JPH05202065A - Novel cephalosporin derivative and its salt - Google Patents

Abstract

(57) [Summary] (Correction) [Structure] Cefalosporin derivatives represented by the general formula and salts thereof. [Wherein R ¹ represents an amino group which may be protected; R 1
² is an alkyl group, a cycloalkyl group or the like; R ³ is an optionally protected carboxyl group or carboxylato group; R ⁴ is a hydrogen atom or an optionally protected amino group; A is CH or C—X (wherein X represents a halogen atom); BD represents a (substituted) amino group,
A (halo) alkoxy group or the like; n is 0 or 1, and Represents a syn or anti isomer or a mixture thereof] [Effect] This compound has a broad antibacterial spectrum and exerts a strong antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus. It is useful as an antibacterial agent.

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 a cyano or carbamoyl group or an alkyl, alkenyl, alkynyl or cycloalkyl group which may be substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylato group;
R ⁴ is a hydrogen atom or an optionally protected amino group; A is CH or C—X (wherein X represents a halogen atom); B is a bond, a methyleneimino group or A lower alkylene or -O-lower alkylene group which may be substituted with an optionally protected hydroxyl group;

[Outside 4] (In the formula, R ⁵ represents a hydrogen atom or an amino protecting group;
⁶ represents a hydrogen atom, a carbamoyl or cyano group, or an alkyl, alkenyl, aryl or cycloalkyl group which may be substituted with a halogen atom, or a carbamoyl group. ) A group represented by;

[Outside 5] Is an alkoxy group which may be substituted with a halogen atom;

[Outside 6] Represents a syn or anti isomer or a mixture thereof; and n represents 0 or 1, respectively. In addition,
One or more R ⁴ may be substituted on the pyridine ring of the thieno [2,3-b] pyridine ring. The present invention relates to a cephalosporin derivative and a salt thereof. The purpose of the present invention is to
It is to provide a novel compound having a broad antibacterial spectrum, exhibiting a strong antibacterial activity particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, and having low toxicity and 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 such circumstances, the 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 (published in 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 a broad antibacterial spectrum, and particularly, methicillin-resistant yellow grape It was found that it exerts strong antibacterial activity against Gram-positive bacteria including cocci,
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-.
Linear or branched C ₁ such as butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or undecyl
~ ₁₂ alkyl groups; lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, se
c- butyl, isobutyl, tert- butyl or straight-chain or branched C ₁ ~ ₅ alkyl group such as pentyl; Alkoxy group, -O- alkyl groups; lower alkylene and -O- lower alkylene the lower alkylene group group, methylene, a C ₁ ~ ₅ alkylene group such as ethylene or propylene group; and alkenyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, straight, such as pentenyl or hexenyl the chain or branched C ₂ ~ ₁₂ alkenyl; alkynyl groups, for example, ethynyl, propynyl, butynyl, or a linear or branched C ₂ ~ ₁₂ alkynyl group, such as pentynyl, or hexynyl; What is a cycloalkyl group?
For example, cyclopropyl, cyclobutyl, C ₃ ~ ₆ cycloalkyl group such as cyclopentyl or cyclohexyl; and an aryl group, a phenyl or naphthyl group;
A lower alkylsulfonyloxy group is a lower alkyl-
SO ₃ — is arylsulfonyloxy and is aryl-
SO ₃ -, and the acyloxy group, for example, formyloxy group, C ₂ ~ ₅ alkanoyloxy group such as acetyloxy or propionyloxy, heterocyclic carbonyloxy, such as arylcarbonyl group or Furoiruokishi groups such as benzoyloxy A group; a halogen atom represents 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 amino-protecting group for R ¹ , R ⁴ and R ⁵ , the hydroxyl-protecting group for B and the optionally protected carboxyl-protecting group for R ³ are conventionally
The amino protecting group, the hydroxyl protecting group, and the carboxyl protecting group which are generally known in the field of cephem compounds can be mentioned, and specifically, Protective Groups in Organic Synthesis [Protective Groups in
Organic Synthesis Theodora W. Green, (1981) John Wiley & Sons, Inc.]
And various protecting groups described in JP-B-60-52755 and the like. In addition, as the salt of the compound of the general formula [1], a salt in a commonly known basic group such as an amino group or an acidic group such as a carboxyl group, a sulfo group or a hydroxyl group or an intramolecular salt 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 magnesium Salts with alkaline earth metals such as; ammonium salts; trimethylamine,
Triethylamine, tributylamine, pyridine, N,
Examples thereof include salts with nitrogen-containing organic bases such as N-dimethylaniline, N-methylpiperidine or N-methylmorpholine; 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 in the molecule, the onium group is
Usually, it may form an inner salt with the carboxylato group in R ³ described above, and may be a halogen anion, a lower alkylsulfonyloxy anion, or an arylsulfonyloxy anion optionally substituted with a lower alkyl group or a halogen atom. And may form a salt. 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 , A, B, D,

[Outside 7] And n each have the same meaning as defined above;
R ^3a represents an optionally protected carboxyl group similar to R ³ ; R ⁷ represents a hydrogen atom or an amino protecting group; and X represents a leaving group. Examples of the amino protecting group for R ⁷ include the same amino protecting group as described for R ¹ . Furthermore, the general formula [1a],
Examples of the salt of the compound of [1b], [2], [3], [4], [5] and [6] include the same salts as those described as the salt of the compound of the general formula [1]. Furthermore, examples of the leaving group for X 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 organic silyl group such as nyl or dimethoxysilanediyl or dimethoxyphosphinyl, 1,3,2-dioxophosphoran-2-yl, 4
Compounds such as -methyl-1,3,2-dioxophosphoran-2-yl or 1,3,2-dioxophosphorinan-2-yl bonded to an amino group which is a reactive site Can be mentioned.

Examples of the reactive derivative of the compound represented by 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 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.Chem]
The compound of the general formula [1] or a salt thereof can be obtained by subjecting it to the method described in Chapter 32, pages 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 hydrocarbons such as methylene chloride and chloroform. Alcohols such as methanol and ethanol; N, N-dimethylformamide and N, N
-Amids such as 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-Dimethylimidazolidinone; Hexamethylphosphoric triamide;
And nitriles such as acetonitrile and propionitrile, etc., and these solvents may be used alone or in combination of two or more. Examples of the base used as necessary 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, sodium hydrogen carbonate or potassium hydrogen carbonate. To use the compound of the general formula [5] in the form of the free acid or its salt, a suitable condensing agent is used. Examples of such condensing agents include N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide. The amount of the compound of general formula [5] or salt thereof or reactive derivative thereof to be used is as follows, based on the compound of general formula [4] or salt thereof or reactive derivative thereof.
The molar ratio is 0.9 times or more, preferably 0.9 to 1.5 times. Further, 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.] Vol. 88, pp. 852-853 (1966) or a method analogous 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] Vol. 35,
2430-2433 (1970), Journal of the Chemical Society [J. Chem. Soc. (C)] 1142-1151
Page (1966) and the method described in JP-A-52-48683 or the like 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] or [6] or the general formula [3]. If any isomers (eg optical isomers, geometric isomers, tautomers, etc.) exist in the compound or salt thereof, all these isomers can be used, and all hydrates , Solvates and various crystalline forms can be used. The thus obtained compound of the general formula [1] of the present invention or a salt thereof 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), various derivatives can be derived with reference to the review by John M. Barker. Thieno [2,3-b] pyridine is described in The Journal of Organic Chemistry [J.Org.Chem.] 34, 347-353 (1969),
Journal Heterocyclic Chemistry [J.He
terocyclic Chem.] Vol. 11, pp. 205-209 (1974),
Vol. 11, pp. 355-361 (1974), method 3,
-Aminothieno [2,3-b] pyridine derivatives are available from Journal Heterocyclic Chemistry [J. Hetero
cyclic Chem.] Vol. 11, pp. 975-977 (1974), ibid.
21st, 587th to 589th (1984), 24th, 85th
89 pages (1987), Journal Practice Chemie [J.Prakt.Chem.] No. 316, pages 1030-1036 (1974)
Year), Pharmaco.Ed.S
ci.] 31st, 21st to 30th (1976), The Journal of Organic Chemistry [J.Org.Chem.]
Vol. 46, pp. 4179-4182 (1981), Journal of Medicinal Chemistry [J.Med.Chem.] No. 27
Pp. 1639-1643 (1984) and German Patent No. 22
It can be obtained according to the method described in 41717 or the like or a method analogous thereto. Further, in addition to the reactions described in these documents, the conventional alkylation reaction, substitution reaction, acylation reaction, oxidation reaction, reduction reaction, etc. are applied,
Furthermore, it is possible 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 ⁷ , 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 material compound, when an active group such as an amino group, a hydroxyl group, a carboxyl group and a mercapto group is present in addition to the reaction site, these groups are previously prepared. It may be protected according to a conventional method, and may be eliminated after the reaction according to 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.

The following compounds may be mentioned as specific examples in the present invention. 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- {3
-(2-Fluoroethyl) amino-7-thieno [2,3
-B] pyridinio} methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (2-Fluoroethoxy) iminoacetamido] -3- (3-formylamino-7-thieno [2,2
3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Yl)-(Z) -2- (2-fluoroethoxy) iminoacetamido] -3- (3-amino-7-thieno [2,2
3-b] pyridinio) methyl-3-cephem-4-carboxylate 3- {3- (2-aminoethoxy) -7-thieno [2,2
3-b] Pyridinio} methyl-7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido-3-cephem-4-carboxylate 3- (5-amino-3) -Formylamino-7-thieno [2,3-b] pyridinio) methyl-7- [2- (2-
Aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Carbamoylmethylamino-7-thieno [2,3-
b] Pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- (3-cyclopropylamino-7-thieno [2,3
-B] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Cyanomethylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Phenylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Fluoromethoxyiminoacetamide]-
3- (3-formylamino-7-thieno [2,3-b]
Pyridinio) methyl-3-cephem-4-carboxylate

3- {3- (2-amino-1-hydroxyethyl) amino-7-thieno [2,3-b] pyridinio} methyl-7- [2- (2-aminothiazole-4-]
Ill)-(Z) -2-methoxyiminoacetamide]-
3-Cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (2,2-Difluoroethoxy) iminoacetamido] -3- (3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4
-Carboxylate 3- {7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido]}-3- (3-semicarbazidemethyl-7-
Thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Allylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Yl)-(Z) -2- (2-chloroallyl) oxyiminoacetamido] -3- (3-formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7 -[2- (2-aminothiazol-4-yl)-
(Z) -2- (2-chloroallyl) oxyiminoacetamido] -3- (3-amino-7-thieno [2,3-
b] Pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-Cyanocyclobutan-1-yl) oxyiminoacetamido] -3- (3-amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1,1-Dichloroallyl) oxyiminoacetamido] -3- (3-amino-7-thieno [2,2
3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Yl)-(Z) -2- (1,1,1-trifluorobut-2-en-1-yl) oxyiminoacetamide]-
3- (3-Amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Fluoromethoxyiminoacetamide]-
3- (3-Cyanomethylamino-7-thieno [2,3-
b] Pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Fluorocyanomethoxyiminoacetamido] -3- (3-formylamino-7-thieno [2,3
-B] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (1-carbamoylcyclobutan-1-yl) oxyiminoacetamide] -3- (3-amino-
7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Yl)-(Z) -2- (1-carbamoylcyclobutan-1-yl) oxyiminoacetamide] -3- (3-
Formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (2-Fluoroethoxy) iminoacetamido] -3- (3-cyanomethylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4
-Carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2- (3-Propinyl) oxyiminoacetamido] -3- (3-amino-7-thieno [2,3-b]
Pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Fluoromethoxyiminoacetamide]-
3- (3-amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- {3- (N-ethylamino) -7-thieno [2,3
-B] pyridinio} methyl-3-cephem-4-carboxylate 7- [2- (2-aminothiazol-4-yl)-
(Z) -2-Methoxyiminoacetamide] -3- (3
-Methoxy-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate

7- [2- (2-aminothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- (3-fluoromethoxy-7-thieno [2,3-
b] Pyridinio) methyl-3-cephem-4-carboxylate 7- [2- (2-amino-5-chlorothiazole-4-
Ill)-(Z) -2-methoxyiminoacetamide]-
3- (3-amino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate

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. , Tablets, soft or hard capsules, powders, syrups, granules, pills, suspensions, emulsions,
It can be orally or parenterally administered in the form of a liquid preparation, powder preparation, suppository, ointment or subcutaneous, intramuscular, intravenous or drip injection. 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). The administration may be performed at 0.1 to 100 mg / kg per day in 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 Table 1, Table 2 and Table 3. The symbols in Table 1, Table 2 and Table 3 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

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

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.

[0032]

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

[0033]

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 in silica gel column chromatography is Kieselgel 60, Art. 7734 (Kieselgel 60, Art.7734) (manufactured by Merck),
Furthermore, the carrier in reverse phase column chromatography is
LC-SORB SP-B-ODS 100G (manufactured by Chemco) was used. The mixing ratios in the eluent are all volume ratios. Further, the abbreviations used below have the following meanings. Ph; phenyl group, Tr; triphenylmethyl group, t-Bu; tert-butyl group, Boc; tert-butoxycarbonyl, PMB; p-methoxybenzyl group, PMB
Z; p-methoxybenzyloxycarbonyl group Furthermore, the wave number of IR shows absorption of carbonyl,
IR in Table 4, Table 5, Table 8, Table 9, Table 10, Table 11, Table 12, and Table 13 shows the measured value by the KBr method, respectively.

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 are added to the reaction solution, the pH is adjusted to 7.0 with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer is separated. 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 give a melting point of 152.
6.5 g of 3-tert-butoxycarbonylaminothieno [2,3-b] pyridine showing ˜154 ° C. are obtained. 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 = 5H
z)

Reference Example 2 (1) 1.0 g of 3-aminothieno [2,3-b] pyridine
Is dissolved in 15 ml of methylene chloride, 0.94 ml of trifluoroacetic anhydride is added dropwise under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. The obtained mixture is poured into 20 ml of water while adjusting the pH to 7.0 with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer is separated. The separated organic layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 10 ml of diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give a melting point of 110-1.
1.15 g of 3-trifluoroacetylaminothieno [2,3-b] pyridine showing 12 ° C. are obtained. IR (KBr) cm ^-1 ; 1725,1705 NMR (CDCl ₃ ) δ value; 7.31 (1H, dd, J = 5Hz, J = 8Hz), 7.92 (1
H, s), 7.98 (1H, dd, J = 2Hz, J = 8Hz), 8.60 (1H, dd, J = 2Hz, J
= 5Hz), 8.88 (1H, bs)

(2) 1.1 g of 3-trifluoroacetylaminothieno [2,3-b] pyridine was added to 5 ml of 1,3-dimethyl-2-imidazolidinone and 5 ml of tetrahydrofuran.
Dissolve it in ml and add sodium hydride (purity 60%) to it.
Add 18 g in portions. After stirring at room temperature for 30 minutes, 0.57 g of 1-bromo-2-fluoroethane is added, and the mixture is stirred at 80 ° C for 3 hours. After cooling the reaction solution, the mixture is poured into a mixed solvent of 20 ml of water and 20 ml of methylene chloride, adjusted to pH 7.0 with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer is separated. 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. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1), 10 ml of hexane was added, and the precipitated crystals were collected by filtration to give 3- [N- (2 0.47 g of -fluoroethyl) trifluoroacetylamino] thieno [2,3-b] pyridine is obtained. IR (KBr) cm ^-1 ; 1705 NMR (CDCl ₃ ) δ value; 4.02 (1H, m), 4.05-4.50 (2H, m), 5.06 (1
H, m), 7.41 (1H, dd, J = 5Hz, J = 8Hz), 7.66 (1H, s), 7.96 (1H, d
d, J = 2Hz, J = 8Hz), 8.68 (1H, dd, J = 2Hz, J = 5Hz)

Reference Example 3 (1) 1.0 g of 3-aminothieno [2,3-b] pyridine
And cyclopropylamine hydrochloride 3.1 g ethanol 10
Dissolve in ml and heat to reflux for 1 hour. The solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added to the obtained residue to dissolve it, and the pH was adjusted to 7 with a saturated aqueous sodium hydrogen carbonate solution.
After adjusting to 0, the organic layer is separated. 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. The obtained residue is purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give 3
-Cyclopropylaminothieno [2,3-b] pyridine
Get 0.6g. NMR (CDCl ₃ ) δ value; 0.53-0.82 (4H, m), 2.60 (1H, m), 3.60 (1
H, m), 6.45 (1H, s), 7.23 (1H, dd, J = 5Hz, J = 8Hz), 7.80 (1H, d
d, J = 2Hz, J = 8Hz), 8.56 (1H, dd, J = 2Hz, J = 5Hz)

(2) In the same manner as in Reference Example 2- (1),
3- (N-Cyclopropyltrifluoroacetylamino) thieno [2,3-b] pyridine is obtained from 3-cyclopropylaminothieno [2,3-b] pyridine. IR (KBr) cm ^-1 ; 1710 NMR (CDCl ₃ ) δ value; 0.40-1.10 (4H, m), 3.45 (1H, m), 7.30-7.
50 (2H, m), 7.93 (1H, dd, J = 2Hz, J = 8Hz), 8.66 (1H, dd, J = 2Hz,
(J = 5Hz)

Reference Example 4 1 g of 3-hydroxythieno [2,3-b] pyridine was added to N,
It is dissolved in 10 ml of N-dimethylformamide, 0.78 g of potassium tert-butoxide is added thereto under ice cooling, and the mixture is stirred for 10 minutes. Then, 1.9 g of p-methoxybenzyloxycarbonylaminoethyl bromide is added, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, adjusted to pH 7.0 with 2N hydrochloric acid, and the organic layer is separated. 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. The obtained residue was subjected to silica gel column chromatography (eluent; toluene: ethyl acetate = 1).
When purified by 0: 1), 3- [2-
1.0 g of (p-methoxybenzyloxycarbonylamino) ethoxy] thieno [2,3-b] pyridine is obtained. IR (KBr) cm ^-1 ; 1710 NMR (CDCl ₃ ) δ value; 3.35 to 3.60 (2H, m), 3.77 (3H, s), 4.2
0 (2H, t, J = 6Hz), 5.02 (2H, s), 6.92 (1H, s), 6.93 (1
H, d, J = 10Hz), 7.27 ~ 7.57 (4H, m), 8.06 (1H, dd, J = 2Hz,
J = 8Hz), 8.65 (1H, dd, J = 2Hz, J = 5Hz)

Reference Example 5 (1) 3-formylthieno [2,3-b] pyridine
8 g of the compound was suspended in 10 ml of methanol, 0.8 ml of nitromethane and 0.2 ml of 28% sodium methoxide methanol solution were sequentially added thereto under ice cooling, and the mixture was further stirred at room temperature for 1 hour. After adding 0.1 ml of acetic acid to the reaction solution at room temperature, 20 ml of ethyl acetate and 20 ml of water are added to separate the organic layer. The separated organic layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) to give 3- (1-hydroxy-2-nitroethyl) thieno [ 0.82 g of 2,3-b] pyridine is obtained. NMR (CDCl ₃ ) δ value; 3.50 (1H, bs), 4.60 to 5.00 (2H, m), 5.84 (1
H, m), 7.32 (1H, dd, J = 4Hz, J = 8Hz), 7.60 (1H, s), 8.22 (1H, d
d, J = 1Hz, J = 8Hz), 8.52 (1H, dd, J = 1Hz, J = 4Hz)

(2) 0.42 g of 3- (1-hydroxy-2-nitroethyl) thieno [2,3-b] pyridine was added to 5% of acetic acid.
Dissolve it in ml, add 5% palladium-carbon 0.1g to it,
Hydrogenate at 50 ° C. for 3 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain 0.4 g of crude 3- (2-amino-1-hydroxyethyl) thieno [2,3-b] pyridine. This is dissolved in 4 ml of N, N-dimethylformamide, 0.56 g of di-tert-butyldicarbonate is added, and the mixture is stirred at room temperature for 30 minutes. 20 ml of water and ethyl acetate in the reaction solution
20 ml was added, the organic layer was separated, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =
If purified by 2: 1), 3- (2-tert-butoxycarbonylamino-1-hydroxyethyl) thieno [2,3-
b] 0.44 g of pyridine is obtained. IR (neat) cm ^-1 ; 1695 NMR (CDCl ₃ ) δ value; 1.39 (9H, s), 3.27 ~ 3.63 (2H, m), 4.60 (1
H, bs), 5.12 (1H, m), 5.50 (1H, bt, J = 6Hz), 7.21 (1H, dd, J = 4H
z, J = 8Hz), 7.47 (1H, s), 8.19 (1H, dd, J = 1Hz, J = 8Hz), 8.43 (1
(H, dd, J = 1Hz, J = 4Hz)

Reference Example 6 0.3 g of 3-formylthieno [2,3-b] pyridine was dissolved in 5 ml of methanol, and semicarbazide hydrochloride 1.2 was added at room temperature.
Add 5 g and stir overnight at the same temperature. The reaction solution was diluted with 10 ml of water and then cooled to 10.0 with 1N aqueous sodium hydroxide solution under ice cooling.
And the precipitated crystals are collected by filtration (thieno [2,3-
b] 0.37 g of pyridin-3-yl) hydrazone is obtained. IR (KBr) cm ^-1 ; 1685 NMR (DMSO-d ₆ ) δ value; 6.40 (2H, bs), 7.48 (1H, dd, J = 4Hz, J = 8H
z), 8.11 (2H, s), 8.60 (1H, d, J = 4Hz), 8.91 (1H, d, J = 8Hz)

Reference Example 7 (1) 2-chloro-3-cyano-5-nitropyridine
To a solution of 3.0 g, 1.46 g of methyl thioglycolate and 15 ml of N, N-dimethylformamide, 2.28 ml of triethylamine was added dropwise over 10 minutes under ice cooling. After stirring for 15 minutes at the same temperature, 50 ml of ethyl acetate and 50 ml of water are added, and the organic layer is separated. The separated organic layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, 20 ml of diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration and dried to obtain 3
3.8 g of -cyano-2-methoxycarbonylmethylthio-5-nitropyridine are obtained. IR (KBr) cm ^-1 ; 1750 NMR (CDCl ₃ ) δ value; 3.80 (3H, s), 4.17 (2H, s), 8.66 (1H, d, J = 2
Hz), 9.39 (1H, d, J = 2Hz)

(2) 3.7 g of 3-cyano-2-methoxycarbonylmethylthio-5-nitropyridine, ethanol
Iron powder 3.24 in a suspension of 37 ml and tetrahydrofuran 10 ml
g, and 14.5 ml of concentrated hydrochloric acid is added dropwise at 30 to 50 ° C over 15 minutes. After stirring at the same temperature for 10 minutes, the insoluble matter is filtered off, and the solvent is distilled off under reduced pressure. The residue obtained was washed with ethyl acetate 50
dissolved in a mixed solvent of 50 ml of water and 50 ml of water, and potassium carbonate.
Adjust to pH 8.0. After filtering off the precipitate on Celite,
Separate the organic layer. The separated organic layer is washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 5-amino-3-cyano-2-methoxycarbonylmethylthiopyridine 2.94.
get g. IR (KBr) cm ^-1 ; 1735 NMR (CDCl ₃ ) δ value; 3.75 (3H, s), 3.97 (2H, s), 4.10 (2H, bs),
7.24 (1H, d, J = 3Hz), 8.15 (1H, d, J = 3Hz)

(3) 2.9 g of 5-amino-3-cyano-2-methoxycarbonylmethylthiopyridine was dissolved in 15 ml of N, N-dimethylformamide, and potassium was added under ice cooling.
Add 50 mg of tert-butoxide and stir for another 15 minutes at the same temperature. 50 ml of ethyl acetate and 50 ml of water were added to the reaction 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. 10 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration and dried,
3.75 g of 3,5-diamino-2-methoxycarbonylthieno [2,3-b] pyridine are obtained. IR (KBr) cm ^-1 ; 1675 NMR (DMSO-d ₆ ) δ value; 3.81 (3H, s), 5.38 (2H, bs), 7.05 (2H, b
s), 7.57 (1H, d, J = 3Hz), 8.22 (1H, d, J = 3Hz)

(4) 2.23 g of 3,5-diamino-2-methoxycarbonylthieno [2,3-b] pyridine was suspended in 20 ml of ethanol, 10 ml of 2N potassium hydroxide aqueous solution was added, and the mixture was stirred at 60 ° C. for 2 hours. To do. The reaction solution is cooled to room temperature, 5.00 ml of 2N hydrochloric acid is added, the solvent is distilled off under reduced pressure, and the mixture is dried. 20 ml of ethanol and 1.14 ml of acetic acid are added to the residual solid, and the mixture is heated under reflux for 2 hours. After evaporating the solvent under reduced pressure, 30 ml of water is added to the reaction solution, the pH is adjusted to 9.0 with 25% aqueous ammonia, and the mixture is extracted with 30 ml of ethyl acetate. The extract is washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3,5-diaminothieno [2,2].
3-b] 0.6 g of pyridine are obtained. NMR (CDCl ₃ ) δ value; 4.14 (4H, bs), 6.28 (1H, s), 7.30 (1H, d, J =
3Hz), 8.13 (1H, d, J = 3Hz)

Reference Examples 8 to 19 The compounds in Tables 4 and 5 are obtained in the same manner as in Reference Examples 1 to 7. In Tables 4 and 5, -BD and R
⁴ is the following formula

[Chemical 3] The substituents of the compound represented by are shown below. The number in R ⁴ indicates the position of substitution on the thieno [2,3-b] pyridine ring.

[0048]

[Table 4]

[0049]

[Table 5]

Reference Example 20 (1) 4.0 g of (Z) -2-hydroxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester was added to dimethyl sulfoxide 20.
It is dissolved in ml, 1.9 g of ground potassium carbonate is added thereto, and the mixture is stirred at room temperature for 10 minutes. Then, 1.4 g of bromofluoroacetic acid ethyl ester was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution is poured into a mixed solvent of 70 ml of ethyl acetate and 70 ml of water, and the organic layer is separated. The separated organic layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 20: 1), and further crystallized from diisopropyl ether to give (Z) -2. -4.5 g of ethoxycarbonylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1750

(2) 5.0 g of (Z) -2-ethoxycarbonylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester was dissolved in 50 ml of anisole and cooled with ice. Below, 25 ml of trifluoroacetic acid is added and stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in 50 ml of ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 30 ml of diisopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration and dried (Z).
-2-Ethoxycarbonylfluoromethoxyimino-2
3.1 g of-(2-triphenylmethylaminothiazol-4-yl) acetic acid are obtained. IR (KBr) cm ^-1 ; 1765

(3) 3.0 g of (Z) -2-ethoxycarbonylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid was added to ethanol.
Dissolve in 20 ml, add 6 ml of 25% ammonia water under ice cooling, and stir at room temperature for 1 hour. The precipitated crystals are collected by filtration and washed with 5 ml of ethanol. The obtained crystals are ethyl acetate 10m
It is suspended in a mixed solvent of 1, 20 ml of tetrahydrofuran and 10 ml of water, 5 ml of 2N sulfuric acid is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. 50 ml of ethyl acetate and 30 ml of water are added to dilute the mixture, and the organic layer is separated. The collected organic layer,
The extract is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 20 ml of diisopropyl ether was added to the obtained crude product, and the precipitated crystals were collected by filtration and dried to give (Z) -2-carbamoylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid. You get 2.6g. IR (KBr) cm ^-1 ; 1705

(4) 2.5 g of (Z) -2-carbamoylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid was dissolved in 30 ml of tetrahydrofuran, and diphenyldiazomethane was added thereto under ice cooling. 5.5 ml of an ethyl acetate solution (1 mmol / ml) of is added dropwise.
Then, after stirring at room temperature for 1 hour, 0.5 ml of acetic acid is added and stirred at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in a mixed solution of 50 ml of ethyl acetate and 50 ml of water, and the pH was adjusted to 7.0 with saturated sodium hydrogen carbonate,
Separate the organic layer. The separated organic layer is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 5: 1), and further crystallized with a mixed solution of diisopropyl ether and hexane. (Z)-
2-carbamoylfluoromethoxyimino-2- (2-
3.1 g of triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1745,1710

(5) (Z) -2-carbamoylfluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester (3.0 g) was dissolved in methylene chloride (30 ml) and ice-cooled. under,
1.2 ml of pyridine and 1.1 ml of trifluoroacetic anhydride are added successively, and the mixture is stirred at the same temperature for 1 hour. The reaction solution is washed successively with water and saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: toluene) to give (Z) -2-cyanofluoromethoxyimino-2- (2-triphenylmethylamino). 1.9 g of thiazol-4-yl) acetic acid diphenylmethyl ester are obtained. IR (KBr) cm ^-1 ; 1745

(6) In the same manner as (2), (Z) -2
-Cyanofluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetic acid diphenylmethyl ester to (Z) -2-cyanofluoromethoxyimino-2- (2-triphenylmethylaminothiazol-4- Il) Acetic acid is obtained. IR (KBr) cm ^-1 ; 1735,1590 NMR (DMSO-d ₆ ) δ value; 6.60 (1H, s), 7.16 (1H, s), 7.20-7.50
(16H, m), 9.00 (1H, s)

Example 1 P-methoxybenzyl = 3-iodomethyl-7-[(Z)
2-Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1.0 g, 3-tert-butoxycarbonylaminothieno [2,3-b] Pyridine 0.34
A mixed solution of 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 solution, 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 give P-methoxybenzyl = 3- (3-te
rt-Butoxycarbonylamino-7-thieno [2,3-
b] Pyridinio) methyl-7-[(Z) -2-methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 1.05 g of iodide is obtained. IR (KBr) cm ^-1 ; 1790,1720,1660

Examples 2 to 29 In the same manner as in Example 1, the compounds shown in Tables 6 and 7 are obtained. A, R ² , -BD and R ⁴ in Tables 6 and 7 are respectively represented by the following formulas.

[Chemical 4] The substituents of the compound represented by are shown below. The number in R ⁴ indicates the position of substitution on the thieno [2,3-b] pyridine ring.

[0058]

[Table 6]

[0059]

[Table 7]

Example 30 In the same manner as in Example 1, P-methoxybenzyl = 3- {3
-[N- (2-Fluoroethyl)] trifluoroacetylamino-7-thieno [2,3-b] pyridinio} methyl-7-[(Z) -2-methoxyimino-2- (5-chloro-2) -Triphenylmethylaminothiazole-4-
Yl) acetamido] -3-cephem-4-carboxylate iodide is obtained. IR (KBr) cm ^-1 ; 1790,1720,1670

Example 31 P-Methoxybenzyl = 3- (3-tert-butoxycarbonylamino-7-thieno [2,3-b] pyridinio) methyl-7-[(Z) -2-methoxyimino-2- (2-
Triphenylmethylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate Iodide (0.5 g) was suspended in anisole (5 ml), and trifluoroacetic acid (5 ml) was added thereto under ice cooling, and the mixture was kept at the same temperature for 30 minutes. Further, stir at room temperature for 1 hour. The solvent is distilled off under reduced pressure, 20 ml of diethyl ether is added to the obtained residue, and the precipitate is collected by filtration. Add 2 ml of acetonitrile and 10 ml of water to dissolve it, adjust to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution, and then concentrate the solvent under reduced pressure to about half volume. The concentrate was purified by reverse phase column chromatography (eluent: 5% aqueous acetonitrile) to give 7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3. -(3-amino-7-thieno [2,3-
b] 0.02 g of pyridinio) methyl-3-cephem-4-carboxylate is obtained. IR (KBr) cm ^-1 ; 1775,1665,1610 NMR (DMSO-d ₆ ) δ value; 3.20-3.70 (2H, m), 3.80 (3H, s), 5.00-
5.82 (4H, m), 6.58 (1H, s), 6.71 (1H, s), 7.12 (4H, bs), 8.05
(1H, m), 8.91 (1H, m), 9.25-9.53 (2H, m)

Example 32 P-methoxybenzyl = 3- (3-formylamino-7-
Thieno [2,3-b] pyridinio) methyl-7-
[(Z) -2-Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamide]
-3-Cephem-4-carboxylate iodide 0.53
g was suspended in 5 ml of anisole, 5 ml of trifluoroacetic acid was added thereto under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with diethyl ether 20
ml is added and the precipitate is collected by filtration. This was dissolved in a mixed solvent of 5 ml of tetrahydrofuran and 5 ml of 50% formic acid, and at 50 ° C.
Stir for 1.5 hours. The solvent is distilled off under reduced pressure, 20 ml of diethyl ether is added to the obtained residue, and the precipitate is collected by filtration. Add 2 ml of acetonitrile and 10 ml of water to dissolve it, adjust to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution, and then concentrate the solvent to about half volume under reduced pressure. Concentrate
Purification by reverse phase column chromatography (eluent; 5% aqueous acetonitrile) gave 7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3- (3. -Formylamino-7-thieno [2,3-b] pyridinio) methyl-3-cephem-4
-0.1 g of carboxylate is obtained. IR (KBr) cm ^-1 ; 1770,1670,1615 NMR (DMSO-d ₆ ) δ value; 3.20-3.50 (2H, m), 3.85 (3H, s), 5.05 (1
H, d, J = 5Hz), 5.45-5.85 (3H, m), 6.70 (1H, s), 7.12 (2H, bs),
8.00-8.40 (3H, m), 8.95-9.25 (2H, m), 9.45 (1H, d, J = 8Hz), 1
0.64 (1H, s)

Example 33 (1) P-methoxybenzyl = 3- {3- [N- (2-
Fluoroethyl)] trifluoroacetylamino-7-
Thieno [2,3-b] pyridinio} methyl-7-
[(Z) -2-Methoxyimino-2- (2-triphenylmethylaminothiazol-4-yl) acetamide]
-3-Cephem-4-carboxylate Iodide was reacted in the same manner as in Example 32 to give 7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamide] -3- {. 3- [N- (2-fluoroethyl)] trifluoroacetylamino-7-thieno [2,2
3-b] Pyridinio} methyl-3-cephem-4-carboxylate is obtained. IR (KBr) cm ^-1 ; 1775,1710,1675,1615

(2) 7- [2- (2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido] -3- {3- [N- (2-fluoroethyl)] trifluoro Acetylamino-7-thieno [2,3-b]
70 mg of pyridinio} methyl-3-cephem-4-carboxylate is dissolved in a mixed solvent of 0.5 ml of acetone and 2 ml of water, 9 mg of sodium hydrogen carbonate is added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to about half volume and then purified by reverse phase column chromatography (eluent: 20% acetonitrile water) to give 7- [2- (2-aminothiazol-4-yl)-( Z) -2-Methoxyiminoacetamide] -3- {3- (2-fluoroethyl) amino-
30 mg of 7-thieno [2,3-b] pyridinio} methyl-3-cephem-4-carboxylate are obtained. IR (KBr) cm ^-1 ; 1770,1665,1615 NMR (DMSO-d ₆ ) δ value; 3.15-3.90 (6H, m), 4.10-4.35 (2H, m),
4.95-5.30 (2H, m), 5.45-5.80 (3H, m), 6.54 (1H, s), 6.70 (1
H, s), 7.10 (3H, bs), 8.10 (1H, m), 8.95 (1H, m), 9.30-9.55 (2
H, m)

Examples 34 to 61 In the same manner as in Examples 31 to 33, Table 8, Table 9, Table 10,
The compounds of Table 11, Table 12 and Table 13 are obtained. Note that R ² , -BD and R ⁴ in Table 8, Table 9, Table 10, Table 11, Table 12 and Table 13 are respectively represented by the following formulas.

[Chemical 5] The substituents of the compound represented by are shown below. The number in R ⁴ indicates the position of substitution on the thieno [2,3-b] pyridine ring.

[0066]

[Table 8]

[0067]

[Table 9]

[0068]

[Table 10]

[0069]

[Table 11]

[0070]

[Table 12]

[0071]

[Table 13]

Example 62 In the same manner as in Examples 31 to 33, 7- [2- (2-amino-5-chlorothiazol-4-yl)-(Z) -2-
Methoxyiminoacetamide] -3- (3-amino-7
-Thieno [2,3-b] pyridinio) methyl-3-cephem-4-carboxylate is obtained. IR (KBr) cm ^-1 ; 1775,1670,1615 NMR (DMSO-d ₆ ) δ value; 3.35-3.60 (2H, m), 3.87 (3H, s), 5.05
(1H, d, J = 5Hz), 5.40-5.85 (3H, m), 6.56 (1H, s), 7.32 (2H,
s), 8.06 (1H, m), 8.88 (1H, m), 9.25-9.50 (2H, m)

Front page continued (72) Inventor Kazuya Hayashi 2764-4, Sumiyoshi 3 ward, Uozu City, Toyama Prefecture (72) Inventor Hiroshi Kanna 1367-4 Tesaki, Kosugi Town, Imizu District, Toyama Prefecture (72) Inventor Kenji Yonezawa Takaoka, Toyama Prefecture 4728 Ichita Nakata (72) Inventor Shinzaburo Minami 627 Tabata, Toyama City, Toyama Prefecture (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 a cyano or carbamoyl group or an alkyl, alkenyl, alkynyl or cycloalkyl group which may be substituted with a halogen atom; R ³ is an optionally protected carboxyl group or carboxylato group;
R ⁴ is a hydrogen atom or an optionally protected amino group; A is CH or C—X (wherein X represents a halogen atom); B is a bond, a methyleneimino group or A lower alkylene or -O-lower alkylene group which may be substituted with an optionally protected hydroxyl group; D is represented by the formula: (In the formula, R ⁵ represents a hydrogen atom or an amino protecting group;
⁶ represents a hydrogen atom, a carbamoyl or cyano group, or an alkyl, alkenyl, aryl or cycloalkyl group which may be substituted with a halogen atom, or a carbamoyl group. A group represented by); Is an alkoxy group which may be substituted with a halogen atom; Represents a syn or anti isomer or a mixture thereof; and n represents 0 or 1, respectively. In addition,
One or more R ⁴ may be substituted on the pyridine ring of the thieno [2,3-b] pyridine ring. The cephalosporin derivative and its salt represented by these.