JPH05262778A - New cephalosporin derivative and its salt - Google Patents

Abstract

PURPOSE:To provide the ' compound having a wide antibacterial spectrum range and especially exhibiting an antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. CONSTITUTION:A derivative of formula I (R<1> is (protected)amino; R<2> is (alkyl(substituted with halogen); R<3> is (protected)carboxyl. carboxylate; R<4> is H, (protected)amino; group of formula II is sym- or anti-isomer, etc.; n is 0.1) and its salt. For example, 3-(3-formylamino-7-thieno[2,3-b]pyridinio)methyl-7-[(Z)-2 methoximino-2-(2-triphenylmethylamino-1,2,4-thiadiazol-3-yl)acetoamido l-3- cephem-4-carboxylate iodide. For example, The compound of formula I is obtained by reacting a compound of formula III with a compound of formula IV in the presence or absence of a base or in the presence or absence of sodium iodide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to novel cephalosporin derivatives and salts thereof, more specifically, general formula [1]

[Chemical 2] [In the formula, R ¹ represents an amino group which may be protected; R ²
Is an alkyl group optionally substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylato group; R ⁴ is an optionally protected amino group;

[Outside 2] Represents a syn or anti isomer or a mixture thereof; and n represents 0 or 1, respectively. The present invention relates to a cephalosporin derivative and a salt thereof. The object of the present invention is to have a broad spectrum antibacterial spectrum,
In particular, it is to provide a novel compound which exhibits a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and has low toxicity and is useful as a medicine for humans and animals.

[0002]

2. Description of the Related Art Conventionally, various cephalosporin antibiotics have been developed which exert a strong antibacterial activity and have a broad antibacterial spectrum. However, no compound is known that exhibits a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus.

[0003]

Under these circumstances, development of cephalosporin derivatives having a broad antibacterial spectrum and particularly having strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus has been sought. Was desired by. [Reference: MRSA, Keizo Matsumoto, Pharmaceutical Journal]
(Issue 1991)]

[0004]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have earnestly studied a cephalosporin derivative, and as a result, the 3rd-position exomethylene group of the cephem ring was
The novel cephalosporin derivative represented by the general formula [1] to which a thieno [2,3-b] pyridinio group having a substituent is bonded and a salt thereof have strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. The present invention has been completed and the present invention has been completed.

The present invention will be described in detail below. In the present specification, unless otherwise specified, the alkyl group is, for example, methyl, ethyl, propyl, isopropyl or n-.
Butyl, sec- butyl, isobutyl, tert- butyl, pentyl, hexyl, heptyl, octyl, nonyl, straight-chain or branched C ₁ ~ ₁₂ alkyl groups such as decyl or undecyl; lower alkylsulfonyloxy The group is lower alkyl-SO _3- , arylsulfonyloxy is phenylsulfonyloxy, p-methylphenylsulfonyloxy, naphthylsulfonyloxy group, and acyloxy group is, for example, formyloxy group, acetyloxy or propionyl. C ₂ ~ ₅ alkanoyloxy group such as oxy, heterocyclic carbonyloxy group such as an aryl carbonyl group or Furoiruokishi groups such as benzoyloxy; the halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom , Respectively.

The compound of the general formula [1] will be described in detail below. The protecting group for the protected amino group in R ¹ and R ⁴ and the protecting group for the optionally protected carboxyl group in R ³ include amino protecting groups conventionally known in the field of cephem compounds and Carboxyl protecting groups are mentioned, and specifically, Protective Groups in Organic Synthesis [Protecti
ve Groups in Organic Synthesis Theodora W. Green, (1981)
John Wiley & S
ons, Inc.)] and each protecting group described in JP-B-60-52755 and the like. In addition, as the salt of the compound of the general formula [1], a salt or inner salt in a generally known basic group such as amino group or acidic group such as carboxyl group can be mentioned. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid; salts with organic carboxylic acids such as formic acid, trichloroacetic acid or trifluoroacetic acid. Methanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalene-2-sulfonic acid or naphthalene-1,5-
A salt with a sulfonic acid such as disulfonic acid; or a salt with an acidic amino acid such as glutamic acid or aspartic acid, and a salt with an acidic group, for example, a salt with an alkali metal such as sodium or potassium; calcium. Or salts with alkaline earth metals such as magnesium; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine,
Examples thereof include salts with nitrogen-containing organic bases such as N, N-dimethylaniline, N-methylpiperidine or N-methylmorpholine; or salts with basic amino acids such as lysine or arginine. Furthermore, in the case where the compound of the general formula [1] has an intramolecular thienopyridinium group and an onium group in addition to this, the onium group usually forms an inner salt with the carboxylato group in R ³ described above. It may be formed, and a salt may be formed with a halogen anion, a lower alkylsulfonyloxy anion, or an arylsulfonyloxy anion optionally substituted with a lower alkyl group or a halogen atom. In addition, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist in the compound of the general formula [1] and salts thereof, the present invention includes all isomers thereof. It also includes all hydrates, solvates and various crystalline forms.

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be synthesized, for example, according to the following production route.

[Formula 1]

[Formula 2]

[Formula 3] "In the formula, R ¹ , R ² , R ³ , R ⁴ ,

[Outside 3] And n each have the same meaning as defined above;
R ^3a represents an optionally protected carboxyl group similar to R ³ ; R ⁵ represents a hydrogen atom or an amino protecting group; and X represents a leaving group. Examples of the amino protecting group for R ⁵ include the same amino protecting group as described for R ¹ . Furthermore, general formulas [1a], [1b], [2],
Examples of the salt of the compound of [3], [4], [5] and [6] include the same salts as those described as the salt of the compound of the general formula [1]. Furthermore, as the leaving group of X,
Examples thereof include an acyloxy group, a carbamoyloxy group, a halogen atom, a lower alkylsulfonyloxy group and an arylsulfonyloxy group.

Examples of the reactive derivative of the compound of the general formula [4] or a salt thereof include, for example, trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilan. An organosilyl group such as nyl or dimethoxysilanediyl or dimethoxyphosphinyl, 1,3,2-dioxophosphoran-2-yl, 4-methyl-1,3,2-dioxophosphorane-2
-Yl or 1,3,2-dioxophosphorinane-2
Examples thereof include compounds in which an organic phosphorus group such as -yl is bonded to an amino group which is a reaction site.

Examples of the reactive derivative of the compound of the general formula [5] or a salt thereof include acid halides, acid anhydrides, mixed acid anhydrides and active acids described in JP-A-59-93085. Examples thereof include amides, active esters, active thioloesters or acid azides, or reactive derivatives of the compound of the general formula [5] with Vilsmeier reagent.

Next, the method for producing the compound of the general formula [1] or a salt thereof will be described in more detail according to the above-mentioned production route. Production Method 1 A compound of the general formula [2] or a salt thereof, in the presence or absence of a base or in the presence or absence of sodium iodide or potassium iodide, a compound of the general formula [3] or a salt thereof. By reacting, the compound of the general formula [1] or a salt thereof can be obtained. Specifically, the compound of the general formula [2] in which the leaving group X is an acyloxy group or a carbamoyloxy group, or a salt thereof is prepared, for example, from Japanese Patent Publication Nos. 39-17936, 46-13023 and 49-45880. And JP-A-48-10077 and 48-68593.
No. 49, No. 49-295, No. 49-5987, No. 49-24992, No. 51-95
088, 55-9048, 56-92290 and The Journal of Organic Chemistry [J. Org. Che
m] The compound of the general formula [1] or a salt thereof can be obtained by subjecting it to the method described in [32], page 500 to 501 (1967), or the like. In addition, a compound of the general formula [2], in which the leaving group X is a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, or a salt thereof is reacted with a compound represented by the general formula in the presence or absence of a base or a deoxidizing agent. The compound of general formula [1] or a salt thereof can be obtained by reacting with the compound of [3] or a salt thereof. Furthermore, a compound of the general formula [2] or a salt thereof, in which the leaving group X is an iodine atom, can be prepared, for example, by tetrahedron letters [Tetrahed
Ron Letters] Vol. 22, pp. 3915-3918 (1981) and U.S. Pat. No. 4,336,253, or a method analogous thereto, to obtain a compound of the general formula [1] or a salt thereof. You can The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include water; ethers such as tetrahydrofuran, diethyl ether and dioxane; halogenated carbonization such as methylene chloride and chloroform. Hydrogens; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; aromatic hydrocarbons such as benzene and toluene; esters such as ethyl acetate and butyl acetate; Ketones such as acetone and methyl ethyl ketone; organic carboxylic acids such as formic acid and acetic acid; dimethyl sulfoxide; 1,3-
Examples thereof include dimethylimidazolidinone; hexamethylphosphoric triamide; and nitriles such as acetonitrile and propionitrile. These solvents may be used alone or in combination of two or more. Examples of the base optionally used in this reaction include alkali hydroxide, alkali hydrogen carbonate, dimethylaminopyridine,
2,6-lutidine, tetramethylguanidine, lithium bistrimethylsilylamide, lithium hexamethyldisilylamide, sodium hydride, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4 .3.0] -5-nonene or methylmagnesium bromide. In addition, examples of the deoxidizing agent used as necessary include molecular sieves and propylene oxide.
The amount of the compound of the general formula [3] or a salt thereof used is 1-fold mol or more with respect to the compound of the general formula [2] or a salt thereof. The amount of the base or deoxidizing agent used, if necessary, is 0.5 to 2 times or 1 times or more the mol of the compound of the general formula [2] or a salt thereof, respectively. Furthermore, the amount of sodium iodide or potassium iodide used as needed is 1-fold or more the molar amount of the compound of the general formula [2] or a salt thereof. Also,
The reaction temperature and the reaction time are not particularly limited, but usually, it may be carried out at -20 ° C to 100 ° C for 5 minutes to 50 hours.

Production Method 2 A compound of the general formula [4] or a salt thereof or a reactive derivative thereof is reacted with a compound of the general formula [5] or a salt thereof or a reactive derivative thereof in the presence or absence of a base. By reacting, the compound of the general formula [1] or a salt thereof can be obtained. Examples of the solvent used in this reaction include the same solvents as described in Production method 1. Examples of the base optionally used in this reaction include sodium acetate, sodium methoxide, potassium tert-butoxide, triethylamine, and the like.
Diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine, N, N-dimethylaniline, N, N-diethylaniline, dicyclohexylamine, 2,6-lutidine, tetramethylguanidine, lithium diisopropylamide, lithium bistrimethylsilylamide, Lithium hexamethyldisilylamide, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5
-Organic bases such as nonene; inorganic bases such as sodium hydride, alkali hydroxide, alkali carbonate or alkali hydrogen carbonate. General formula [5]
To use the compound in the form of free acid or its salt,
Use a suitable condensing agent. Examples of such condensing agents include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide.
The compound of the general formula [5] or a salt thereof or a reactive derivative thereof is used in an amount of 0.9 times or more, preferably 0.9 times or more the molar amount of the compound of the general formula [4] or a salt thereof or a reactive derivative thereof. ~ 1.5 times the molar amount. Also,
The reaction temperature and the reaction time are not particularly limited, but usually, it may be carried out at -50 to 80 ° C for 5 minutes to 30 hours.

Production Method 3 (1) Isomerization The compound of the general formula [1b] or a salt thereof can be obtained by reacting the compound of the general formula [6] or a salt thereof with a base. This reaction is, for example, the Journal of the American Chemical Society [J.
Amer. Chem. Soc.] 88, 852-853 (1966)
It can be carried out by the method described in 1) or a method similar thereto. (2) Oxidation / Reduction Alternatively, the compound of the general formula [1a] can be obtained by subjecting the compound of the general formula [6] or a salt thereof to an oxidation reaction usually used in the field of conventional cephem compounds. Alternatively, the compound of the general formula [1a] or its salt is subjected to a reduction reaction usually used in the field of conventional cephem compounds to give a compound of the general formula [1
It is also possible to obtain the compound of b] or a salt thereof. These oxidation / reduction reactions are described, for example, in The Journal of Organic Chemistry [J.Org. Chem] No. 35.
Vol. 2430-2433 (1970), Journal of the Chemical Society [J. Chem. Soc. (C)] 114.
It can be carried out by the method described on pages 2 to 1151 (1966) and JP-A-52-48683 or a method analogous thereto.

A compound of the general formula [4] or [5] or a salt thereof or a reactive derivative thereof; and a compound of the general formula [2], [6] or the general formula [3] in the above-mentioned production method. In the case where isomers (for example, optical isomers, geometrical isomers, tautomers, etc.) exist in the salt, all these isomers can be used, and all hydrates, solvents Japanese hydrates and various crystal forms can be used. The compound of the general formula [1] or a salt thereof of the present invention thus obtained is
It can be isolated and purified by a conventional method such as extraction, crystallization and column chromatography.

Next, a method for producing the compound of the general formula [3] or a salt thereof, which is a raw material for producing the compound of the present invention; and the method of producing the compound of the general formula [4] or a salt thereof will be described. (A). The compound of the general formula [3] or a salt thereof, which is the starting material compound in Production Method 1, can be produced by a known method or a method analogous thereto, and specifically, for example, Advanced・ Heterocyclic Chemistry [Adv. Heterocyclic Chem.] No. 21
Volumes, pp. 65-117 (1977) can be derived into various derivatives by reference to the review article by John M. Barker. 3-aminothieno [2,3-b]
Pyridine derivatives are available in Journal Heterocyclic
Chemistry [J. Heterocyclic Chem.] Vol. 11, 975
~ 977 (1974), ibid, 21st, 587-589 (1984)
, Pp. 85-89 (1987), Journal Practice Chemie [J. Prakt. Chem.] No. 316
Page, pages 1030 to 1036 (1974), Pharmaco Eddie
Science [Farmaco. Ed. Sci.] Section 31, pages 21-30 (1976), The Journal of Organic Chemistry [J. Org. Chem.] Section 46, pages 4179-4182 ( 1981), Journal of Medicinal Chemistry [J. Med. Chem.] No. 27, 1639-1643 (198).
4 years) and German Patent No. 2241717 or the like or a method similar thereto. In addition to the reactions described in these documents,
A usual substitution reaction, an acylation reaction, a reaction for introducing an amino-protecting group, and the like can be applied to induce a raw material compound for other purposes. (B). The compounds of the general formulas [4] and [6] and the salts thereof, which are the raw material compounds in the production methods 2 and 3, may be produced by combining the production method 1 and a method known per se. it can. The compound of the general formula [4] or a salt thereof can be produced according to the following production route.

[Formula 4] "In the formula, R ³ , R ⁵ , X and n each have the same meaning as described above."

In the above-described method for producing the compound of the present invention and the method for producing the starting compound, when an active group such as an amino group and a carboxyl group is present in addition to the reaction site,
These groups may be protected in advance by a conventional method and, after the reaction, may be eliminated by a conventional method. After the completion of the reaction, the target product of the reaction can be directly used in the next reaction without isolation, or may be isolated and purified by a usual method such as recrystallization or column separation.

When the compound of the present invention is used as a medicine, excipients usually used for formulation, usual pharmaceutical carriers, and formulation auxiliary agents such as diluents may be appropriately mixed. In accordance with, tablets, soft or hard capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, ointments or subcutaneous, muscle,
It can be orally or parenterally administered in a form such as an intravenous or infusion solution. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the age, weight and symptoms of the patient, and usually for adults, oral or parenteral (for example, injection, infusion or rectal site). , Etc.) 0.1 to 100 mg / kg daily
May be administered once or in several divided doses.

Next, the antibacterial action of the representative compounds of the present invention will be explained. Test Method Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY]
Vol. 29, No. 1, pp. 76-79 (1981)], the test strains cultured overnight in a growth medium were adjusted to 10 ⁶ cells / ml, 1 platinum loop of which contained a drug-containing heart. Infusion
Agar (Heart Infusion agar) medium (manufactured by Eiken Chemical Co., Ltd.) was inoculated and incubated at 37 ° C for 20 hours, and then the presence or absence of bacterial growth was observed, and the MIC (μg / μg / μg / μg /
ml). The results are shown in Tables 1 and 2. The symbols in Table 1 have the following meanings. *: Β-lactamase-producing bacteria **: Methicillin-resistant Staphylococcus aureus

Test Compounds: The example numbers were cited and cited. Control compound Compound A: 7- [2- (2-aminothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- (2-amino-5-thieno [3,2-c] pyridinio) methyl-3-cephem-4-carboxylate Compound B: 7- [2- (2-aminothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- (2-methyl-5-thieno [3,2-c] pyridinio) methyl-3-cephem-4-carboxylate (hereinafter blank)

[0019]

[Table 1] (Below margin)

[0020]

[Table 2]

From the above test results, it can be easily understood that the compound of the general formula [1] of the present invention or a salt thereof exhibits an excellent antibacterial action.

[0022]

Therefore, it is clear that the compounds of the present invention are extremely useful compounds as antibacterial agents.

[0023]

EXAMPLES Next, the production method of the compound of the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The carrier used in reverse phase column chromatography is LC-SORB SP-B-ODS 100G.
(Manufactured by Chemco) was used. The abbreviations used below have the following meanings. Me; Methyl group, Et; Ethyl group, Tr; Triphenylmethyl group; Boc; tert-Butoxycarbonyl group Further, the IR wave number indicates carbonyl absorption.

Reference Example 1 5 g of 3-aminothieno [2,3-b] pyridine was added to N, N-
Dissolve in 20 ml of dimethylformamide and add di-tert.
-Add 10 g of butyl dicarbonate and stir at room temperature for 6 hours. 100 ml of water and 100 ml of ethyl acetate were added to the reaction mixture, and the pH was adjusted to 7.0 with a saturated aqueous sodium hydrogen carbonate solution,
Separate the organic layer. The separated organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 50 ml of diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain 6.5 g of 3-tert-butoxycarbonylaminothieno [2,3-b] pyridine having a melting point of 152 to 154 ° C. IR (KBr) cm ^-1 ; 1715 NMR (CDCl ₃ ) δ value; 1.56 (9H, s), 6.90 (1H, bs), 7.33 (1
H, dd, J = 5Hz, J = 8Hz), 7.98 (1H, dd, J = 1Hz, J = 8Hz), 8.65
(1H, dd, J = 1Hz, J = 5Hz)

Using allyloxycarbonyl chloride instead of di-tert-butyl dicarbonate, the following compounds are obtained in the same manner as above. 3-allyloxycarbonylaminothieno [2,3-
b] Pyridine IR (KBr) cm ^-1 ; 1730 NMR (CDCl ₃ ) δ value; 4.72 (2H, d, J = 6Hz), 5.17-5.50 (2H, m), 5.
80-6.20 (1H, m), 7.05 (1H, bs), 7.30 (1H, dd, J = 5Hz, J = 8Hz),
7.64 (1H, s), 7.91 (1H, dd, J = 2Hz, J = 8Hz), 8.60 (1H, dd, J = 2H
(z, J = 5Hz)

Example 1 p-Methoxybenzyl = 3-iodomethyl-7-[(Z)
2-Methoxyimino-2- (5-triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate 1.0
g, 3-formylaminothieno [2,3-b] pyridine
A mixed solution of 0.34 g and 5 ml of N, N-dimethylformamide is stirred at room temperature for 6 hours. 50 ml of diisopropyl ether was added to the reaction mixture, an oily substance was separated by decantation, 30 ml of diethyl ether was added, and the precipitate was collected by filtration and dried under reduced pressure to obtain p-methoxybenzyl = 3-
(3-Formylamino-7-thieno [2,3-b] pyridinio) methyl-7-[(Z) -2-methoxyimino-
1.05 g of 2- (5-triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate iodide are obtained. IR (KBr) cm ^-1 ; 1790,1720,1660

Example 2 (1) p-Methoxybenzyl = 7- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z)
2-methoxyiminoacetamido] -3-iodomethyl-3-cephem-4-carboxylate 1-oxide 1.0 g, 3-formylaminothieno [2,3-b] pyridine 0.4 g and N, N-dimethylformamide 5 ml The mixed solution is stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 ml of diisopropyl ether, the oily precipitate was collected, 50 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hr.
If the precipitate is collected by filtration, p-methoxybenzyl = 7- [2
-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamide] -3
1.4 g of-(3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 1-oxide iodide are obtained. IR (KBr) cm ^-1 ; 1800,1725,1685

(2) p-methoxybenzyl = 7- [2
-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamide] -3
A solution of 0.2 g of-(3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 1-oxide iodide and 1 ml of N, N-dimethylformamide at -35 ° C. 0.1 ml of phosphorus trichloride
Then, a solution of 0.5 ml of methylene chloride is added dropwise, and the mixture is stirred at the same temperature for 90 minutes. The reaction mixture is poured into a mixed solution of 10 ml of methylene chloride and 10 ml of water containing 50 mg of potassium iodide under ice cooling while maintaining the pH at 2.0 with a saturated aqueous solution of sodium hydrogen carbonate. The precipitate was collected by filtration, washed successively with 5 ml of water and 5 ml of methylene chloride and dried to give p-methoxybenzyl = 7- [2- (5-amino-1,2,4-thiadiazol-3-yl)- (Z) -2-Methoxyiminoacetamido] -3- (3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4
-0.13 g of carboxylate iodide is obtained. IR (KBr) cm ^-1 ; 1785,1720,1685

Examples 3 to 6 In the same manner as in Examples 1 and 2, the compounds in Table 3 are obtained.
In addition, R ¹ , R ² and R ⁴ in Table 3 are respectively
The formula

[Chemical 3] The substituents of the compound represented by are shown below.

[0030]

[Table 3]

Example 7 (1) p-Methoxybenzyl = 3- (3-formylamino-7-thieno [2,3-b] pyridinio) methyl-7
-[(Z) -2-methoxyimino-2- (5-triphenylmethylamino-1,2,4-thiadiazole-3-
(Il) acetamide] -3-cephem-4-carboxylate 5.5 g of iodide was suspended in 55 ml of anisole, 55 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 1 hour. .. Then, concentrated hydrochloric acid 1.
Add 3 ml and stir for another hour. The solvent was distilled off under reduced pressure, 30 ml of diethyl ether was added to the obtained residue,
The precipitate is collected by filtration. This was suspended in 30 ml of water, adjusted to pH 7.0 with a saturated aqueous sodium hydrogen carbonate solution, and then subjected to reverse phase column chromatography (eluent: 5% aqueous acetonitrile).
Purified by 7- [2- (5-amino-1,2,4-
Thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3- (3-formylamino-7-
1.8 g of thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; 1765,1670,1615 NMR (CD ₃ CN-D ₂ O) δ value; 3.00-3.40 (2H, m), 3.98 (3H, s), 5.15
(1H, d, J = 5Hz), 5.67 (2H, s), 5.80 (1H, d, J = 5Hz), 7.95-8.50
(3H, m), 8.80-9.13 (2H, m)

(2) 7- [2- (5-amino-1,
2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3- (3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3
-Cephem-4-carboxylate 100 mg methanol 1
It is suspended in ml, 0.034 ml of methanesulfonic acid is added at room temperature, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture was diluted with 3 ml of water, adjusted to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution, and purified by reverse phase column chromatography (eluent: 5% acetonitrile water) to give 7- [2- (5- Amino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Methoxyiminoacetamido] -3- (3-amino-7-thieno [2,3-b] pyridinio) methyl-3-
70 mg of cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; 1770,1665,1615 NMR (CD ₃ CN-D ₂ O) δ value; 3.20 (1H, d, J = 18Hz), 3.33 (1H, d, J = 1
8Hz), 4.00 (3H, s), 5.15 (1H, d, J = 5Hz), 5.62 (2H, s), 5.78 (1
H, d, J = 5Hz), 6.78 (1H, s), 7.92 (1H, dd, J = 8Hz, J = 5Hz), 8.67
-8.98 (2H, m)

Example 8 p-Methoxybenzyl = 3- (3-tert-butoxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7-[(Z) -2-methoxyimino-2- (5-
Triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate Iodide was reacted in the same manner as in Example 7 to give 7- [2- (5-amino -1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3- (3-amino-7-thieno [2,3-
b] Pyridinio) methyl-3-cephem-4-carboxylate is obtained. The physical properties of this compound were consistent with those of the compound obtained in Example 7.

Example 9 (1) p-Methoxybenzyl = 3- (3-allyloxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7-[(Z) -2-methoxyimino- 2-
(5-Triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-
4-Carboxylate Iodide was reacted in the same manner as in Example 7 to give 3- (3-allyloxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7-.
[2- (5-amino-1,2,4-thiadiazole-3
-Yl)-(Z) -2-methoxyiminoacetamide]
-3-Cephem-4-carboxylate is obtained. IR (KBr) cm ^-1 ; 1775,1720,1670,1615

(2) 3- (3-allyloxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7- [2- (5-amino-1,2,4-thiadiazole-3-) 80 mg of (yl)-(Z) -2-methoxyiminoacetamide] -3-cephem-4-carboxylate
Was dissolved in a mixed solvent of 2.1 ml of acetonitrile and 0.9 ml of water and tetrakis (triphenylphosphine) was added at room temperature.
Palladium (0) 10 mg and triphenylphosphine 10 mg are sequentially added, and the mixture is stirred at the same temperature for 8 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to reverse phase column chromatography (eluent: 5% aqueous acetonitrile).
Purified by 7- [2- (5-amino-1,2,4-
Thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3- (3-amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4
30 mg of carboxylate are obtained. The physical properties of this compound are
It was in agreement with the physical properties of the compound obtained in Example 7.

Examples 10 to 12 In the same manner as in Examples 7 to 9, the compounds in Table 4 are obtained. Incidentally, R ² and R ⁴ in Table 4, respectively, of the following formula

[Chemical 4] The substituents of the compound represented by are shown below.

[0037]

[Table 4]

Further, the NMR data of the compounds in Examples 10 to 12 in the table are described below. (Compound of Example 10) NMR (CD ₃ CN-D ₂ O) δ value; 3.20 (1H, d, J = 17Hz), 3.40 (1H, d, J = 1)
7Hz), 5.15 (1H, d, J = 5Hz), 5.32 (1H, s), 5.70 (2H, s), 5.80 (1
H, d, J = 5Hz), 6.22 (1H, s), 7.90-8.25 (2H, m), 8.45 (1H, s),
8.80-9.08 (2H, m) (Compound of Example 11) NMR (CD ₃ CN-D ₂ O) δ value; 3.15 (1H, d, J = 16Hz), 3.32 (1H, d, J = 1)
6Hz), 5.15 (1H, d, J = 5Hz), 5.31 (1H, s), 5.62 (2H, s), 5.80 (1
H, d, J = 5Hz), 6.20 (1H, s), 6.77 (1H, s), 7.80-8.04 (1H, m),
8.65-8.95 (2H, m) (Compound of Example 12) NMR (CD ₃ CN-D ₂ O) δ value; 1.27 (3H, t, J = 7Hz), 3.20 (1H, d, J = 16)
Hz), 3.33 (1H, d, J = 16Hz), 4.20 (2H, q, J = 7Hz), 5.15 (1H, d, J
= 5Hz), 5.62 (2H, s), 5.78 (1H, d, J = 5Hz), 6.78 (1H, s), 7.92
(1H, dd, J = 5Hz, J = 8Hz), 8.67-8.97 (2H, m)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuya Hayashi 2764-4 Sumiyoshi-san, Uozu-shi, Toyama Prefecture (72) Inventor Hiroshi Kanna 1367-4 Tezaki, Kosugi Town, Imizu-gun, Toyama Prefecture (72) Inventor Kenji Yonezawa 4728 Nakada, Takaoka City, Toyama Prefecture 72 72 Inventor Shinzaburo Minami 627 Tabata, Toyama City, Toyama Prefecture 72 (72) Inventor Yasuo Watanabe 1 247, Machimura, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents an amino group which may be protected; R ²
Is an alkyl group which may be substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylato group; R ⁴ is an optionally protected amino group; ] Represents a syn or anti isomer or a mixture thereof; and n represents 0 or 1, respectively. The cephalosporin derivative and its salt represented by these.