to give an imino ether, and then hydrolyzing this,
The compound of the general formula [V] or [Ib] or a salt thereof can be derived. Furthermore, specifically, the Journal of the Chemical x Society (J.Chem.So
c.) Volume 83, page 320 (1903), Canadian Patent 770125.
To obtain a compound of the general formula [V] or [Ib] or a salt thereof by the method described in Japanese Patent No. 1041985, Japanese Patent Publication No. 45-40899, Japanese Patent Publication No. 40-40479, or the like. You can

In addition, R ⁵ is an amino protecting group represented by the general formula [III] or [I
A compound of the general formula [V] or [Ib] or a salt thereof can be obtained by subjecting a compound of a] or a salt thereof to an elimination reaction of a commonly used amino protecting group.

(4) Acylation The compound of the general formula [V] or [Ib], a salt thereof or a reactive derivative thereof is reacted with the compound of the general formula [XI
The compound of general formula [VI] or [Ic] or a salt thereof can be obtained by reacting a compound of I], a salt thereof or a reactive derivative thereof.

Examples of the reactive derivative of the compound of the general formula [XII] include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, active thioloesters and acid azides described in JP-A-59-93085. And a reactive derivative of the compound of the general formula [XII] and Vilsmeier reagent.

In addition, examples of the reactive derivative of the compound of the general formula [V] or [Ib] or a salt thereof include trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, Organic silyl groups such as dimethylmethoxysilanyl and dimethoxysilanediyl, or dimethoxyphosphinyl, 1,3,2-dioxophosphoran-2-yl, 4-methyl-1,3,2-dioxophosphorane -2-yl, 1,3,2-
Examples thereof include compounds in which an organic phosphorus group such as dioxophosphoryl-2-yl is bonded to an amino group which is a reaction site.

The solvent used in this reaction can be used without particular limitation as long as it is a solvent inert to the reaction, for example,
Water; ethers such as tetrahydrofuran, diethyl ether and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; nitriles such as acetettonitrile; alcohols such as methanol, ethanol and isopropanol; N, N-dimethyl Formamide, N, N-
Amides such as dimethylacetamide; aromatic hydrocarbons such as benzene and toluene; esters such as methyl acetate and ethyl acetate; ketones such as acetone; dimethyl sulfoxide; pyridine and the like. Two or more kinds of the above-mentioned solvents can be mixed and used.

Also, this reaction can be carried out in the presence of a base. Examples of the base used include pyridine, dimethylaminopyridine, triethylamine, dimethylaniline, diethylaniline, 1,8-diazabicyclo [5.4.0] undec-7
-Organic bases such as ene and sodium acetate; inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium carbonate.

When the compound of the general formula [XII] is used in the form of a salt with a free acid or a nitrogen-containing organic base, a suitable condensing agent is used. As such a condensing agent, for example, N, N'-disubstituted carbodiimide such as N, N'-dicyclohexylcarbodiimide is used.

The compound of the general formula [XII], a salt thereof or a reactive derivative thereof is used in an amount of 0.9 times or more the molar amount of the compound of the general formula [V] or [Ib], a salt thereof or a reactive derivative thereof, respectively. , Preferably 0.9 to 1.5 times the molar amount.

This reaction may be carried out usually at -50 to 80 ° C for 5 minutes to 30 hours.

(5) Quaternization By subjecting a compound of the general formula [Ic], [VI] or [VII] or a salt thereof to a quaternization reaction using a compound of the general formula [XIII] in the presence of a solvent, A compound of the general formula [Id], [VIII] or [IX] or a salt thereof can be obtained, respectively. Examples of the leaving group represented by Y include a halogen atom, a lower alkanesulfonyloxy group, and an arenesulfonyloxy group which may be substituted with a lower alkyl or a halogen atom.

The solvent used in this reaction can be used without particular limitation as long as it is a solvent inert to the reaction, for example,
Water; ethers such as tetrahydrofuran, diethyl ether, dioxane; halogenated hydrocarbons such as methylene chloride, chloroform; alcohols such as methanol, ethanol, isopropanol; N, N-dimethylformamide, N, N-dimethylacetamide, etc. Amides; aromatic hydrocarbons such as benzene and toluene; esters such as methyl acetate and ethyl acetate; dimethyl sulfoxide and the like. Two or more kinds of the above-mentioned solvents can be mixed and used.

The amount of the compound of the general formula [XIII] used is
The compound of [VI] or [VII], if any, is equimolar or more, preferably 1 to 10 mol per mol of the salt.

This reaction may be carried out usually at 0 to 100 ° C. for 30 minutes to 120 hours.

In each step described above, in the general formulas [Ia], [Ib],
[Ic], [Id], [II], [III], [IV], [V],
When isomers and the like exist in the compounds of [VI], [VII], [VIII] and [IX], they can be separated and purified by a usual method, and further, a protecting group is introduced by a usual method, Desorption and conversion into a salt can be performed.

Further, when the isomerization from the Δ ² form to the Δ ³ form is carried out without carrying out an acid and reduction reaction, it can be carried out by utilizing an equilibrium reaction. Specifically, the Δ ² form can be subjected to acylation in the presence of an organic solvent. By reacting with the same base as explained in the chemical reaction, Δ ³
Can be converted to the body.

Next, it is a raw material for producing the compound of the present invention. The compound of the general formula [X] or [XI] can be produced by a known method. Specifically, for example, Organic Reactions Volume 6,
Pp. 367-409 (1951), Chemical Abstracts, Vol. 48, 8923f (1955), Heterocyclic Compo
und) Volume 5 (1957) and the like, by the method of the general formula Y—CH ₂ R ^2a [wherein, R ^2a and Y have the same meaning as described above. ] The thiazole compound represented by [Wherein R ^8a , R ^8b and R ^8c have the same meaning as described above. ] The phosphorus compound represented by the formula: Organic Reactions (Organic Reactions) Vol. 14, 270-490 (196
Compounds of general formula [X] or [XI] can be obtained by reacting according to the method described in 5 years).

In addition, as a separate method for producing the compound [I] of the present invention, for example, JP-A-48-76888, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 20, 1082-1.
The method described on page 085 (1977) can be mentioned.

The compound of the general formula [I] or a salt thereof of the present invention can be orally or parenterally administered to humans and animals.

When administered to humans and animals, the dosage forms normally applied to penicillins and cephalosporins, for example,
It is prepared in the form of tablets, capsules, syrups, injections, suppositories, etc., and oral or parenteral administration methods are applied.

The dose is appropriately selected according to the symptoms of the patient, or is generally 1 mg to 400 mg / Kg / day in an adult (preferably about 2 mg
The dose of up to 100 mg / Kg / day) may be administered once to several times.

[Effects of the Invention] Next, the pharmacological effects of the representative compounds of the present invention will be described.

1. Antibacterial activity Regarding the minimum inhibitory concentration (MIC: μg / ml) against representative bacteria of Gram-positive and Gram-negative bacteria, the Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY Vol. 29,
No. 1, pp. 76-79 (1981)]. Heart infusion agar containing a drug containing bacterial solution cultured at 37 ° C for 20 hours in Peptone broth (Eiken Chemical Co., Ltd.)
After inoculating into a medium (manufactured by Eiken Chemical Co., Ltd.) and culturing at 37 ° C. for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). However, the inoculum size was 10 ⁴ cells / plate (10 ⁶ cells / ml).

The results are shown in Table-1.

Test compound 7- [2-2-aminothiazol-4-yl] -2-
(Z) -Methoxyiminoacetamide] -3- [2-
Inner salt of (1-methyl-4-pyridinio) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid [Examples] Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Isothionicotinamide (25 g) was added to a solution of 1,3-dichloroacetone (25.3 g) and ethanol (300 ml), and the mixture was refluxed for 8 hours.
React for hours. The solvent is distilled off under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water are added to the obtained residue. After adjusting the pH to 7.5 with a saturated aqueous sodium hydrogen carbonate solution, the insoluble matter is filtered off. Separate the organic layer, and add 50 ml of water and 50 ml of saturated saline.
After washing with ml sequentially, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under pressure, and the obtained residue was purified by column chromatography [alumina neutral, ART 1077, manufactured by Merck, eluent: 1% methanol-methylene chloride] to give a melting point of 117 to 119 ° C. 12.4 g (yield 32.3%) of 4-chloromethyl-2- (pyridin-4-yl) thiazole shown is obtained.

NMR (CDCl ₃ ) δ value; 4.72 (2H, s), 7.38 (1H, s), 7.75 (2H, d, J = 6Hz), 8.65
(2H, d, J = 6Hz) Reference Example 2 A mixed solution of 9.77 g of 4-chloromethyl-2- (pyridin-4-yl) thiazole, 12.18 g of triphenylphosphine and 100 ml of toluene is reacted under reflux for 20 hours. Then, the precipitated crystals were collected by filtration, washed with 30 ml of toluene, and dried to give [2- (pyridin-4-yl) thiazol-4-yl] methyltriphenylphosphonium having a melting point of 220 to 222 ° C. (decomposition). Obtained 17.71 g of chloride (80.7% utilization).

Example 1 [2- (Pyridin-4-yl) thiazol-4-yl] was added to a mixed solution of 3-hydroxy-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester 5 g, dioxane 50 ml and water 0.2 ml. ] 5 g of methyltriphenylphosphonium chloride and 890 mg of sodium hydrogencarbonate are added, and it is made to react at 80-90 degreeC for 10 hours. Further, [2- (pyridin-4-yl) thiazol-4-i] methyltriphenylphosphonium chloride (3 g) and sodium hydrogencarbonate (530 mg) are added, and the mixture is reacted at 90 ° C. for 8 hours.
Then, the reaction solution is added to a mixed solution of 150 ml of water and 100 ml of ethyl acetate, and the insoluble matter is filtered off. Separate the organic layer and wash with water 50
ml, and saturated saline 50 ml, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Kieselgel 6
0, ART 7734, manufactured by Merck & Co., Inc., eluent; toluene: ethyl acetate = 3: 1 (capacitance)] to give 7-phenylacetamido-3- [2- (pyridin-4-yl) thiazole-4. -Yl] methyl-2-cephem-4-carboxylic acid diphenylmethyl ester (Compound A) and 7-
Phenylacetamido-3- [2- (pyridin-4-yl) thiazol-4-yl] methyl-3-cephem-4
2.27 g (34.2% yield) of a mixture of carboxylic acid diphenylmethyl ester (Compound B) is obtained. The mixing ratio of this product was 7: 2 by NMR.

○ 7-phenylacetamide-3- [2- (pyridine-
4-yl) thiazol-4-yl] methyl-2-cephem-4-carboxylic acid diphenylmethyl ester (Compound A) IR (KBr) cm ^-1 ; νco 1770,1745,1660 NMR (CDCl ₃ ) δ value; 3.59 (4H, s), 5.15 (1H, d, J = 5Hz), 5.50 (1H, dd, J = 5H
z, J = 8Hz), 6.02 (1H, s), 6.65 (1H, d, J = 8Hz), 6.83
(1H, s), 6.90 (1H, s), 7.05 to 7.68 (18H, m), 8.55 (2
H, d, J = 4 Hz) 7-Phenylacetamide-3- [2- (pyridine-
4-yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester (Compound B) IR (KBr) cm ^-1 ; νco 1765,1720,1655 NMR (CDCl ₃ ) δ value; 3.50 (2H, s), 3.55 (2H, s) 3.88 (2H, s), 4.90 (1H, d, J
= 5Hz), 5.75 (1H, dd, J = 5Hz, J = 9Hz), 6.20 (1H, d, J =
9Hz), 6.87 (1H, s), 6.95 (1H, s), 7.18 (15H, s), 7.62
(2H, m), 8.57 (2H, m) Example 2 900 mg of the compound (mixture of compound A and compound B) obtained in Example 1 was dissolved in 8 ml of methylene chloride, and m-
Add 240 mg of chloroperbenzoic acid (80% purity), and add 1 at the same temperature.
Incubate for 5 minutes. Then, add 15 ml of methylene chloride to the reaction mixture.
Sodium hydrogen carbonate 40
Add mg. The organic layer was separated, 15 ml of water and saturated saline solution.
After sequentially washing with 15 ml, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Kieselgel 60, Art 7734, Merck, eluent; toluene: ethyl acetate = 1: 1 (volume ratio)]. 600 mg of 7-phenylacetamido-3- [2- (pyridin-4-yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide showing a melting point of 151-160 ° C.
(Yield 65.0%) is obtained.

IR (KBr) cm ^-1 ; νco 1775,1720,1670 Example 3 7-Phenylacetamide-3- [2- (viridin-4)
-Yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide 1.2 g was dissolved in N, N-dimethylformamide 5 ml,
A solution of 0.79 ml of phosphorus trichloride and 2 ml of methylene chloride was added dropwise at -30 ° C over 2 minutes, and the mixture was reacted at the same temperature for 10 minutes.
Then, the reaction solution is added to a mixed solution of 30 ml of ethyl acetate and 30 ml of water while maintaining a saturated aqueous solution of sodium hydrogen carbonate at pH 6 to 7. The organic layer is separated, washed twice with 10 ml each of water and successively with 10 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Kieselgel 60, ART 7734, manufactured by Merck & Co., eluent; toluene: ethyl acetate =
5: 1 (volume ratio)], 7-phenylacetamide-3- [2- (pyridine-4) having a melting point of 175 to 177 ° C.
-Yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester 730 mg (yield 62.4%) is obtained. IR and NMR of this product are shown in Example 1.
Compound B of

Example 4 7-Phenylacetamide-3- [2- (pyridine-4)
-Yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester 700 mg, pyridine 0.18 ml and methylene chloride 10 ml in a mixed solution at -30 ° C.
Then, 320 mg of phosphorus pentachloride is added, and the mixture is reacted at the same temperature for 15 minutes and further at -10 to -5 ° C for 1 hour. Next, 0.87 ml of methanol was added to this reaction solution at -30 ° C, the temperature was raised to 0 ° C over 15 minutes, and the reaction was carried out at the same temperature for 1 hour. Then, after adding 10 ml of diethyl ether and stirring for 15 minutes,
The precipitated crystals were collected by filtration, suspended in a mixed solution of 15 ml of methylene chloride and 15 ml of water, and the pH was adjusted to 8.0 with saturated aqueous sodium hydrogen carbonate solution.
Adjust to. The organic layer was separated, 10 ml of water and saturated saline
It is washed successively with 10 ml and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography- [Kieselgel 60, ART 7734, Merck, eluent: toluene; ethyl acetate = 2: 1 (volume ratio)]. 330 mg of 7-amino-3- [2- (pyridin-4-yl) thiayl-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester having a melting point of 130 to 132 ° C. (yield 57.9% ) Get.

IR (KBr) cm ^-1 ; νco 1750,1715 Example 5 7-Amino-3- [2- (pyridin-4-yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester 250 mg was dissolved in 5 ml anhydrous tetrahydrofuran, and 2- (Z) -methoxyimino-
2- (2-triphenylmethylaminothiazole-4-
Il) acetic acid (230 mg), 1-hydroxybenztriazole monohydrate (80 mg) and N, N'-dicyclohexylcarbodiimide (110 mg) are added, and the mixture is reacted at room temperature for 12 hours. Then, the precipitated crystals were collected by filtration, added to a mixed solution of 20 ml of ethyl acetate and 20 ml of water, and then adjusted to pH 7.
Adjust to 0. The organic layer is separated, washed successively with 10 ml of water and 10 ml of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Kieselgel 60, Art 7734, manufactured by Merck, eluent; toluene: ethyl acetate = 5: 1 (capacity)]. 7- [2- showing a melting point of 150-160 ° C
(Z) -Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamide] -3-
[2- (pyridin-4-yl) thiazol-4-yl]
Methyl-3-cephem-4-carboxylic acid diphenylmethyl ester 340 mg (yield 75.6%) is obtained.

IR (KBr) cm ^-1 ; νco 1770,1720,1670 Similarly, the following compound is obtained.

○ 7- (cis-2-chlorovinyl) thioacetamide-
3- [2-Pyridin-4-yl) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester IR (KBr) cm ^-1 ; νco 1765,1720,1650 Example 6 7- [ 2- (Z) -Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamido] -3- [2- (pyridin-4-yl) thiazole-
A solution of 4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester 340 mg, methyl iodide 0.11 ml and N, N-dimethylformamide 5 ml was added at room temperature to 12
React for hours. Then, the solvent is distilled off under reduced pressure, 5 ml of diethyl ether is added to the obtained residue, and the precipitate is collected by filtration. If washed twice with 1 ml of diethyl ether and dried, 7- [2- (Z)-showing a melting point of 173-176 ° C (decomposition).
Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamide] -3- [2-
380 mg (yield 97.4%) of (1-methyl-4-pyridinio) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester iodide is obtained.

IR (KBr) cm ⁻¹ ; νco 1770,1720,1655 NMR (d ₆ -DMSO) δ value; 3.66 (2H, s), 3.81 (3H, s), 4.00 (2H, s), 4.36 (3H,
s), 5.20 (1H, d, J = 5Hz), 5.69 (1H, dd, J = 5Hz, J = 8H
z), 6.70 (1H, s), 6.90 (1H, s), 7.28 (25H, s), 7.68
(1H, s), 8.42 (2H, d, J = 6Hz), 8.64 (1H, s), 8.93 (2
H, d, J = 6 Hz), 9.43 (1H, d, J = 8 Hz) Similarly, the following compound is obtained.

○ 7- (cis-2-chlorovinyl) thioacetamide-
3- [2- (1-Methyl-4-pyridinio) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester iodide IR (KBr) cm ^-1 ; νco 1760,1720,1670 -[2- (1-Methyl-4-pyridinio) thiazol-4-yl] methyl-7-phenylacetamide-3-
Cephem-4-carboxylic acid diphenylmethyl ester iodide Melting point; 178-180 ° C (decomposition) IR (KBr) cm ^-1 ; νco 1760,1720,1650 ○ 3- [2- (1-cyclopropylmethyl-4-pyridinio) ) Thiazol-4-yl] methyl-7-phenylacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester ruiodide Melting point; 149 to 150 ° C (decomposition) IR (KBr) cm ^-1 ; νc = o 1760, 1720,1650 Example 7 7- [2- (Z) -Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamido] -3- [2- (1-methyl-4-pyridinio) Thiazol-4-yl] methyl-3-cephem-4-carboxylic acid diphenylmethyl ester iodide (380 mg) is suspended in anisole (4 ml), trifluoroacetic acid (2 ml) is added under ice-cooling, and the mixture is reacted at room temperature for 1 hour. Then, the solvent is distilled off under reduced pressure, 5 ml of tetrahydrofuran and 5 ml of 50% formic acid are added to the obtained residue, and the mixture is reacted at 50 to 55 ° C. for 1 hour. The solvent was distilled off under reduced pressure, 5 ml of tetrahydrofuran and 5 ml of 50% formic acid were added to the obtained residue, and the mixture was stirred at 50-55 ° C for 1
React for hours. The solvent is distilled off under reduced pressure, and 5 ml of diethyl ether is added to the obtained residue. The precipitate is filtered off,
Suspend in 10 ml of water and 5 ml of ethyl acetate, adjust to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution and dissolve. The aqueous layer was separated, and the aqueous layer was concentrated under reduced pressure to about 5 ml, and then purified by column chromatography [LC-SORB40-60: Chemco Co., eluent; 10% acetonitrile aqueous solution] to give a melting point of 255.
7- [2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3- [2- (1-methyl-4-pyridinio)-, which exhibits a decomposition (decomposition) or higher.
130 mg (yield 65.0%) of an inner salt of thiazol-4-yl] methyl-3-cephem-4-carboxylic acid is obtained.

IR (KBr) m ^-1 ; νo 17501650,1620 NMR (d ₆ -DMSO + d ₁ -TFA) δ value; 3.67 (2H, s), 3.92 (3H, s), 4.08 (2H, s), 4.37 (3H,
s), 5.17 (1H, d, J = 5Hz), 5.73 (1H, dd, J = 5Hz, J = 8H
z), 6.89 (1H, s), 7.85 (1H, s), 8.50 (2H, d, J = 6Hz),
8.96 (2H, d, J = 6Hz), 9.60 (1H, d, J = 8Hz) Similarly, the following compound is obtained.

○ 7- (cis-2-chlorovinyl) thioacetamide-
Intramolecular salt of 3- [2- (1-methyl-4-pyridinio) thiazol-4-yl] methyl-3-cephem-4-carboxylic acid Melting point: 180 ° C or higher (decomposition) IR (KBr) cm ^-1 ; νco 1750,1650,1600 NMR (d ₆ -DMSO + d ₁ TFA) δ value; 3.53 (2H, s), 3.69 (2H, s), 4.09 (2H, s), 4.39 (3H,
s), 5.13 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5Hz, J = 8H
z), 6.30 (1H, d, J = 6Hz), 6.75 (1H, d, J = 6Hz), 7.85
(1H, s) 8.52 (2H, d, J = 6Hz), 8.97 (2H, d, J = 6Hz), 9.
73 (1H, d, J = 8Hz) 3- [2- (1-Methyl-4-pyridinio) thiazol-4-yl] methyl-7-phenylacetamide-3
-Cephem-4-carboxylic acid inner salt Melting point: 185 to 190 ° C (decomposition) IR (KBr) cm ^-1 ; νc = o 1750, 1650, 1590 NMR (d ₆ -DMSO) δ value; 3.49 (4H, s), 3.93 (2H, s), 4.30 (3H, s), 4.85 (1H, d,
J = 5Hz), 5.36 (1H, dd, J = 5Hz), J = 8Hz), 7.18 (5H,
s), 7.83 (1H, s), 8.39 (2H, m), 8.72 to 9.05 (3H, m) 3- [2- (1-cyclopropylmethyl-4-pyridinio) thiazol-4-yl] methyl- Intramolecular salt of 7-phenylacetamido-3-cephem-4-carboxylic acid Melting point: 185 to 190 ° C. (decomposition) IR (KBr) cm ⁻¹ ; νc = o 1750,1650 (sh), 1580 NMR (d ₆ − DMSO + d ₁ -TFA) δ value; 0.65 (4H, m), 1.41 (1H, m), 3.55 (2H, s), 3.68 (2H ,,
s), 4.07 (2H, s), 4.54 (2H, d, J = 8Hz), 5.08 (1H, d, J
= 5Hz), 5.63 (1H, dd, J = 5Hz, J = 8Hz), 7.23 (5H, s),
7.85 (1H, s), 8.55 (2H, d, J = 6Hz), 8.95 (1H, d, J = 8H
z), 9.07 (2H, d, J = 6Hz)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display location // A61K 31/545 ADZ 7431-4C (72) Inventor Isamu Isakawa 7 Oizumi Nakamachi, Toyama City, Toyama Prefecture −52 Examiner Masato Ikeda

Claims (1)

[Claims] 1. A general formula [Wherein R ¹ is a hydrogen atom, an amino-protecting group or an acyl group, R ² is an optionally substituted thiazolyl group which forms a carbon-carbon bond with the 3-position exomethylene group, and R ³ is optionally protected. It represents a good carboxyl group or carboxylato group. ] Cephalosporins and its salt represented by these.