JP3025910B2 - Penam derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel penum derivative and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION The penum derivative of the present invention is a novel compound which has not been described in any literature, and the present invention has a broad antibacterial spectrum, that is, excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria as described below. It is an object of the present invention to provide the above-mentioned penam derivative which has a stable activity against β-lactamase and can exhibit excellent antibacterial activity against resistant bacteria.

Another object of the present invention is to provide a compound useful as an intermediate for synthesizing other penum derivatives.

[0004]

According to the present invention, the general formula

[0005]

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[Wherein R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group,
It represents a lower alkyl group, a hydroxyl group or a protected hydroxyl group having a lower alkyl group, a hydroxyl group or a protected hydroxyl group as a substituent. Alternatively, R ¹ and R ² may combine with each other to form an oxo group. R ³ represents a hydrogen atom or a carboxylic acid protecting group. n represents 0, 1 or 2. Y is a halogen atom, a group —N ₃ , a group —ONO ₂ , a group —OR ⁴ , a group —OCOR ⁴ , a group —SCSOR ⁴ , a group —SCSN
(R ⁴ ) ₂ , group —SR ⁴ , group —SO ₂ R ⁴ , group —NHR
⁴ , a group —N (R ⁴ ) ₂ or a nitrogen-containing heterocyclic group having a free valence at nitrogen which may have a substituent. R ⁴ represents a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent. And a salt thereof.

The groups shown in the present specification are more specifically as follows.

As the halogen atom, for example, a fluorine atom,
Examples thereof include a chlorine atom, a bromine atom and an iodine atom. Examples of the lower alkyl group include C _1-4 linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups. . Examples of the aryl group include a phenyl and naphthyl group.

The protected amino group represented by R ¹ includes Protective Group in Organic
Synthesis (Protective Groups in Organic Synthesi)
s, by Theodora W. Greene;
In addition to the various groups described in Chapter 7 (pages 218 to 287), acyl groups usually used in the field of penicillin and cephalosporin compounds can be mentioned. For example, specific examples of acyl groups derived from carboxylic acids include formyl, acetyl, 2,6-dimethoxyphenylcarbonyl, 5-methyl-3-phenylisoxazol-4-ylcarbonyl, 4-aminomethylphenylacetyl, Hydroxyacetyl, phenoxyacetyl, 1-
Tetrazolylacetyl, cyanomethylthioacetyl, carboxyethylthioacetyl, 2-thienylacetyl,
α-bromo-2-thienylacetyl, 5-methoxy-2
-Thienylacetyl, phenylacetyl, α-aminophenylacetyl, α-hydroxyphenylacetyl, α
-Carboxyphenylacetyl, α-sulfophenylacetyl, 3-bromophenylacetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (4-ethyl-2,
3-dioxo-1-piperazinecarboxamide) -α-
(P-hydroxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-dihydroxyphenyl) acetyl, α- (4-ethyl-2,3- Dioxo-1-piperazinecarboxamide) -α- (3,4-diacetoxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-
Diacetoxy-6-chlorophenyl) acetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (3,4-diacetoxy-6-fluorophenyl) acetyl, α- (4-ethyl-2,3-
Dioxo-1-piperazinecarboxamide) -α- (2
-Aminothiazol-4-yl) acetyl, α- (4-
Ethyl-2,3-dioxo-1-piperazinecarboxamide) -α- (6-chloro-3,4-dihydroxyphenyl) acetyl, α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -α -(6-fluoro-3,4-dihydroxyphenyl) acetyl, α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) benzothienylacetyl, α- (4-cyclopropyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- (2- Oxo-1-imidazolidinecarboxamide) -α-phenylacetyl, α- [3- (methylsulfonyl) -2-oxo-1-imidazolidinecarboxamide] -α-phenylacetyl, α- (4-hydroxy-1,5 -Naphthyridine-3-carboxamide) -α-phenylacetyl,
α- (4-phenyl-2,3-dioxo-1-piperazinecarboxamide) -α-phenylacetyl, α- [4
-(2,4-dichlorophenyl) -2,3-dioxo-
1-piperazinecarboxamide] -α-phenylacetyl, α- (4-oxo-4H-thiopyran-3-ylcarboxamide) -α-phenylacetyl, 2-thienyl-2-methoxyiminoacetyl, 2- (2-aminothiazole -4-yl) acetyl, 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl, α-
Difluoromethylthioacetyl, α- (cis-2-cyanovinyl) thioacetyl, α- [3- (4-phenylphenylcarbonyl) -3-methyl-1-ureido] -α
-Phenylacetyl, α-{[4- (4-chlorophenylimidazol) -2-yl] carboxamide} -α-
Phenylacetyl, isobutyryl, 2- (5-amino-
1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl, α- {1,2-dihydro-2-oxo-6- [2- (2-pyridyl) ethenyl] -3-pyridylcarboxamide} -Α- (4-hydroxyphenyl) acetyl, α- (5-hydroxy-4-pyridone-
2-carbonylamino) -α- (2-aminothiazol-4-yl) acetyl, 2- (6,7-sihydrooxychromone-3-carboxamide) -2- (4-hydroxyphenyl) acetyl, 2- ( 4-hydroxy-6-methylpyridin-3-yl) carboxamide-2- (4-
Hydroxyphenyl) acetyl, 2- {3- [2- (4
-Sulfamoylphenyl) amino-4-hydroxy-
5-pyrimidinyl]} ureido-2- (4-hydroxyphenyl) acetyl group and the like.

The lower alkoxy group represented by R ² includes, for example, a C _1-4 straight-chain or a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy group or the like. And branched alkoxy groups.

The lower acyl group represented by R ² includes, for example, a C _1-4 linear or branched acyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

The protected hydroxyl group of a lower alkyl group having a hydroxyl group or a protected hydroxyl group represented by R ² as a substituent and the protected hydroxyl group of a protected hydroxyl group represented by R ² are described in Chapter 2 of the above-mentioned document. (Pages 10 to 72). The above-mentioned substituted lower alkyl group represented by R ² may be the same or different type of a substituent selected from a hydroxyl group or the protected hydroxyl group shown above, and may be substituted on the same or different carbon by one or more. Good.

As the protecting group for the carboxylic acid represented by R ³ , besides various groups described in Chapter 5 (pages 152 to 192) of the above document, benzyl group, p-methoxybenzyl group, p-methoxybenzyl group -Nitrobenzyl group, diphenylmethyl group,
Examples thereof include a trichloroethyl group and a tert-butyl group.

Examples of the nitrogen-containing heterocyclic group having a free valence at nitrogen represented by Y include piperidino, morpholino,
1-piperazinyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 2-pyrolin-1-yl, 2-imidazolin-1-yl, 3-pyrazolin-1
-Yl, 1-indolinyl, 2-isoindolinyl, 1
-Pyrrolyl, 2-isoindolyl, 1-imidazolyl,
1-pyrazolyl, 1-benzimidazolyl, 1H-1-
Indazolyl, 1-triazolyl, 1-tetrazolyl,
And a phthaloyl group.

The heterocyclic ring of the above-mentioned substituted heterocyclic group represented by R ⁴ includes, for example, thienyl, furyl, pyrrolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, 1,2,2 3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, pyramidinyl, pyrazinyl, pyridazinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,4-triazinyl, imidazo [1,2 -B] [1,2,4] triazinyl, pyrrolidinyl, morpholinyl, quinuclidinyl, 2,3,4-
A 4-member containing at least one atom selected from oxygen, nitrogen and sulfur atoms such as a tritetrahydroquinolyl group;
5-membered, 6-membered or fused heterocyclic groups are mentioned. Further, the heterocyclic group containing a nitrogen atom may be quaternized.

The substituents which may be substituted on the above-mentioned substituted nitrogen-containing heterocyclic group represented by Y and the above-mentioned substituted lower alkyl group, substituted aryl group or substituted heterocyclic group represented by R ⁴ include halogen atoms, Hydroxyl group, nitro group, cyano group, aryl group, lower alkyl group, amino group, mono-lower alkylamino group, di-lower alkylamino group, mercapto group,
Group R ⁵ S- (R ⁵ is a lower alkyl group or an aryl group) alkylthio group or an arylthio group represented by, formyloxy group, a group R ⁵ COO- acyloxy group (R ⁵ is as defined above) represented by a formyl group , based on R ⁵ CO-
Acyl group (R ⁵ is as defined above) represented by the group R ⁵ O
An alkoxy group or an aryloxy group, a carboxy group, a group R ⁵ OCO— represented by — (R ⁵ is the same as described above)
(R ⁵ is the same as described above), for example, an alkoxycarbonyl group or an aryloxycarbonyl group. Further, the nitrogen-containing heterocyclic group represented by Y and the lower alkyl group, aryl group or heterocyclic group represented by R4 are the same or different types of substituents selected from the above substituents,
One or more may be substituted on the same or different atoms.

The compound of the present invention of the general formula (1) wherein n is 1 or 2 has the general formula

[0018]

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Wherein R ¹ , R ² and R ³ are as defined above.
m represents 1 or 2. ] To the 2-exomethylene penamoxide derivative represented by the general formula YH (3) wherein Y is the same as defined above. And a nucleophile represented by the following formula:

This reaction is performed in a suitable solvent.
Such solvents include, for example, methanol, ethanol,
Propanol, isopropanol, butanol, tert-
Alcohols such as butanol, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate,
Lower alkyl esters of lower carboxylic acids such as ethyl propionate, acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, ketones such as diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether,
Ethers such as dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and benzene , Toluene, xylene, chlorobenzene, substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as freons, Aliphatic hydrocarbons such as pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane; dimethylform Amides such as dimethylacetamide, and dimethyl sulfoxide. These may be used alone or as a mixture of two or more. Further, these organic solvents may contain water as necessary. Such a solvent is used in an amount of usually about 10 to 200 l, preferably 2 to 1 kg of the compound of the formula (2).
It is preferable to use about 0 to 100 l.

A base may be present in the reaction system of the reaction. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, calcium hydroxide, barium hydroxide and the like. Alkaline earth metal hydroxides, alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydrides such as lithium hydride, potassium hydride and sodium hydride, methyllithium, n
Alkyl or aryl lithium such as -butyllithium and phenyllithium; The base is used in an amount of usually 0.001 to 10 times, preferably 0.01 to 1 times the mole of the compound of the formula (2).

The amount of the nucleophile represented by the formula (3) is usually 1 to 50 times, preferably 1 to 10 times the mol of the compound of the formula (2). Is good. Prior to the reaction, a nucleophile of the general formula (3) is reacted with a base to give a general formula YM (4) wherein M represents an alkali metal or an alkaline earth metal. May be prepared in advance.

The above reaction is carried out usually at about -78 to 100 ° C, preferably at about -78 to 50 ° C.

The compound of the present invention of the general formula (1) wherein n is 1 or 2 obtained by the above reaction can be obtained by a conventional isolation and purification means, for example, filtration, recrystallization, column chromatography, preparative thin-layer chromatography and the like. Can be isolated and purified from the reaction mixture.

The compound of the general formula (1) in which n is 1 or 2 is subjected to a usual reduction treatment known in the art, and specifically, according to J. Chem. Soc., Perkin. Trans.
1,932 (1973), Tetrahedron Lett., 13,971 (1976), Japanese Patent Publication No. 56-24675, or a method analogous thereto, the corresponding general formula (1) wherein n is 0 The compound of the present invention can be derived.

The compound of the present invention represented by the general formula (1) wherein n is 0 obtained by the above reaction can be reacted by a conventional isolation and purification means such as filtration, recrystallization, column chromatography, preparative thin layer chromatography and the like. It can be isolated and purified from a mixture.

In the present invention, the 2-exomethylene penamoxide derivative represented by the general formula (2) used as a starting material is produced, for example, by the following method. That is, the general formula

[0028]

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Wherein R ¹ , R ² and R ³ are as defined above. ] Can be easily produced by oxidizing the 2-exomethylene penum derivative represented by the formula [1] using an oxidizing agent.

This reaction is performed in a suitable solvent.
Such solvents include, for example, methanol, ethanol,
Propanol, isopropanol, butanol, tert-
Alcohols such as butanol, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate,
Lower alkyl esters of lower carboxylic acids such as ethyl propionate, acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, ketones such as diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether,
Ethers such as dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and benzene , Toluene, xylene, chlorobenzene, substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as freons, Aliphatic hydrocarbons such as pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane; dimethylform Amides such as dimethylacetamide, and dimethyl sulfoxide. These may be used alone or as a mixture of two or more. Further, these organic solvents may contain water as necessary. Such a solvent is used in an amount of usually about 10 to 200 l, preferably 2 to 1 kg of the compound of the formula (5).
It is preferable to use about 0 to 100 l.

As the oxidizing agent used in this reaction, the oxidizing agent widely used for oxidizing sulfides can be used.
Specifically, manganese dioxide, chromate, lead tetraacetate, ruthenium tetroxide, inorganic oxides such as potassium permanganate, periodate, periodic acids such as sodium periodate, N-bromosuccinimide, N-halocarboxylic acid amides such as N-chlorosuccinimide;
Examples thereof include organic peracids such as butyl, hydrogen peroxide, formic acid, peracetic acid, and metachloroperbenzoic acid, and combinations of hydrogen peroxide with lower carboxylic acids such as formic acid and acetic acid. The amount of the oxidizing agent used is n = 2 when the substrate or target substance is n = 1.
The amount is usually 1 to 20 times, preferably 1 to 5 times the mol of the compound of the general formula (5).

The reaction temperature of the above reaction is usually -50 to 80
° C, preferably about -10 to 50 ° C.

The compound of the general formula (2) obtained by the above reaction is isolated and purified from the reaction mixture by a usual isolation and purification means, for example, filtration, recrystallization, column chromatography, preparative thin layer chromatography and the like. obtain.

The compound of the above general formula (5) used as a starting material in the above is, for example,

[0035]

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Wherein R ¹ , R ² and R ³ are as defined above.
X is a group -SO ₂ R ⁴ or a group -SR ^4. Where R ⁴
Is the same as above. Can be easily synthesized by reacting the allenyl β-lactam compound represented by the formula [1] with a metal reducing agent.

The reaction for obtaining the compound of the general formula (5) from the compound of the general formula (6) is carried out in an organic solvent. As the organic solvent, conventionally known organic solvents can be widely used as long as they dissolve the compound of the general formula (6) and are inert under the conditions of the reaction. For example, methanol, ethanol, propanol, isopropanol, butanol, tert. Alcohols such as butanol, lower alkyl esters of lower carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate, acetone , Methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone,
Ketones such as diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, ethers such as methyl cellosolve, dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, acetonitrile, propio Nitriles such as nitrile, butyronitrile, isobutyronitrile, valeronitrile, benzene, toluene, xylene, chlorobenzene,
Substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, and fluorocarbons; aliphatic hydrocarbons such as pentane, hexane, heptane, and octane; cyclopentane, cyclohexane, cycloheptane, and cyclooctane such as cyclooctane Examples thereof include alkanes, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. These may be used alone or as a mixture of two or more. Further, these organic solvents may contain water as necessary. Such a solvent is 1 kg of the compound of the general formula (6).
It is usually good to use about 0.5 to 200 l, preferably about 10 l.

Examples of the metal reducing agent used in the above reaction include metal lead, metal titanium, metal zirconium, metal gallium, metal bismuth, metal antimony and the like. The shape of these metals to be reacted is not particularly limited, and a wide range of forms such as powder, plate, lump, and wire can be used. In order to complete the above reaction at a lower temperature and in a shorter time, it is advantageous to use a powdered metal. When a powdery metal is used as the metal reducing agent, its particle size can be appropriately selected from a wide range, but it is preferable to use one having a mesh size of about 10 to 500 mesh. The amount of the metal reducing agent to be used is generally about 1 to 10 times, preferably about 1 to 4 times the molar atom of the compound of the formula (6).

In the above reaction, it is preferable that a metal having a higher ionization tendency than the above-mentioned metal reducing agent coexist in the reaction system. By coexisting such a metal, the amount of the metal reducing agent used can be extremely reduced, the post-treatment after the reaction is facilitated, and the reaction is performed at a lower temperature and in a shorter time. Can be. Specific examples of the combination of the metal reducing agent and a metal having a higher ionization tendency include Pb / Al, Bi / Al, and Ti / Z.
n, Ga / Zn, Zr / Zn, Sb / Zn, Te / Z
n, Pb / Zn, Bi / Zn, Bi / Mg, Bi / S
n, Sb / Sn, and the like. The shape of these metals coexisting with the metal reducing agent is also not particularly limited, and may be powdery, plate-like,
A wide range of forms such as foil, lump, and wire can be used,
In order to complete the above reaction at a lower temperature and in a shorter time, it is advantageous to use a powdered metal. The particle size of the powdery metal can be appropriately selected from a wide range.
It is desirable to use one having about 0 mesh. The amount of these metals used is usually 1 to the compound of the general formula (6).
It is good to be about 50 times mole atom, preferably about 1 time to 10 times mole atom.

In the above reaction, when a metal having a higher ionization tendency than the above-mentioned metal reducing agent is used in combination, it is more preferable to use a compound of such a metal instead of the above-mentioned metal reducing agent. Specific examples of such metal compounds include lead halides such as lead fluoride, lead chloride, lead bromide, and lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate, and the like. Inorganic lead, fatty acid lead such as lead acetate, lead oxalate, lead stearate, etc., titanium oxide such as lead oxide, lead hydroxide, titanium fluoride, titanium chloride, titanium bromide, titanium iodide, titanium sulfate, nitric acid Inorganic acid titanium such as titanium, gallium fluoride, gallium chloride, gallium bromide, gallium halide such as gallium iodide, gallium sulfate, gallium nitrate, inorganic gallium such as gallium perchlorate, zirconium fluoride, zirconium chloride, Zirconium halides such as zirconium bromide and zirconium iodide, zirconium sulfate, tellurium chloride, tellurium bromide, tellurium halide such as tellurium iodide, bismuth fluoride, and vinyl chloride Mass, bismuth bromide, halides of bismuth, such as iodide bismuth, bismuth nitrate, bismuth inorganic acids such as sulfuric acid bismuth, bismuth oxide,
Examples include antimony halides such as antimony fluoride, antimony chloride, antimony bromide, and antimony iodide, inorganic antimony such as antimony sulfate, and antimony oxide. The amount of use of these metal compounds may theoretically be such that one molecule is present in the reaction system, but is usually about 0.0001 to 2 times the molar amount of the compound of the general formula (6). Good to do.

The reaction temperature of the above reaction varies depending on the starting materials, the organic solvent used, and the like, and cannot be determined unconditionally.
The temperature is about 20 to 100 ° C, preferably about 0 to 50 ° C.

Incidentally, in the reaction, when the reaction is carried out under irradiation of ultrasonic waves, the reaction may proceed more quickly.

After completion of the above reaction, the desired 2-exomethylenepenam derivative of the general formula (5) can be isolated in a substantially pure form by, for example, performing a usual extraction operation. If further purification is necessary, conventional purification means such as recrystallization and column chromatography may be employed.

The compound represented by the general formula (6) is
For example, the general formula

[0045]

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[Wherein R ¹ , R ² , R ³ and X are as defined above. R ⁶ represents a lower alkyl group which may have a substituent or an aryl group which may have a substituent. The azetidinone derivative represented by the above formula is reacted with a base.

In this reaction, the base used is preferably an aliphatic amine or an aromatic amine, and specifically, triethylamine, diisopropylamine, ethyldiisopropylamine, tributylamine, 1,5-diazabicyclo [3.4.0] ] Nonene-5 (DBN),
1,5-diazabicyclo [5.4.0] undecene-5
(DBU), 1,4-diazabicyclo [2.2.0] octane (DABCO), piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, morpholine, N-methylmorpholine, N, N -Dimethylaniline, N, N-dimethylaminopyridine and the like. The amount of the base to be used is generally 1 to 12 moles, preferably 1 to 6 moles, per 1 mole of the compound of the formula (4). In addition, as the solvent, the general formula (7)
Can be widely used as long as it dissolves the compound of formula (I) and is inactive under the conditions of the reaction. Examples thereof include methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, and the like. Lower alkyl esters of lower carboxylic acids such as butyl acetate, methyl propionate, and ethyl propionate; ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, and dimethoxyethane , Tetrahydrofuran, cyclic ethers such as dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, benzene, toluene, xylene, chlorobenzene,
Substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, and fluorocarbons; aliphatic hydrocarbons such as pentane, hexane, heptane, and octane; cyclopentane, cyclohexane, cycloheptane, and cyclooctane such as cyclooctane Examples thereof include alkanes, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. These may be used alone or as a mixture of two or more. Further, these solvents may contain water as necessary. Such a solvent is generally used in an amount of about 0.5 to 200 l, preferably 1 to 50 l, per kg of the compound of the formula (7).
It should be used to a degree. The reaction is -70 to 100
C, preferably in the range of -50 to 50C. The compound of the general formula (6) thus obtained is, after completion of the reaction,
Although it can be obtained as a substantially pure product by performing a usual extraction operation or crystallization operation, it is needless to say that purification can be performed by other methods.

The compound of the general formula (7) is described in, for example,
It is manufactured according to the method described in 1-116567.

Examples of the salt of the penum derivative of the present invention include commonly known salts of a basic group such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group. Examples of the salt in the basic group include a salt with a mineral acid such as hydrochloric acid and sulfuric acid; a salt with a carboxylic acid such as formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; Salts with sulfonic acids such as toluenesulfonate, mesitylenesulfonic acid, naphthalenesulfonic acid and the like, and salts in the acidic group such as salts with alkali metals such as sodium and potassium; alkaline earths such as calcium and magnesium Salts with similar metals; ammonium salts; triethylamine, triethylamine, tributylamine, pyridine, N, N-
Dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β
And salts with nitrogen-containing organic bases such as -phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine and the like.

When isomers (eg, optical isomers, geometric isomers, tautomers, etc.) are present in the compound of the formula (1) and salts thereof, the present invention includes all such isomers. And also encompasses all crystal forms and hydrates.

The penum derivative of the general formula (1) obtained in the present invention can further be prepared, for example, by esterification, hydrolysis, addition, acylation, oxidation, reduction, cyclization, halogenation, alkylation,
Commonly known methods such as amination, thiolation, quaternization, aryloxylation, alkylamination, Wittig reaction and the like, and useful synthesis which can be derived into other penum derivatives by appropriately combining these methods It is also an intermediate.

The compound of the general formula (1) or a salt thereof can be prepared by a method widely known in the art, for example, J. Chem. Soc., 83 , 3
20 (1903), JP-B-49-40479, JP-B-45
According to the method, or a method analogous thereto described in -40899 Patent Publication, by leaving an acyl group or an amino protecting group of the protected amino group represented by R ^1, the general formula R ¹ is an amino group (1 ) Can be produced.

Further, the compound of the general formula (1) wherein R ¹ is an amino group or a reactive derivative at the amino group is described in, for example, JP-A-59-9308 and JP-A-62-13.
Reaction with a carboxylic acid corresponding to the acyl group exemplified as the acyl group for R ¹ or a reactive derivative of the carboxyl group thereof according to the method described in JP-A-5577, JP-A-63-115888, or a method analogous thereto. Can be acylated.

The reactive derivative at the amino group of the compound of the general formula (1) wherein R ¹ is an amino group includes, for example, silyl derivatives formed by reaction with bis (trimethylsilyl) acetamide, trimethylsilylacetamide, etc .; isocyanates; Thiocyanates; Schiff bases formed by reaction with aldehydes such as acetaldehyde and benzaldehyde, and ketones such as acetone and methyl ethyl ketone, and enamine-type tautomers thereof.

Examples of the reactive derivative at the carboxyl group of the carboxylic acid corresponding to the acyl group exemplified as the acyl group for R ¹ include acid halides such as acid chlorides and acid bromides; substituted phosphoric acids, dialkyl phosphorous acids, and the like. Acid anhydrides with acids such as sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate, organic carboxylic acids, etc .; active acid amides with imidazole, dimethylpyrazole, etc .; p-nitrophenol, benzenethiol, 2-benzothiazolylthiol, etc. Active thioesters with thiols; active esters with N-hydroxy compounds such as N-hydroxypiperidine, N-hydroxysuccinimide, N-hydroxyphthalimide and the like.

In the compound of the general formula (1) of the present invention,
When R ³ is a carboxylic acid protecting group, the elimination method of various carboxylic acid protecting groups described in Chapter 5 (pages 152 to 192) of the above document, JP-A-50-17991, JP-A-52-106891, JP-A-61-26398
The compound of the general formula (1) in which R ³ is a hydrogen atom can be derived by the method described in JP-A No. 4 (1994) -104, etc.

The compound of the general formula (1) of the present invention has high antibacterial activity and is useful as an agent for preventing or treating bacterial infections.

In administering the compound of the general formula (1) of the present invention and a salt thereof for the purpose of prevention and treatment, the compound contains the compound as an active ingredient and is suitable for oral, parenteral and external administration. It is used in a conventional formulation mixed with a pharmaceutically acceptable carrier such as an organic or inorganic, solid or liquid excipient. The preparation may be in the solid state such as tablets, granules, powders, capsules or the like, or in the liquid state such as solutions, suspensions, syrups, emulsions, lemonades and the like. In addition, if desired, the above preparations may be supplemented with auxiliary substances, stabilizers, lubricants and other conventional additives such as lactose, magnesium stearate, china clay, sucrose, corn starch, talc, stearic acid, gelatin, Agar, pectin, peanut oil,
Olive oil, cocoa butter, ethylene glycol and the like may be mixed.

The dose of the compound of the general formula (1) is selected according to the age and condition of the patient, the type of the disease, the type of the compound of the general formula (1) to be administered, and the like. Generally 1mg a day
From about 4000 mg, or even higher, to a patient. For the treatment of pathogenic infections, the average dose of the compound of the general formula (1) per dose is about 50 mg, 100 m
g, 250 mg, 500 mg, 1000 mg, 2000
mg amounts can be used.

[0060]

The present invention will be further clarified with reference to the following Reference Examples and Examples.

[0061]

REFERENCE EXAMPLE 1 A compound of the general formula (7) wherein R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a diphenylmethyl group, X is a phenylsulfenyl group and R ⁵ is a trifluoromethyl group 1 g of “compound (7a)” is dissolved in 10 ml of N, N-dimethylformamide, which is cooled to −30 ° C.
43 ml was added, and the mixture was stirred and reacted at -30 ° C for 1 hour.
The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous sodium sulfate. When the extract is concentrated under reduced pressure, R ¹ is a phenylacetamide group, R ² is a hydrogen atom,
A compound of the general formula (6) wherein R ³ is a diphenylmethyl group and X is a phenylsulfenyl group (hereinafter referred to as “compound (6
a) is obtained in a yield of 99%.

NMR (CDCl ₃ ): δ ppm; 3.6
1 (s, 2H), 5.31 (dd, 1H, J = 5 Hz and 7 Hz), 5.57 and 5.70 (ABq, 2H, J
= 15 Hz), 5.84 (d, 1H, J = 5 Hz),
6.02 (d, 1H, J = 7 Hz), 6.81 (s, 1
H), 7.22-7.73 (m, 20H)

[0063]

Reference Example 2-7 The same reaction as in Reference Example 1 was carried out using the starting compounds shown in Table 1 to obtain the following compounds.

[0064]

[Table 1]

The following summarizes the NMR data.

NMR (CDCl ₃ ): δ ppm; Compound (6b): 3.58 (s, 2H), 3.80
(S, 3H), 5.10 (s, 2H), 5.32 (d
d, 1H, J = 5 Hz and 8 Hz), 5.60 and 5.
47 (ABq, 2H, J = 15 Hz), 5.87 (d,
1H, J = 5 Hz), 6.08 (d, 1H, J = 8H)
z), 6.85-7.83 (m, 14H) Compound (6c): 3.59 (s, 2H), 3.74
(S, 3H), 5.33 (dd, 1H, J = 5 Hz and 8 Hz), 5.54 and 5.64 (ABq, 2H, J =
5.15 (d, 1H, J = 5 Hz);
02 (d, 1H, J = 8 Hz), 7.20-7.90
(M, 10H) Compound (6d): 3.67 (s, 2H), 5.25 (d
d, 1H, J = 5 Hz and 8 Hz), 5.69 (d, 1
H, J = 5 Hz), 5.60 and 5.76 (ABq, 2
H, J = 15 Hz), 6.71 (s, 1H), 7.00
-7.34 (m, 20H) Compound (6e): 3.02 (dd, 1H, J = 2.6H)
z and 15.7 Hz), 3.58 (dd, 1H, J =
5.4 Hz and 15.7 Hz), 3.79 (s, 3
H), 5.17 (s, 2H), 5.47 and 5.60.
(ABq, 2H, J = 15.2 Hz), 5.62 (d
d, 1H, J = 2.6 Hz and 5.4 Hz), 6.87
-7.89 (m, 9H)

[0067]

Reference Example 8-10 The same reaction as in Reference Example 1 was carried out except that the reaction solvent and the reaction temperature were changed.
Are obtained in the yields indicated.

[0068]

[Table 2]

[0069]

Reference Example 11 100 mg of the compound (6a) was dissolved in 1 ml of N, N-dimethylformamide. To this, 50 mg of zinc powder was added, followed by 50 mg of BiCl ₃ ,
The reaction was carried out with stirring at room temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution thus obtained, and the mixture was extracted with ethyl acetate. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. When the obtained concentrated residue was purified using silica gel column chromatography, R
¹ is a phenylacetamide group, R ² is a hydrogen atom and R ³
Is a p-methoxybenzyl group (hereinafter referred to as “compound (5a)”) in a yield of 92%.

NMR (CDCl ₃ ): δ ppm; 3.6
1 (ABq, 2H, J = 16 Hz), 3.80 (s, 3
H), 5.11 (s, 2H), 5.18 (t, 1H, J
= 1 Hz), 5.24 (t, 1H, J = 1 Hz), 5.24.
35 (t, 1H, J = 1 Hz), 5.57 (d, 1H,
J = 4 Hz), 5.75 (dd, 1H, J = 4 Hz and 9 Hz), 6.07 (d, 1H, J = 9 Hz), 6.8
5-7.40 (m, 9H)

[0071]

Reference Example 12 A compound of the general formula (6) wherein R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a diphenylmethyl group and X is a phenylsulfenyl group (hereinafter referred to as “compound (6b)”) The same reaction as in Reference Example 11 was performed using 200 mg, and R ¹ was a phenylacetamide group, R ²
Is a hydrogen atom and R ³ is a diphenylmethyl group (hereinafter referred to as “compound (5b)”) in a yield of 89%.

NMR (CDCl ₃ ): δ ppm; 3.6
2 (s, 2H), 5.26-5.28 (m, 2H),
5.37 (t, 1H, J = 2 Hz), 5.61 (d, 1
H, J = 4 Hz), 5.76 (dd, 1H, J = 4 Hz)
And 9 Hz), 6.14 (d, 1H, J = 9 Hz),
6.82 (s, 1H), 7.20-7.41 (m, 15
H)

[0073]

Reference Example 13 A compound of the general formula (6) wherein R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a methyl group and X is a phenylsulfenyl group (hereinafter referred to as “compound (6
c) 50 mg) in 0.5 ml of N, N-dimethylformamide. Add 50mg of zinc powder and T
10 μl of iCl ₄ was added and reacted while stirring at room temperature for 25 minutes. The same post-processing as in Reference Example 11 was performed, and R ¹
Is a phenylacetamide group, R ² is a hydrogen atom and R ³ is a methyl group (hereinafter referred to as “compound (5c)”) in a yield of 95%.

NMR (CDCl ₃ ): δ ppm; 3.6
2 (ABq, 2H, J = 16 Hz), 3.78 (s, 3
H), 5.19 (t, 1H, J = 2 Hz), 5.28
(T, 1H, J = 2 Hz), 5.40 (t, 1H, J =
2 Hz), 5.60 (d, 1H, J = 4 Hz), 5.7
7 (dd, 1H, J = 4 Hz and 9 Hz), 6.20
(D, 1H, J = 9 Hz), 7.27-7.39 (m,
5H)

[0075]

[Reference Example 14] R ¹ and R ² are both hydrogen atoms, and R ³ is p
A compound of the general formula (6) wherein -methoxybenzyl group and X is a phenylsulfenyl group (hereinafter referred to as “compound (6d)”
189 mg of the compound of the general formula (5) in which both R ¹ and R ² are hydrogen atoms and R ³ is a p-methoxybenzyl group (hereinafter referred to as “compound (5d)”). ) Was obtained with a yield of 88%.

NMR (CDCl ₃ ): δ ppm; 3.1
6 (dd, 1H, J = 1.5 Hz and 16 Hz);
66 (dd, 1H, J = 4 Hz and 16 Hz), 3.8
2 (s, 3H), 5.13 (s, 2H), 5.24 (d
d, 1H, J = 1.8 Hz and 1.8 Hz), 5.28
(Dd, 1H, J = 1.8 Hz and 1.8 Hz), 5.
32 (dd, 1H, J = 1.8 Hz and 1.8 Hz),
5.38 (dd, 1H, J = 1.5 Hz and 4 Hz),
6.87-7.30 (m, 4H)

[0077]

Reference Example 15-20 Except that the metal and the metal salt were changed,
The same reaction as in Reference Example 11 is carried out to obtain compound (5a). Table 3 shows the results.

[0078]

[Table 3]

[0079]

Reference Example 21 50 mg of the compound (5a) was dissolved in 3 ml of methylene chloride. 30 mg of m-chloroperbenzoic acid is added thereto under ice cooling, and the mixture is stirred and reacted for 30 minutes. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. When the concentrated residue is purified by silica gel column chromatography, R
General formula (2) wherein ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a p-methoxybenzyl group and n is 1.
(Hereinafter referred to as “compound (2a)”) with a yield of 90
%.

NMR (CDCl ₃ ): δ ppm; 3.6
0 (s, 2H), 3.81 (s, 3H), 4.80
(D, 1H, J = 4.4 Hz), 4.11 and 5.24
(ABq, 2H, J = 11.7 Hz), 5.44 (d
d, 1H, J = 2.4 Hz, 2.4 Hz), 5.91
(Dd, 1H, J = 2.4 Hz, 2.4 Hz), 6.1
5 (dd, 1H, J = 4.4 Hz, 10.4 Hz),
6.19 (dd, 1H, J = 2.4 Hz, 2.4H
z), 7.11 (d, 1H, J = 10.4 Hz), 6.
85-6.93 (m, 2H), 7.22-7.40
(M, 7H)

[0081]

Reference Example 22 51.4 mg of the compound (5a) was dissolved in 3 ml of methylene chloride. M-chloroperbenzoic acid 1
26 mg is added and reacted by stirring at room temperature for 6 hours. When the reaction mixture was post-treated in the same manner as in Example 1, a compound of the general formula (2) in which R ¹ was a phenylacetamide group, R ² was a hydrogen atom, R ³ was a p-methoxybenzyl group, and n was 2 (hereinafter referred to as “ Compound (2b) ") in a yield of 90%.

NMR (CDCl ₃ ): δ ppm; 3.6
6 (s, 2H), 3.82 (s, 3H), 4.60
(D, 1H, J = 4.4 Hz), 5.11 and 5.25
(ABq, 2H, J = 11.7 Hz), 5.26 (d
d, 1H, J = 2.6 Hz, 2.6 Hz), 5.97
(Dd, 1H, J = 2.6 Hz, 2.6 Hz), 6.1
4. (dd, 1H, J = 2.6 Hz, 2.6 Hz);
17 (dd, 1H, J = 4.4 Hz, 10.7 Hz),
6.97 (d, 1H, J = 10.7 Hz), 6.86 −
6.93 (m, 2H), 7.23-7.40 (m, 7
H)

[0083]

REFERENCE EXAMPLE 23 A compound of the formula (5) in which R ¹ is a phenylacetamide group, R ² is a hydrogen atom and R ³ is a diphenylmethyl group (hereinafter referred to as “compound (5b)”) 30
mg in 1 ml of methylene chloride. To this, 15 mg of m-chloroperbenzoic acid is added under ice cooling, and the mixture is stirred and reacted for 20 minutes. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate, hypo-water, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. When the concentrated residue was purified by silica gel column chromatography, R ¹ was a phenylacetamide group,
R ² is a hydrogen atom, R ³ is a diphenylmethyl group and n is 1
(Hereinafter referred to as “compound (2c)”) in a yield of 92%.

NMR (CDCl ₃ ): δ ppm; 3.6
3. 0 and 3.61 (ABq, 2H, J = 16 Hz);
82 (d, 1H, J = 4 Hz), 5.35 (t, 1H,
J = 2.5 Hz) 5.80 (t, 1H, J = 2.5H
z), 6.14 (t, 1H, J = 2.5 Hz), 6.1
8 (dd, 1H, J = 4 Hz and 10 Hz), 6.95
(S, 1H), 7.13 (d, 1H, J = 10 Hz),
7.02-7.40 (m, 15H)

[0085]

Reference Example 24 85 mg of the compound (5d) is dissolved in 6 ml of methylene chloride. M-chloroperbenzoic acid 30
0 mg is added, and the mixture is stirred and reacted at room temperature for 2 hours. When the reaction mixture was treated in the same manner as in Example 1, a compound of the general formula (2) in which both R ¹ and R ² were a hydrogen atom, R ³ was a p-methoxybenzyl group and n was 2 (hereinafter referred to as “compound (2d)
Is obtained with a yield of 78%.

NMR (CDCl ₃ ): δ ppm; 3.4
9 (dd, 1H, J = 2.3 Hz and 15.9 Hz),
3.58 (dd, 1H, J = 3.6 Hz and 15.9H
z), 3.83 (s, 3H), 4.52 (dd, 1H,
J = 2.3 Hz and 3.6 Hz), 5.13 and 5.2
6 (ABq, 2H, J = 11.6 Hz), 5.25 (d
d, 1H, J = 2.7 Hz and 2.7 Hz), 6.02
(Dd, 1H, J = 2.7 Hz and 2.7 Hz), 6.
23 (dd, 1H, J = 2.7 Hz and 2.7 Hz),
6.89-7.33 (m, 4H)

[0087]

Example 1 0.6 mg of sodium hydride (content 60
%) Is weighed into a reactor and dried under reduced pressure. 1 ml of tetrahydrofuran and 15.2 mg of methyl 3-mercaptopropionate are added thereto, and the mixture is stirred at room temperature for 30 minutes. Subsequently, the reactor is cooled by immersing it in a dry ice-acetone bath, a solution of 30 mg of compound (2a) dissolved in 1 ml of tetrahydrofuran is added, and the mixture is stirred and reacted at -50 ° C for 1 hour. The reaction mixture was extracted with ethyl acetate,
The extract is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure and purifying by column chromatography, R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a p-methoxybenzyl group, Y is a 2-methoxycarbonylethylthio group and n
Is 1 (hereinafter referred to as “compound (1
a) ") in a yield of 95%.

IR (CHCl ₃ ): 1798, 173
8,1682,1613,1518,1439cm ^-1

[0089]

Example 2 A compound of the general formula (3) in which Y is an allylthio group was used instead of methyl 3-mercaptopropionate, and R ¹ was a phenylacetamide group and R ² was a hydrogen atom in the same manner as in Example 1. , A compound of the general formula (1) in which R ³ is a p-methoxybenzyl group, Y is an allylthio group and n is 1 (hereinafter referred to as “compound (1b)”) in a yield of 85%
Is obtained.

IR (CHCl ₃ ): 1800, 174
4,1684,1613,1516cm ^-1

[0091]

Example 3 General formula (3) wherein Y is a 2-hydroxyethylthio group instead of methyl 3-mercaptopropionate
In the same manner as in Example 1, R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a p-methoxybenzyl group, Y is a 2-hydroxyethylthio group and n
Is 1 (hereinafter referred to as “compound (1
c) ") in a yield of 91%.

IR (CHCl ₃ ): 3382,296
4,1796,1744,1682,1613,151
8cm ^-1

[0093]

Example 4 Y is (CH ₃ CONH) (CH ₃ COO) CHCH ₂ instead of methyl 3-mercaptopropionate
Using a compound of the general formula (3), which is an S-group ((2-acetamido-2-methoxycarbonyl) ethylthio group), as in Example 1, R ¹ is a phenylacetamido group, R ² is a hydrogen atom, A compound of the general formula (1) in which R ³ is a p-methoxybenzyl group, Y is a (2-acetamido-2-methoxycarbonyl) ethylthio group and n is 1 (hereinafter referred to as “compound (1d)”) has a yield of 95. %.

IR (CHCl ₃ ): 2960, 179
8, 1744, 1676, 1615, 1586, 151
8cm ^-1

[0095]

Example 5 The compound (1a) was obtained in the same manner as in Example 1 except that the compound of the general formula (3) in which Y was a 2-methoxycarbonylethylthio group was used instead of methyl 3-mercaptopropionate. Obtained at 76%.

IR (CHCl ₃ ): 2936,179
4,1744,1667,1615,1586,151
8cm ^-1

[0097]

Example 6 3-mercapto in place of methyl propionate with a compound of the general formula Y is 2-furyl methyl thio group (3), in the same manner as in Example 1, R ¹ is phenylacetamido group, R ² Is a hydrogen atom, R ³ is a p-methoxybenzyl group, Y is a 2-furylmethylthio group and n is 1 (hereinafter referred to as “compound (1e)”) in a yield of 59%. Can be

IR (CHCl ₃ ): 2938, 179
2,1734,1661,1615,1589,149
5cm ^-1

[0099]

Example 7 36.2 mg of the compound (1a) was dissolved in 2 ml of N, N-dimethylformamide and cooled to -30 ° C. To this, 12 µl of phosphorus tribromide was added, and the mixture was added at -30 ° C for 1 hour.
Stir for hours to react. The reaction mixture was extracted with ethyl acetate, washed with saturated saline, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure and purifying by column chromatography, R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a p-methoxybenzyl group, Y is a 2-methoxycarbonylethylthio group and a compound of the general formula (1) wherein n is 0 (hereinafter referred to as “compound (1
f) ") in a yield of 85%.

IR (neat): 1785, 1734, 1
669, 1615, 1586, 1518, 1456, 1
439 cm ^-1

[0101]

Example 8 Using compound (1b) and treating in the same manner as in Example 7, R ¹ is a phenylacetamide group, R ² is a hydrogen atom, R ³ is a p-methoxybenzyl group, Y is an allylthio group and n Is 0 (hereinafter, referred to as “compound (1g)”) in a yield of 74%.

IR (neat): 1787, 1744, 1
667, 1613, 1586, 1518, 1456cm
^-1

[0103]

Example 9 13 mg of the compound (1f) was added to 1 ml of phenol melted at 45 ° C., and 2 μl of 35% hydrochloric acid was added thereto.
Add l. After reacting with stirring at the same temperature for 2 hours, the mixture was diluted with ethyl acetate and extracted with a 5% aqueous potassium hydrogen carbonate solution. After neutralizing the extracted aqueous solution with 5% hydrochloric acid, it is released on a Sephadex LH-20 column, and the product-containing release is collected and lyophilized to give R ^{1 a} phenylacetamide group, R ^{2 a} hydrogen atom, A compound of the general formula (1) in which ³ is K and Y is a 2-methoxycarbonylethylthio group and n is 0 (hereinafter, referred to as “compound (1h)”) is obtained.

IR (KBr): The in-vitro antibacterial activity test was performed on the compound (1h): 1782, 1740, 1672, 1624 cm ^-1 according to the following method. That is, the antibacterial activity in a test tube was determined by a two-fold agar plate dilution method. Each test species 20-hr cultured tested species in broth for measuring sensitivity (viable bacterial count: about 10 ⁸ / ml) and 0.005ml of inoculation sensitive measuring agar medium containing antimicrobial agent at various concentrations And 37
After incubation for 20 hours at ℃, the minimum inhibitory concentration (MIC)
It was measured in g / ml. Table 4 shows the results.

[0105]

[Table 4]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 499/46 C07D 499/04 E 499/87 499/897 (72) Inventor Michio Sasaoka 463 Kasuno, Kawauchi-cho, Tokushima, Tokushima Prefecture Otsuka Inside the Tokushima Research Laboratories of Chemical Co., Ltd. (72) Inventor Takashi Shiro 463 Kagasuno, Kawauchi-machi, Tokushima City, Tokushima Prefecture Inside the Tokushima Research Laboratories Co., Ltd. (56) References JP-A-3-258784 (JP, A) JP-A-2-204494 (JP, A) JP-A-3-206038 (JP, A) JP-A-1-283288 ( JP, A) JP-A-2-72180 (JP, A) Chem. Soc. , Perkin Trans. 1 (1974), (1), pages 22-25. Chem. Soc. , Chem. Commun. (1986), (3), pages 273-275 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 499/00-499/82 A61K 31/43 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent, a hydroxyl group, or a protected hydroxyl group. Alternatively, R ¹ and R ² may combine with each other to form an oxo group. R ³ represents a hydrogen atom or a carboxylic acid protecting group. n represents 0, 1 or 2. Y is a halogen atom,
Group -N _3, group -ONO _2, group -OR ^4, group -OCO
R ⁴ , group —SCSOR ⁴ , group —SCSN (R ⁴ ) ₂ , group —SR ⁴ , group —SO ₂ R ⁴ , group —NHR ⁴ , group —N (R
⁴ ) A nitrogen-containing heterocyclic group having a free valence at ₂ or an optionally substituted nitrogen. R ⁴ represents a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent. And a salt thereof. 2. A compound of the general formula Wherein R ¹ , R ² and R ³ are the same as above. m is 1 or 2
Is shown. And a general formula YH wherein Y is the same as defined above. A method for producing a penum derivative, characterized in that the compound of the formula (1) is obtained by reacting a nucleophile represented by the formula (1). 3. A method for producing a penum derivative according to claim 1, wherein the sulfoxide of the compound wherein n of the penum derivative is 1 is reduced to obtain a compound wherein n of the penum derivative is 0.