JP3140525B2 - Novel cephalosporin derivatives and their salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephalosporin derivative and a salt thereof, and more particularly, to a compound represented by the general formula

Embedded image "In the formula, R ^1, protected or unprotected amino group; R ²
Is an alkyl group optionally substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylate 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. And a salt thereof. The object of the present invention is to have a broad antibacterial spectrum,
In particular, it is an object of the present invention 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 pharmaceutical for humans and animals.

[0002]

2. Description of the Related Art Various cephalosporin antibiotics exhibiting a strong antibacterial activity and having a wide antibacterial spectrum have been developed. However, there is no known compound that exhibits a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus.

[0003]

Under such circumstances, development of a cephalosporin derivative having a broad antibacterial spectrum and particularly having a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus has been desired. Was desired. [Ref: MRSA Keizo Matsumoto Pharmaceutical Journal
(Issued in 1991)]

[0004]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies on cephalosporin derivatives, and as a result, have found that
A novel cephalosporin derivative represented by the general formula [1] to which a thieno [2,3-b] pyridinio group having a substituent binds and a salt thereof have a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. They have found that the present invention has been completed.

Hereinafter, the present invention will be described in detail. In the present specification, unless otherwise specified, an alkyl group means, for example, methyl, ethyl, propyl, isopropyl, 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 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.

Hereinafter, the compound represented by formula (1) will be described in detail. Examples of the protecting group for the protected amino group in R ¹ and R ⁴ and the protecting group for the carboxyl group which may be protected in R ³ include amino protecting groups conventionally known in the field of cephem compounds. Carboxyl protecting groups; specifically, Protective Groups in Organic Synthesis [Protecti
ve Groups in Organic Synthesis Theodora. W. Green (1981)
John Wiley & Sons
ons, Inc.)] and JP-B-60-52755. Examples of the salt of the compound represented by the general formula [1] include a commonly known salt or an inner salt in a basic group such as an amino group or an acidic group such as a carboxyl group. As the salt in the basic group, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid; a salt with an organic carboxylic acid 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-
Salts with sulfonic acids such as disulfonic acid; salts with acidic amino acids such as glutamic acid or aspartic acid; and salts in the acidic group, for example, salts with alkali metals such as sodium or potassium; calcium Or salts with alkaline earth metals such as magnesium; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine,
Salts with a nitrogen-containing organic base such as N, N-dimethylaniline, N-methylpiperidine or N-methylmorpholine; and salts with a basic amino acid such as lysine or arginine. Furthermore, when the compound of the general formula [1] has a thienopyridinium group in the molecule and an onium group in addition to the above, the onium group is usually formed by combining the above-mentioned carboxylate group in R ³ with the inner salt. And may form a salt with a halogen anion, a lower alkylsulfonyloxy anion, or an arylsulfonyloxy anion which may be substituted with a lower alkyl group or a halogen atom. When isomers (eg, optical isomers, geometric isomers, tautomers, and the like) exist in the compound of the general formula [1] and salts thereof, the present invention includes all such isomers. And also encompasses all hydrates, solvates and various crystal 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.

(Equation 1)

(Equation 2)

(Equation 3) Wherein R ¹ , R ² , R ³ , R ⁴ ,

[Outside 3] And n each have the same meaning as described above;
R ^3a represents a carboxyl group which may be protected as in 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 groups as described for R ¹ . Furthermore, the general formulas [1a], [1b], [2],
Examples of the salt of the compound of [3], [4], [5] and [6] include the same salts as described as the salt of the compound of general formula [1]. Furthermore, as the leaving group for X,
Examples include an acyloxy group, a carbamoyloxy group, a halogen atom, a lower alkylsulfonyloxy group, and an arylsulfonyloxy group.

The reactive derivative of the compound of the formula [4] or a salt thereof includes, for example, trimethylsilanyl, dimethylsilanediyl, isopropyldimethylsilanyl, trimethoxysilanyl, dimethoxymethylsilanyl, dimethylmethoxysilanyl. Organic silyl groups 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
And compounds in which an organic phosphorus group such as yl is bonded to an amino group which is a reaction site.

The reactive derivative of the compound of the general formula [5] or a salt thereof includes, for example, acid halides, acid anhydrides, mixed acid anhydrides and active acids described in JP-A-59-93085. Examples include amides, active esters, active thioloesters or acid azides, or reactive derivatives of the compound of the general formula [5] with the 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 is combined with a compound of the general formula [3] or a salt thereof in the presence or absence of a base or in the presence or absence of sodium iodide or potassium iodide. By reacting, a compound of the general formula [1] or a salt thereof can be obtained. Specifically, the compound of the general formula [2] or a salt thereof, wherein the leaving group X is an acyloxy group or a carbamoyloxy group, can be prepared by, for example, using JP-B-39-17936, JP-B-46-13023 and JP-A-49-45880. No .; and JP-A-48-10077 and JP-A-48-68593.
Nos. 49-295, 49-5987, 49-24992, 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 the method described in Vol. 32, pp. 500-501 (1967) or a method analogous thereto. The compound of the general formula [2] or a salt thereof in which the leaving group X is a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group can be prepared by converting the compound represented by the general formula The compound of general formula [1] or a salt thereof can be obtained by reacting with the compound of [3] or a salt thereof. Further, the compound of the general formula [2] or a salt thereof in which the leaving group X is an iodine atom can be used, for example, with tetrahedron letters [Tetrahed.
ron Letters], Vol. 22, pp. 3915-3918 (1981) and U.S. Pat. No. 4,325,253 to obtain a compound of the formula [1] or a salt thereof by subjecting it to a method or a method analogous thereto. Can be. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include water; ethers such as tetrahydrofuran, diethyl ether and dioxane; halogenated carbons 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. The base used as necessary in this reaction includes, for example, 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 needed include molecular sieves and propylene oxide.
The amount of the compound of the general formula [3] or a salt thereof to be used is at least 1 mol of the compound of the general formula [2] or a salt thereof. The amount of the base or deoxidizing agent used as required is 0.5 to 2 times or 1 or more times the molar amount of the compound of the general formula [2] or a salt thereof, respectively. Further, the amount of sodium iodide or potassium iodide used as needed is 1 mol or more with respect to 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, the reaction may be carried out at -20C to 100C 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, a compound of the general formula [1] or a salt thereof can be obtained. Examples of the solvent used for this reaction include the same solvents as described in Production method 1. Bases used as needed in this reaction include, for example, sodium acetate, sodium methoxide, potassium tert-butoxide, triethylamine,
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; and inorganic bases such as sodium hydride, alkali hydroxide, alkali carbonate and alkali hydrogen carbonate. General formula [5]
To use the compound of the present invention in the form of a free acid or a salt thereof,
Use a suitable condensing agent. Such condensing agents include, for example, N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide.
The amount of the compound represented by the general formula [5] or a salt thereof or a reactive derivative thereof is 0.9 times or more, preferably 0.9 mol or more with respect to the compound of the general formula [4] or a salt thereof or a reactive derivative thereof. It is about 1.5 times mol. Also,
The reaction temperature and the reaction time are not particularly limited, but usually, the reaction may be carried out at −50 to 80 ° C. for 5 minutes to 30 hours.

Production Method 3 (1) Isomerization A compound of the general formula [1b] or a salt thereof can be obtained by reacting a compound of the general formula [6] or a salt thereof with a base. This reaction is described, for example, by the Journal of the American Chemical Society [J.
Amer. Chem. Soc.], Vol. 88, pp. 852-853 (1966)
Or a method analogous thereto. (2) Oxidation / Reduction Alternatively, the compound of the general formula [1a] may be subjected to an oxidation reaction conventionally used in the field of cephem-based compounds to give the compound of the general formula [1a]. Or a salt thereof, and then subjecting the compound of the general formula [1a] or a salt thereof to a reduction reaction conventionally used in the field of cephem-based compounds to obtain a compound of the general formula [1a].
Compound b) or a salt thereof can also be obtained. 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
The method can be carried out by the method described in pages 2 to 1151 (1966) and JP-A-52-48683 or a method analogous thereto.

The compound of the general formula [4] or [5] or a salt thereof or a reactive derivative thereof in the above-mentioned production method; and the compound of the general formula [2], [6] or [3] When isomers (eg, optical isomers, geometric isomers, tautomers, and the like) are present in a salt thereof, all of these isomers can be used, and all hydrates and solvents Japanese hydrates and various crystal forms can be used. The compound of the general formula [1] of the present invention or a salt thereof thus obtained is
It can be isolated and purified according to a conventional method such as extraction, crystallization and column chromatography.

Next, a method for producing a compound of the general formula [3] or a salt thereof as a raw material for producing the compound of the present invention; and a method of producing a compound of the general formula [4] or a salt thereof will be described. (A) The compound of general formula [3] or a salt thereof, which is a starting compound in Production Method 1, can be produced according to a known method or a method analogous thereto.・ Heterocyclic Chemistry [Adv. Heterocyclic Chem.] No. 21
Vol. 65-117 (1977) can be led to various derivatives with reference to the review by John M. Barker. 3-aminothieno [2,3-b]
Pyridine derivatives are available from journal heterocyclic
Chemistry [J. Heterocyclic Chem.] Volume 11, 975
977 (1974), Vol. 21, 587-589 (1984)
Year, Vol. 24, pp. 85-89 (1987), J. Prakt. Chem. 316
Vol., Pages 1030 to 1036 (1974), Pharmaco Eddie
Science [Farmaco. Ed. Sci.] Vol. 31, pp. 21-30 (1976), The Journal of Organic Chemistry [J. Org. Chem.] Vol. 46, pp. 4179-4182 ( 1981), Journal of Medicinal Chemistry [J. Med. Chem.] Vol. 27, pp. 1639-1643 (198
4 years) and German Patent No. 2421717, or a method analogous thereto. In addition to the reactions described in these documents,
A general substitution reaction, acylation reaction, reaction for introducing an amino-protecting group, or the like can be applied to further induce another starting material compound. (B) The compounds of the general formulas [4] and [6], which are the starting compounds in the production methods 2 and 3, and their salts can be produced by a combination of 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.

(Equation 4) "In the formula, R ³ , R ⁵ , X and n each have the same meaning as described above.”

In the method for producing the compound of the present invention and the method for producing the starting compound described above, when the compound has an active group such as an amino group and a carboxyl group in addition to the reaction site,
These groups may be protected in advance according to a conventional method, and may be removed after the reaction according to a conventional method. After completion of the reaction, the target product can be used for the next reaction without isolation, and 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 auxiliaries such as diluents may be appropriately mixed. Tablet, soft or hard capsule, powder, syrup, granule, pill, suspension, emulsion, liquid, powder formulation, suppository, ointment or subcutaneous, muscle,
It can be administered orally or parenterally in such forms as intravenous or drip injections. In addition, the administration method, dosage and number of administrations can be appropriately selected according to the age, weight, and condition of the patient. Usually, for adults, oral or parenteral (for example, injection, infusion, or rectal site) 0.1-100 mg / kg per day depending on the administration
May be divided and administered once to several times.

Next, the antibacterial action of the representative compounds of the present invention will be described. Test method Japanese Society of Chemotherapy standard method [CHEMOTHERAPY
Vol. 29, No. 1, pp. 76-79 (1981)], the test bacteria cultured overnight in a growth medium was adjusted to 10 ⁶ cells / ml, and one platinum loop was inserted into a heart containing a drug. Infusion
After inoculating an agar (Heart Infusion agar) 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 MIC (μg / μg /
ml). The results are shown in Tables 1 and 2. In addition, the symbol in Table 1 shows the following meaning, respectively. *: Β-lactamase producing bacteria **: Methicillin-resistant Staphylococcus aureus

Test compound: Reference was made by describing the example number. Control compound Compound A: 7- [2- (2-aminothiazole-4-
Yl)-(Z) -2-methoxyiminoacetamide]-
3- (2-amino-5-thieno [3,2-c] pyridinio) methyl-3-cephem-4-carboxylate Compound B: 7- [2- (2-aminothiazole-4-
Yl)-(Z) -2-methoxyiminoacetamide]-
3- (2-methyl-5-thieno [3,2-c] pyridinio) methyl-3-cephem-4-carboxylate (margin)

[0019]

[Table 1] (Below)

[0020]

[Table 2]

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

[0022]

Therefore, it is clear that the compound of the present invention is a very useful compound as an antibacterial agent.

[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 to these. The carrier in the reverse phase column chromatography is LC-SORB SP-B-ODS 100G
(Manufactured by Chemco). The abbreviations used below have the following meanings, respectively. Me; methyl group, Et; ethyl group, Tr; triphenylmethyl group; Boc; tert-butoxycarbonyl group Further, the wave number of IR indicates absorption of carbonyl.

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 solution of sodium hydrogen carbonate.
Separate the organic layer. The separated organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. 50 ml of diisopropyl ether is added to the obtained residue, and the precipitated crystals are 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)

The following compounds are obtained in the same manner as above, using allyloxycarbonyl chloride instead of di-tert-butyl dicarbonate. 3-allyloxycarbonylaminothieno [2,3-
b] Pyridine IR (KBr) cm ^-1 ; 1730 NMR (CDCl ₃ ) δ value; 4.72 (2H, d, J = 6 Hz), 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. After adding 50 ml of diisopropyl ether to the reaction mixture and separating the oily substance by decantation, 30 ml of diethyl ether was added, and the precipitate was collected by filtration and dried under reduced pressure to give p-methoxybenzyl = 3-.
(3-formylamino-7-thieno [2,3-b] pyridinio) methyl-7-[(Z) -2-methoxyimino-
There are obtained 1.05 g of 2- (5-triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate iodide. 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 1.0 g of 1-oxide, 0.4 g of 3-formylaminothieno [2,3-b] pyridine and 5 ml of N, N-dimethylformamide 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 separated, 50 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour.
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
-(3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 1-oxide A solution of 0.2 g of iodide and 1 ml of N, N-dimethylformamide at -35 ° C. 0.1 ml of phosphorus trichloride
And a solution of 0.5 ml of methylene chloride is added dropwise and stirred at the same temperature for another 90 minutes. The reaction mixture is poured under ice cooling into a mixture of 10 ml of methylene chloride and 10 ml of water containing 50 mg of potassium iodide while maintaining the pH at 2.0 with a saturated aqueous solution of sodium hydrogen carbonate. The precipitate is 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 shown in Table 3 are obtained.
Note that R ¹ , R ² and R ⁴ in Table 3 are respectively
The following equation

Embedded image Represents a substituent of the compound represented by

[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-
Yl) acetamide] -3-cephem-4-carboxylate 5.5 g of iodide are suspended in 55 ml of anisole, 55 ml of trifluoroacetic acid is added under ice-cooling, stirred at the same temperature for 30 minutes, and further stirred at room temperature for 1 hour. . Then concentrated hydrochloric acid 1.
Add 3 ml and stir for an additional hour. The solvent was distilled off under reduced pressure, and 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 solution of sodium hydrogen carbonate, and then subjected to reverse phase column chromatography (eluent: 5% aqueous acetonitrile).
Purification 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 in methanol 1
The mixture was suspended at room temperature, and 0.034 ml of methanesulfonic acid was added at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was diluted with 3 ml of water, adjusted to pH 7.0 with a saturated aqueous solution of sodium hydrogen carbonate, and purified by reversed-phase column chromatography (eluent: 5% aqueous acetonitrile) 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 (1 H, d, J = 18 Hz), 3.33 (1 H, d, J = 1
8Hz), 4.00 (3H, s), 5.15 (1H, d, J = 5Hz), 5.62 (2H, s), 5.78 (1H
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-
By reacting triphenylmethylamino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-4-carboxylate iodide in the same manner as in Example 7, 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. 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-
By reacting 4-carboxylate iodide in the same manner as in Example 7, 3- (3-allyloxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7-
[2- (5-amino-1,2,4-thiadiazole-3]
-Yl)-(Z) -2-methoxyiminoacetamide]
This gives -3-cephem-4-carboxylate. 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- Il)-(Z) -2-methoxyiminoacetamide] -3-cephem-4-carboxylate 80 mg
Is dissolved in a mixed solvent of 2.1 ml of acetonitrile and 0.9 ml of water, and tetrakis (triphenylphosphine) is added at room temperature.
10 mg of palladium (0) and 10 mg of triphenylphosphine are sequentially added, and the mixture is stirred at the same temperature for 8 hours. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to reverse phase column chromatography (eluent: 5% acetonitrile water).
Purification 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
This was consistent 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 shown in Table 4 are obtained. Incidentally, R ² and R ⁴ in Table 4, respectively, of the following formula

Embedded image Represents a substituent of the compound represented by

[0037]

[Table 4]

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 = 17 Hz), 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 = 16 Hz), 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 = 7 Hz), 3.20 (1H, d, J = 16)
Hz), 3.33 (1H, d, J = 16 Hz), 4.20 (2H, q, J = 7 Hz), 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)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 501: 00) (72) Inventor Kenji Yonezawa 4728 Nakata, Takaoka City, Toyama Prefecture (72) Inventor Minami Saburo 627 Tabata, Toyama City, Toyama Prefecture ( 72) Inventor Yasuo Watanabe 1-1247 Municipal Village, Toyama Pref. Examiner Shinobu Tanio (56) References JP-A-58-57390 (JP, A) (58) Field investigated (Int. Cl. ⁷ , DB name) C07D 519/06 A61K 31/546 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula "In the formula, R ^1, protected or unprotected amino group; R ²
Is an alkyl group optionally substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylate 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. And a salt thereof.