JPWO2008114831A1 - Antibacterial agent having sulfonamide group - Google Patents

Abstract

Provided is an antibacterial agent having a simple structure, which can be easily produced at low cost on an industrial scale, and which has a compound having an excellent antibacterial effect against drug-resistant bacteria such as MRSA and VRE. In addition, compounds useful as prodrugs of the compounds are provided. An antibacterial agent containing compound (I) or a salt thereof or a prodrug thereof. Compound (II) or a salt thereof. (In the formula, each symbol has the same meaning as in the specification.)

Description

  The present invention relates to a compound having excellent antibacterial effect against drug-resistant bacteria (particularly methicillin-resistant Staphylococcus aureus (hereinafter referred to as MRSA), vancomycin-resistant enterococci (hereinafter referred to as VRE)) and the like, The present invention relates to an antibacterial agent containing the prodrug, a prodrug of the compound and a salt thereof, and the like.

In recent years, various new drugs have been developed as therapeutic agents for nosocomial infections caused by drug-resistant bacteria represented by MRSA and VRE (see, for example, Patent Document 1). However, since many of these drugs are structurally complex, pharmacokinetics and metabolism are difficult to predict, and unexpected side effects may occur. Moreover, since the structure is complicated, the number of manufacturing steps is large, which is industrially disadvantageous. Furthermore, it becomes an expensive medicine, and as a result, it imposes a high medical cost burden on the public. In addition, since many chemical substances are used as raw materials and synthetic reagents in the manufacturing process, environmental pollution due to waste liquids may be a problem.
In Patent Document 2, the formula:

In the formula, X and Y each represent a halogen atom, a nitro group or a haloalkyl group having 1 to 3 carbon atoms, Z represents a halogen atom, n represents 0, 1, 2, or 3; W represents a halogen atom, a nitro group, an alkyl group having 1-3 carbon atoms or a haloalkyl group having 1-3 carbon atoms, and m represents 1, 2, 3, 4 or 5. Agricultural disinfectants containing 1,5-disubstituted benzenesulfonic acid anilides as active ingredients are described.
Patent Document 3 discloses a general formula.

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower haloalkyl group or a halogen atom. R ³ represents an ethynyl group, a cyano group, a lower alkoxy group or a lower alkoxycarbonyl group. X and Y may be the same or different and may have a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a lower haloalkoxy group, a phenoxy group which may have a substituent, or a substituent. A phenyl group, a pyridyloxy group which may have a substituent, a cyano group, a nitro group, a lower alkylthio group or a lower alkylsulfonyl group. m and n each represent an integer of 1 to 3. Insecticides, acaricides and nematicides containing a sulfonamide derivative represented by the formula: However, Patent Documents 2 and 3 do not describe antibacterial agents having an excellent antibacterial effect against drug-resistant bacteria such as MRSA and VRE. Patent Documents 2 and 3 relate to agricultural fungicides or insecticides, acaricides and nematicides.
Therefore, a novel antibacterial agent that is easy and inexpensive to manufacture and has an excellent antibacterial effect against drug-resistant bacteria such as MRSA and VRE is desired.
JP 2003-267910 A JP-A-2-72151 JP-A-9-227501

  The present invention relates to an antibacterial agent comprising a compound having a simple structure, which can be produced easily and inexpensively on an industrial scale, and has an excellent antibacterial effect against drug-resistant bacteria such as MRSA and VRE, and a prodrug of the compound The purpose is to provide.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a compound represented by the following formula (I) (hereinafter also referred to as compound (I)) and a salt thereof with respect to MRSA and VRE And found to have excellent antibacterial activity. In addition, the present inventors have found a compound represented by the following formula (II) (hereinafter also referred to as compound (II)) useful as a prodrug of compound (I) and a salt thereof and a salt thereof, and further studied To complete the present invention. Compound (II) and its salt are novel compounds.

  Here, the molecular structure of the compound (I) of the present invention is very similar to that of a sulfa drug known as an antibacterial agent, but the compound (I) of the present invention is para-positioned to the sulfonyl group on the benzenesulfonyl group essential for the sulfa drug (described later). In the formula (I), not only does the amino group located at the phenyl group or the aromatic heterocyclic group represented by B (corresponding to the para-position) essential but also its introduction reduces the antibacterial activity of the compound of the present invention. . Therefore, it can be said that this invention compound is a compound different from a sulfa drug.

That is, the present invention is as follows.
[1] Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
Or a salt thereof or a prodrug thereof.
[2] The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom or a carbon which may be substituted with a halogen atom. The antibacterial agent according to the above [1], which is an alkoxy group of formulas 1 to 3, a nitro group or a cyano group.
[3] (1) (i) whether ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A;
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) The antibacterial agent according to [1] or [2] above, wherein ring B is a benzene ring, m is 1, and the substitution position of Y is 4-position of phenyl represented by B.
[4] A compound represented by the formula (I) is:
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) The antibacterial agent according to the above [1], which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.
[5] The antibacterial agent according to any one of [1] to [4], which is for antistaphylococci or antienterococci.
[6] The antibacterial agent according to any one of [1] to [4], which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci.
[7] The antibacterial agent according to any one of [1] to [6], wherein the antibacterial agent is a pharmaceutical product.
[8] Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
The antibacterial method including coexisting the compound shown by these, its salt, or its prodrug with an antibacterial treatment object.
[9] The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, or a carbon which may be substituted with a halogen atom. The method of the above-mentioned [8], which is an alkoxy group of formula 1 to 3, a nitro group or a cyano group.
[10] (1) (i) whether ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A;
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) The method according to [8] or [9] above, wherein ring B is a benzene ring, m is 1, and the substitution position of Y is 4-position of phenyl represented by B.
[11] A compound represented by the formula (I) is:
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) The method according to [8] above, which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.
[12] The method according to any one of [8] to [11] above, which is for antistaphylococci or antienterococci.
[13] The method according to any one of [8] to [11] above, which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci.
[14] Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
A method for preventing or treating a bacterial infection, comprising administering a compound represented by the above or a salt thereof or a prodrug thereof to an administration subject.
[15] Formula (I) for the production of an antibacterial agent:

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
Or a salt thereof or a prodrug thereof.
[16] The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, or a carbon which may be substituted with a halogen atom. The use according to [15] above, which is an alkoxy group of formula 1 to 3, a nitro group or a cyano group.
[17] (1) (i) whether ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A;
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) The use according to the above [15] or [16], wherein the ring B is a benzene ring, m is 1, and the substitution position of Y is the 4-position of phenyl represented by B.
[18] A compound represented by formula (I) is:
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) The use according to [15] above, which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.
[19] The use according to any one of [15] to [18], which is for antistaphylococci or antienterococci.
[20] The use according to any one of [15] to [18], which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci.
[21] The use according to any one of [15] to [20], wherein the antibacterial agent is a pharmaceutical product.
[22] Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
And a composition containing the compound or a salt thereof, or a prodrug thereof, and that the composition can or should be used for antibacterial applications or prevention or treatment of bacterial infections Commercial package containing the described items.
[23] Formula (II):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent.
n and m are the same or different and each represents an integer of 0 to 3; and R represents —CH ₂ OR ′ or —COR ′ (wherein R ′ represents 1 to 3 carbon atoms substituted with carboxy. Or an alkyl group having 1 to 3 carbon atoms substituted with amino). ]
Or a salt thereof.

The compound (I) and salts thereof of the present invention have an excellent antibacterial effect against drug-resistant bacteria such as MRSA and VRE. Further, the compound (I) of the present invention has a simple structure, and as a result, it can be produced efficiently (high yield) and industrially inexpensively with a small number of steps using inexpensive raw materials. As a result, according to this invention, the conventional subject about a high medical cost burden of a public and an environmental problem can be solved. Furthermore, it has been confirmed that the compound (I) of the present invention is not toxic in a test using mice, and is useful as a pharmaceutical product, a research reagent or the like.
In addition, among the compounds (I) of the present invention, a compound having a sulfonanilide skeleton can be synthesized in a small number of steps, has good crystallinity, is not easily oxidized, and is chemically stable. Advantageous in synthesis and storage of pharmaceuticals.
In addition, the compound (II) and salts thereof of the present invention are useful as prodrugs of the compound (I) and salts thereof. The compound (II) of the present invention is a compound in which a carboxy or a —CH ₂ O—C _1-3 alkyl or —CO—C _1-3 alkyl is bonded to the nitrogen atom of the sulfonamide group of the compound (I) and a salt thereof. Since it has amino, it can form salts with bases or acids, and these salts are advantageous in that they are highly soluble in water and easy to formulate.

Hereinafter, the present invention will be described in detail.
Compound (I) of the present invention includes, for example,
(I) Compound (I) in which Ring A and Ring B are benzene rings,
(Ii) Compound (I) in which Ring A is a benzene ring and Ring B is an aromatic heterocyclic ring having 1 or 2 nitrogen atoms as constituent atoms of the ring,
(Iii) ring A is an aromatic heterocycle having 1 or 2 nitrogen atoms as ring constituent atoms, ring B is a benzene ring (I), and (iv) ring A and ring B are 1 Or the compound (I) etc. which are aromatic heterocyclic rings which have two nitrogen atoms as a ring structural atom are included.

Hereinafter, the definition of each symbol in this specification will be described.
In the present specification, “aromatic heterocycle having 1 or 2 nitrogen atoms as ring constituent atoms” includes compounds in which one or two of the nitrogen atoms constituting the ring form an N oxide. It is. Examples of the “aromatic heterocycle having 1 or 2 nitrogen atoms as ring constituent atoms” represented by ring A and ring B include pyridine and pyrimidine. Examples of the “aromatic heterocycle having 1 or 2 nitrogen atoms as ring constituent atoms” include 4-pyridyl, 3-pyridyl, 2-pyridyl, 2,6-pyrimidinyl, 2,4-pyrimidinyl and the like. 4-pyridyl, 2,6-pyrimidinyl and the like are preferable.

  Examples of the “substituent” represented by X and Y include, for example, an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, and 1 to 3 carbon atoms which may be substituted with a halogen atom. An alkoxy group, a nitro group, a cyano group, a carboxy group, a hydroxy group, an amino group, and the like, and an alkyl group having 1 to 3 carbon atoms that may be substituted with a halogen atom, a halogen atom, or a halogen atom. Preferred are an alkoxy group having 1 to 3 carbon atoms, a nitro group, a cyano group, and the like. However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group.

  Here, examples of the “alkyl group having 1 to 3 carbon atoms” of the “alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom” include methyl, ethyl, propyl, isopropyl and the like. Methyl, ethyl and the like are preferable, and methyl is particularly preferable. Examples of the “halogen atom” in the “alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is preferred. The number of substitution of “halogen atom” is not particularly limited, but 3 is preferable. The substitution position of “halogen atom” may be any position where substitution is possible. Examples of the “alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom” include methyl, trifluoromethyl and the like, and trifluoromethyl and the like are preferable.

  Examples of the “halogen atom” which is the “substituent” represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom, a chlorine atom and the like are preferable, and a chlorine atom is particularly preferable.

  Examples of the “C1-C3 alkoxy group” of the “C1-C3 alkoxy group optionally substituted with a halogen atom” include methoxy, ethoxy, propoxy, isopropoxy and the like. Ethoxy and the like are preferable, and methoxy is particularly preferable. Examples of the “halogen atom” of the “C1-C3 alkoxy group optionally substituted with a halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and the like are preferable. The number of substitution of “halogen atom” is not particularly limited, but 3 is preferable. The substitution position of “halogen atom” may be any position where substitution is possible. Examples of the “C 1-3 alkoxy group optionally substituted with a halogen atom” include methoxy, trifluoromethoxy and the like, and trifluoromethoxy and the like are preferable.

  When there are two or more “substituents” represented by X and Y, each substituent may be the same or different.

  n is preferably 1 or 2. m is preferably 1 or 2.

Ring A is preferably a benzene ring, pyridine or the like. When ring A is pyridine, the group represented by A is preferably 4-pyridyl or the like.
Ring B is preferably a benzene ring or the like.

  When ring A is a benzene ring and n is 1, the substitution position of X includes the 3-position, 4-position, 5-position and the like of phenyl represented by A, and the 4-position is preferred. When ring A is a benzene ring and n is 2, the substitution position of X includes 3-position, 5-position, 3-position and 4-position of phenyl represented by A, and 3-position and 5-position are preferable.

  When ring A is pyridine, the group represented by A is 4-pyridyl, and n is 2, the substitution positions of X are preferably 2-position and 6-position of 4-pyridyl represented by A.

  When ring B is a benzene ring and m is 1, examples of the substitution position of Y include 3-position, 4-position, 5-position and the like of phenyl represented by B, and 4-position is preferred. When ring B is a benzene ring and m is 2, the substitution positions of Y include 3-position, 5-position, 3-position and 4-position of phenyl represented by B, and 3-position and 5-position are preferable.

As compound (I),
(1) (i) Ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A,
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) A compound or the like in which ring B is a benzene ring, m is 1, and the substitution position of Y is 4-position of phenyl represented by B is preferable.

  When n is 2, X is preferably an alkyl optionally substituted with a halogen atom (eg, trifluoromethyl), a halogen atom (eg, a chlorine atom, a fluorine atom) or the like. It is preferable that When m is 2, Y is preferably alkyl optionally substituted with a halogen atom (eg, trifluoromethyl), halogen atom (eg, chlorine atom, fluorine atom) and the like, and particularly, two Y are the same. It is preferable that

  Specific examples of the compound (I) of the present invention include compounds 1 to 16 obtained in Examples 1 to 16 described later.

  In addition, as the compound (I) of the present invention, the following formula (Ia):

[Wherein, A, B and C are the same or different,
A represents N, N oxide, or C (R ¹ ) (wherein R ¹ represents a hydrogen atom, a halogen atom, a C 1-3 alkyl group substituted with a halogen atom, a cyano group, or a nitro group. )
B represents N, N oxide or C (R ² ) (wherein R ² represents a hydrogen atom, a halogen atom, a C 1-3 alkyl group substituted with a halogen atom, a cyano group, or a nitro group. )
C represents N, N oxide or C (R ³ ) (wherein R ³ represents a hydrogen atom, a halogen atom, a C 1-3 alkyl group substituted with a halogen atom, a cyano group, or a nitro group. )
W is the formula ae:

(In each formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are the same or different and are each substituted with a halogen atom or a halogen atom. Or an alkyl group having 1 to 3 carbon atoms, a cyano group, or a nitro group). ]
(However, a compound in which the para-position of the phenyl group or heterocyclic group represented by the formulas a to e is an amino group is excluded.)

^{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, R 9, R 10, "halogen atom" represented by R ^{11, R 12} and ^{R 13,} the "halogen atom Illustrative and preferred examples of the “substituted alkyl group having 1 to 3 carbon atoms” include “halogen atom” in X and Y of the formula (I), “1 to 3 carbon atoms optionally substituted with halogen atom” Examples and preferred examples of the “alkyl group (excluding unsubstituted alkyl group)” are the same.

  Moreover, as compound (I) of this invention, the compound shown to the following Tables 1-3 is mentioned.

  Compound (I) may form a salt. For example, when compound (I) is a nitrogen-containing heterocyclic compound or has a basic substituent, an acid addition salt can be mentioned. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; for example, acetate, propionate, lactate, and maleic acid. Organic acid salts such as salts, fumarate, tartrate, malate, citrate, ascorbate; sulfones such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate Acid salts; for example, acidic amino acids such as aspartate and glutamate. In the case where compound (I) has an acidic group such as a carboxy group, examples of the basic addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; Ammonium salts; for example, trimethylamine salts, triethylamine salts; aliphatic amine salts such as dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; Heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzylto Butylammonium salt, methyl trioctyl ammonium salts, quaternary ammonium salts such as tetrabutylammonium salts; arginine; basic amino acid salts such as lysine salt and the like.

  Compound (I) and a salt thereof can also be used as a prodrug. Compound (II) is preferred as a prodrug of compound (I) and salts thereof.

In compound (II), the definitions and examples of ring A, ring B, X, Y, n, and m are the same as those described above for compound (I). Compound (II) is a compound in which the hydrogen atom of NH on the sulfonamide bond of compound (I) or a salt thereof is substituted with R described in detail below.
R represents —CH ₂ OR ′ or —COR ′ (wherein R ′ represents an alkyl group having 1 to 3 carbon atoms substituted with carboxy, or an alkyl group having 1 to 3 carbon atoms substituted with amino). .)

Examples of the “alkyl group having 1 to 3 carbon atoms” of the “alkyl group having 1 to 3 carbon atoms substituted with carboxy” represented by R ′ include methyl, ethyl, propyl, isopropyl, and the like. Isopropyl and the like are preferable. The number of substitution of “carboxy” is not particularly limited, but 1 is preferable. The substitution position of “carboxy” may be any substitutable position. Examples of the “carboxy group having 1 to 3 carbon atoms substituted with carboxy” include —CH ₂ COOH, —CH ₂ CH ₂ COOH, —CH (CH ₃ ) COOH, —CH ₂ CH ₂ CH ₂ COOH, — CH (CH ₃ ) CH ₂ COOH, —CH ₂ CH (CH ₃ ) COOH and the like can be mentioned, and —CH ₂ CH ₂ CH ₂ COOH and the like are preferable.

Examples of the “alkyl group having 1 to 3 carbon atoms” of the “alkyl group having 1 to 3 carbon atoms substituted with amino” represented by R ′ include methyl, ethyl, propyl, isopropyl, and the like. Isopropyl and the like are preferable. The number of substitution of “amino” is not particularly limited, but 1 is preferable. The substitution position of “amino” may be any substitutable position. Examples of the “amino-substituted alkyl group having 1 to 3 carbon atoms” include, for example, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —CH (CH ₃ ) NH ₂ , —CH ₂ CH ₂ CH _{2. NH 2, -CH (CH 2)} CH 2 NH 2, -CH 2 CH (CH 3) NH 2 and the _{like, -CH 2 CH 2 CH 2 NH} 2 and the like are preferable.

As “—CH ₂ OR ′” represented by R, —CH ₂ OCH ₂ CH ₂ CH ₂ COOH is preferable. As “—COR ′” represented by R ⁹ , —COCH ₂ CH ₂ CH ₂ COOH is preferable.

  Compound (II) may form a salt. As the salt of compound (II), when R has a carboxy group, basic addition salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts For example, ammonium salt; for example, trimethylamine salt, triethylamine salt; aliphatic amine salt such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt; aralkylamine salt such as N, N-dibenzylethylenediamine; A heterocyclic aromatic amine salt such as pyridine salt, picoline salt, quinoline salt, isoquinoline salt; for example, tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, Jill tributylammonium salt, methyl trioctyl ammonium salts, quaternary ammonium salts such as tetrabutylammonium salts; arginine; basic amino acid salts such as lysine salt and the like. When R has an amino group, examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; , Propionate, lactate, maleate, fumarate, tartrate, malate, citrate, ascorbate, and other organic acid salts; for example, methanesulfonate, isethionate, benzenesulfonate And sulfonates such as p-toluenesulfonate; acidic amino acids such as aspartate and glutamate. In the salt, when there are isomers (for example, optical isomers, geometric isomers and interchangeable isomers), the present invention includes these isomers, and also includes solvates, hydrates, and various forms. These crystals are included.

  The salts of compound (I) and compound (II) are preferably acceptable salts depending on the mode of use, for example, food hygiene acceptable salts, cosmetically acceptable salts, pharmacologically. Acceptable salts are mentioned.

  The compound (I) of the present invention, a salt thereof and a prodrug thereof (eg, compound (II)) (hereinafter collectively referred to as the compound of the present invention) can be used for various antibacterial applications. That is, the compound of the present invention can be used as an antibacterial agent as it is or together with an appropriate carrier (excipient, solvent, etc.).

  The compound of the present invention can be subjected to antibacterial treatment, for example, by allowing it to coexist with the antibacterial treatment product at a concentration of usually about 1 to 10 μg / mL, preferably 0.5 to 5 μg / mL. . The coexistence means a state in which the compound of the present invention and the antibacterial product are present together, and specifically, for example, a state where the compound is in contact with and mixed with the antibacterial product. Here, the antibacterial object to be treated is a concept including all those that generate bacteria, and examples thereof include foods and drinks, cosmetics, quasi-drugs, pharmaceuticals, medical devices, daily necessities and the like.

  Examples of the bacterial species when the compound of the present invention is used for antibacterial applications include staphylococci (eg, Staphylococcus aureus), gram-positive bacteria including enterococci, and the like. The compounds of the present invention are particularly effective against Staphylococcus aureus, enterococci, and these drug-resistant bacteria (particularly MRSA, VRE). The compounds of the present invention are particularly useful in that they are also effective against VRE having resistance to vancomycin.

  In addition, the compound of the present invention can be used as a composition for prevention of infectious diseases caused by the bacteria exemplified above as it is or as a composition together with pharmacologically acceptable carriers (excipients, solvents, etc.) generally used in pharmaceutical preparations. It can be used as a therapeutic drug. In addition, the compound of the present invention is contained in a skin cleanser such as soap, a hair cosmetic such as shampoo, and a skin cosmetic such as lotion, and is used for the prevention or treatment of infectious diseases caused by bacteria as exemplified above (especially fingers and fingers). , For antibacterial use such as hair). The compounding ratio of the compound of the present invention in the pharmaceutical is not particularly limited.

  When the compound of the present invention is used as a pharmaceutical, examples of administration subjects include mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys), poultry (eg, chickens) and the like. Is mentioned.

  The compounds of the present invention are particularly effective against Staphylococcus aureus, enterococci and their drug-resistant bacteria (especially MRSA, VRE), etc., and therefore prevent bacterial infections, especially diseases such as nosocomial infections. Alternatively, it can be used for treatment.

  The pharmaceutical dosage form of the present invention is not particularly limited, and examples thereof include oral preparations such as tablets and capsules, and parenteral preparations such as injections, ointments, eye drops, and external liquid preparations. These preparations can be produced by methods commonly used in the technical field of preparations.

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, type of causative bacteria, etc., but for example, it is usually about 100 to 200 mg per day for adults. Dosing in 3 doses.

Hereafter, the manufacturing method of compound (I) is demonstrated.
Compound (I) can be produced, for example, by the method shown in the following scheme 1.

Starting materials (III) and (IV) can be produced by a method known per se, and commercially available products can also be used. Compound (IV) can also be synthesized according to the method described in JP-A 63-104952 or a method analogous thereto.
Compound (I) is obtained, for example, by reacting a compound represented by formula (III) (compound (III)) with a compound represented by formula (IV) (compound (IV)) in an argon or nitrogen atmosphere. Can do.
The usage-amount of compound (III) is about 0.9-2 equivalent with respect to compound (IV). The reaction solvent is not limited as long as it does not inhibit the reaction, and examples thereof include anhydrous pyridine. The amount of reaction solvent used is usually about 0.5 mL to 5 mL with respect to 1 mmol of compound (III). The reaction temperature is usually from room temperature (about 20 degrees) to 60 degrees. The reaction time is usually about 30 minutes to 22 hours.

  Isolation of compound (I) can be carried out by subjecting the reaction solution to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, drying, solvent distillation, crystallization, etc.). Compound (I) of the present invention may be converted to a salt by a method known per se.

Next, a method for producing compound (II) (ie, an example of prodrug formation of compound (I)) will be described.
The prodrug formation of the active compound can be synthesized according to the following synthesis scheme 2 based on commercially available raw materials, regardless of whether the R ′ group of compound (II) has a carboxy group or an amino group.

(In each formula, X ′ is Cl, Br or I, Y ′ is CH ₂ O or CO, Z ′ is (alkyl having 1 to 3 carbon atoms) —CO ₂ R ″ (wherein R ″ represents methyl, ethyl, or t-butyl.), Or (C 1-3 alkyl) -NHCOOt-Bu, Z represents (C 1-3 alkyl) CO ₂ H or (carbon In the formula (1-3) alkyl, NH ₂ , other symbols are as defined above.

  For example, when alkyl having a carboxy or amino group is introduced onto the sulfonamide group of compound (I) via methyloxy, compound (I) is dissolved in a solvent such as anhydrous N, N-dimethylformamide, sodium hydride, etc. Then, a carboxy prepared by a commercially available or known method is protected with an alkyl ester such as methyl ester or an alkyl halide in which the amino group is protected with t-butyloxycarbonyl (in the scheme, X′-Y ′ After the reaction with the compound represented by -Z ', each protecting group can be subjected to a known deprotection method.

  When introducing an alkyl having a carboxy or amino group via a carbonyl onto the sulfonamide group of Compound (I), Compound (I) is added with a base such as sodium hydride in a solvent such as anhydrous N, N-dimethylformamide. After the treatment, a carboxy prepared by a commercially available or known method is protected with an alkyl ester such as methyl ester or an alkyl carboxylic acid chloride in which an amino group is protected with t-butyloxycarbonyl (in the scheme, X′-Y′-Z After the reaction with a compound represented by '), each protecting group can be subjected to a known deprotection method.

The usage-amount of the compound shown by X'-Y'-Z 'is 1-2 equivalent normally with respect to compound (I). The usage-amount of a base is 1-2 equivalent normally with respect to compound (I). The amount of reaction solvent to be used is generally 0.5 mL to 5 mL with respect to 1 mmol of compound (I). The reaction temperature is usually room temperature (about 20 degrees) to 60 degrees. The reaction time is 30 minutes to 22 hours. Isolation of the obtained intermediate can be performed by subjecting the reaction solution to post-treatment by a conventional method (for example, extraction, water washing, drying, solvent distillation, crystallization, etc.), but the next deprotection is performed as it is. You may attach to reaction.
Deprotection may be performed using, for example, lithium hydroxide in a mixed solvent of tetrahydrofuran and water for a carboxylic acid ester. The amount of the solvent to be used is generally 0.5 mL to 5 mL with respect to 1 mmol of the compound. The usage-amount of lithium hydroxide is 1-2 equivalent normally with respect to a compound.
Deprotection of the nitrogen protecting group with t-butyloxycarbonyl may be performed using trifluoroacetic acid or the like using methylene chloride as a solvent. The usage-amount of a solvent is 0.5 mL-5 mL normally with respect to 1 mmol of compounds. The amount of trifluoroacetic acid used is usually 1 to 2 equivalents relative to the compound.

  The target compound (Compound II) can be isolated by subjecting the reaction solution to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, drying, solvent distillation, crystallization, etc.). Compound (II) of the present invention may be converted to a salt by a method known per se.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited at all by these.

Example 1 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (229 mg, 1.0 mmol) was added to anhydrous pyridine ( (1.0 mL), 4-chlorobenzenesulfonyl chloride (211 mg, 1.0 mmol) was added, the atmosphere was replaced with argon, and the mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 5). A 2N HCl solution (6.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL × 3), and then the ethyl acetate layer was washed with water (20 mL × 2) and saturated brine (40 mL). Furthermore, it dried with anhydrous magnesium sulfate and the solvent was depressurizingly distilled. This was recrystallized with a mixed solvent of dichloromethane / hexane to obtain the title compound (white needle crystals, 158 mg). Yield 39%.
Melting point 115-117 ° C. IR (KBr) cm ^-1 : 3265 (NH), 1345, 1157 (SO ₂ ). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.29 (1H, s, NH), 7.82 (2H, dd, J = 6.5, 2.0 Hz, Ar-H), 7.79 (1H, s, Ar- H), 7.68 (2H, dd, J = 6.5, 2.0 Hz, Ar-H), 7.66 (2H, s, Ar-H). FAB ^- MS m / z: 403 (M) ⁺ , 404 (M + H) ⁺ , 405 (M + 2) ⁺ , 406 (M + 2 + H) ⁺

Example 2 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (115 mg, 0.5 mmol) was prepared. It was dissolved in anhydrous pyridine (2.0 mL), 4-trifluoromethoxybenzenesulfonyl chloride (130 mg, 0.5 mmol) was added, the atmosphere was replaced with argon, and the mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). A 2N HCl solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The ethyl acetate layer was washed with water (20 mL × 2) and saturated brine (20 mL). Furthermore, it dried with anhydrous magnesium sulfate and the solvent was depressurizingly distilled. This was recrystallized with a mixed solvent of dichloromethane / hexane to obtain the title compound (white needle crystals, 70 mg). Yield 67%.
Melting point 74-76 ° C. IR (KBr) cm ^-1 : 3270 (NH), 1346, 1157 (SO ₂ ). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.87 (2H, dd, J = 7.0, 2.0 Hz, Ar-H), 7.64 (1H, s, Ar-H), 7.53 (2H, s, Ar- H), 7.33 (2H, dd, J = 9.0, 1.0 Hz, Ar-H), 6.99 (1H, s, NH). FAB ^- MS m / z: 453 (M) ⁺ (Gly)

Example 3 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (114 mg, 0.5 mmol) was prepared. It was dissolved in anhydrous pyridine (2.5 mL), 4-trifluoromethylbenzenesulfonyl chloride (122 mg, 0.5 mmol) was added, the atmosphere was replaced with argon, and the mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). A 2N HCl solution (8.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The ethyl acetate layer was washed with water (20 mL × 2) and saturated brine (20 mL). Furthermore, it dried with anhydrous magnesium sulfate and the solvent was depressurizingly distilled. This was recrystallized with a mixed solvent of dichloromethane / hexane to obtain the title compound (white flocculent crystals, 102 mg). Yield 91%.
Melting point 122-124 ° C. IR (KBr) cm ^-1 : 3269 (NH), 1325, 1161 (SO ₂ ). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.95 (2H, d, J = 8.0 Hz, Ar-H), 7.78 (2H, d, J = 8.0 Hz, Ar-H), 7.65 (1H, s , Ar-H), 7.55 (2H, s, Ar-H), 7.05 (1H, s, NH). FAB ^- MS m / z: 437 (M) ⁺ , 438 (M + H) ⁺

Example 4 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (229 mg, 1.0 mmol) was converted to anhydrous pyridine (2.0 mL), 4-cyanobenzenesulfonyl chloride (222 mg, 1.1 mmol) was added, the atmosphere was replaced with argon, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction with a TLC plate (ethyl acetate: hexane = 1: 4), 2N HCl solution (10 mL) was added to the reaction solution, poured into water (20 mL), and extracted with ethyl acetate (30 mL × 3). The ethyl acetate layer was washed with water (30 mL × 2) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a crude product (280 mg, 71%). . Next, the product was separated by flash column chromatography (ethyl acetate: hexane = 1: 3), and the target fraction was distilled off under reduced pressure to obtain a crude product (202 mg). This was recrystallized with a mixed solvent of dichloromethane / methanol to obtain the title compound (white needle crystals, 55 mg). Yield 51%.
Mp 172-175 ° C. IR (KBr) cm ^-1 : 3269 (NH), 1347, 1161 (SO ₂ ). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 11.48 (1H, s, NH), 8.08 (2H, dd, J = 8.8, 2.0 Hz, Ar-H), 7.97 (2H, dd, J = 8.8, 2.0 Hz, Ar-H), 7.78 (1H, s, Ar-H), 7.65 (2H, s, Ar-H). FAB ^- MS m / z: 394 (M) ⁺ , 395 (M + H) ⁺

Example 5 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (3437 mg, 15.0 mmol) was added to anhydrous pyridine ( 5.0 mL), 4-nitrobenzenesulfonyl chloride (3324 mg, 15.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 2: 5). Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with 2N HCl solution (50 mL), water (30 mL × 3), saturated brine (30 mL), and anhydrous sulfuric acid. It dried with magnesium and the solvent was depressurizingly distilled. The white residue was isolated by flash column chromatography (methanol: chloroform = 1: 100) to give the title compound. Yield 76%.
Melting point: 143.5-144 ° C. IR (KBr) cm ^-1 : 3242 (NH), 1348, 1170 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.53 (1H, s, NH), 8.40 (2H, d, J = 9.0 Hz, Ar-H), 8.06 (2H, d, J = 9.0 Hz, Ar-H), 7.82 (1H, br s, Ar-H), 7.68 (2H, br s, Ar-H). FAB ^- MS m / z: 414 (M) ⁺

Example 6 Synthesis of 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide 3,4-Difluoroaniline (65 mg, 0.5 mmol) was added to anhydrous pyridine (1. (0 mL), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (172 mg, 0.55 mmol) was added, and the mixture was stirred under an argon atmosphere at room temperature for 3 hours, and then TLC plate (ethyl acetate: hexane = 1: 2). The completion of the reaction was confirmed. To the reaction solution was added 3N HCl (4 mL) solution, and the mixture was extracted with ethyl acetate (30 mL × 3). Ethyl acetate was washed with water (30 mL × 2) and physiological saline (30 mL), dried over anhydrous magnesium sulfate, and solvent. Was distilled off under reduced pressure to obtain an orange-red residue (188 mg). The residue was recrystallized from dichloromethane / hexane to give the title compound (skin colored needles). Yield 98%.
Melting point 97-100 ° C. IR (KBr) cm ^-1 : 3216 (NH), 1281, 1165 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.74 (1H, br s, NH), 8.51 (1H, s, Ar-H), 8.26 (2H, s, Ar-H), 7.37 (1H, m, Ar-H), 7.14 (1H, m, Ar-H), 6.90 (1H, m, Ar-H).

Example 7 Synthesis of 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide 3,5-difluoroaniline (129 mg, 1.0 mmol) was added to anhydrous pyridine (2. 0,3), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (344 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere, and then on a TLC plate (ethyl acetate: hexane = 1: 4). The completion of the reaction was confirmed. To the reaction solution was added 2N HCl (14 mL) solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The ethyl acetate layer was washed with water (40 mL × 2) and physiological saline (40 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an orange-red residue (347 mg). This residue was recrystallized from chloroform / hexane to obtain the title compound (yellow plate crystal). Yield 86%.
Melting point 98-101 ° C. IR (KBr) cm ^-1 : 3234 (NH), 1363, 1167 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.08 (1H, br s, NH), 8.52 (1H, s, Ar-H), 8.36 (2H, s, Ar-H), 6.98 (1H, t, J = 2.3 Hz, Ar-H), 6.81 (2H, dd, J = 11.0, 2.1 Hz, Ar-H). FAB ^- MS m / z: 406 (M + H) ⁺

Example 8 Synthesis of 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide 3,5-dichloroaniline (162 mg, 1.0 mmol) was added to anhydrous pyridine (1.0 mL). ), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (344 mg, 1.1 mmol) was added, and the mixture was stirred under an argon atmosphere at room temperature for 1.5 hours, and TLC plate (ethyl acetate: hexane = 1: 4) The completion of the reaction was confirmed. 2N HCl solution was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the ethyl acetate layer was washed with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the solvent was reduced in pressure. Distillation gave a powdery residue. This residue was recrystallized from chloroform / hexane to give the title compound (white feathery crystals). Yield 79%.
Melting point 128-128.5 ° C. IR (KBr) cm ^-1 : 3261 (NH), 1361, 1173 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.09 (1H, s, NH), 8.63 (1H, s, Ar-H), 8.32 (2H, br s, Ar-H), 7.36 (1H, t, J = 1.8 Hz, Ar-H), 7.11 (2H, d, J = 1.8 Hz, Ar-H). FAB ^- MS m / z: 437 (M) ⁺ , 438 (M + H) ⁺ , 439 (M + 2) ⁺ , 440 (M + 2 + H) ⁺ , 441 (M + 4) ⁺ , 442 (M + 4 + H) ⁺

Example 9 Synthesis of 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide 4-Trifluoromethylaniline (86 mg, 0.5 mmol) was added to anhydrous pyridine (1.0 mL). ), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (159 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. TLC plate (ethyl acetate: hexane = 1: 4) The completion of the reaction was confirmed. 2N HCl solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). Ethyl acetate was washed with water (20 mL × 2) and physiological saline (20 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. A white residue was obtained. This residue was recrystallized from dichloromethane / hexane to obtain the title compound (white needle crystals). Yield 40%.
Mp 142-143 ° C. IR (KBr) cm ^-1 : 3283 (NH), 1325, 1124 (SO ₂ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.21 (2H, s, Ar-H), 8.07 (1H, s, Ar-H), 7.58 (2H, d, J = 8.7 Hz, Ar-H), 7.22 (2H, d, J = 8.7 Hz, Ar-H), 7.09 (1H, br s, NH). FAB ^- MS m / z: 437 (M) ⁺

Example 10 Synthesis of 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide 4-Nitroaniline (152 mg, 1.0 mmol) was dissolved in anhydrous pyridine (2.0 mL), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (313 mg, 1.1 mmol) was added, and the mixture was stirred overnight at room temperature under an argon atmosphere, and the completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). did. 2N HCl (12 mL) solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). Ethyl acetate was washed with water (20 mL × 2) and physiological saline (20 mL), dried over anhydrous magnesium sulfate, and solvent Was distilled off under reduced pressure to obtain a red residue (361 mg). This residue was isolated by flash column chromatography (ethyl acetate: hexane = 1: 4) to give a yellow solid. This was recrystallized from ethyl acetate / hexane to give the title compound (yellow needle crystals). Yield 53%.
Melting point 183-185 ° C. IR (KBr) cm ^-1 : 3332 (NH), 1366, 1183 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.55 (1H, br s, NH), 8.51 (1H, s, Ar-H), 8.41 (2H, s, Ar-H), 8.16 (2H, dd, J = 9.3, 2.2 Hz, Ar-H), 7.36 (2H, dd, J = 9.3, 2.2 Hz, Ar-H). FAB ^- MS m / z: 415 (M) ⁺

Example 11 Synthesis of N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide 3,5-Dichloroaniline (162 mg, 1.0 mmol) was dissolved in anhydrous pyridine (1.0 mL) and p. -Trifluoromethylbenzenesulfonyl chloride (269 mg, 1.1 mmol) was added, and the mixture was stirred under an argon atmosphere at room temperature for 1.5 hours, and the completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). A 2N HCl solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. A brown residue was obtained. This residue was recrystallized from chloroform / cyclohexane to obtain the title compound (white needle crystals). Yield 60%.
Melting point 118-119 ° C. IR (KBr) cm ^-1 : 3255 (NH), 1326, 1132 (SO ₂ ).
¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.11 (1H, s, NH), 8.02 (4H, s, Ar-H), 7.29 (1H, t, J = 1.9 Hz, Ar-H), 7.11 (2H, d, J = 1.9 Hz, Ar-H). FAB ^- MS m / z: 369 (M) ⁺ , 370 (M + H) ⁺ , 371 (M + 2) ⁺ , 372 (M + 2 + H) ⁺

Example 12 Synthesis of 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide 3,5-Difluoroaniline (129 mg, 1.0 mmol) was dissolved in anhydrous pyridine (2.0 mL). 3,5-Dichlorobenzenesulfonyl chloride (270 mg, 1.1 mmol) was added, the mixture was stirred at room temperature for 3 hours under an argon atmosphere, and the completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). 2N HCl solution (12 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (40 mL × 2) and saturated brine (40 mL), dried over anhydrous magnesium sulfate, and solvent Was distilled off under reduced pressure to obtain an orange-red residue (272 mg). This residue was recrystallized from dichloromethane / hexane to give the title compound (colorless plate crystals, 222 mg). Yield 80%.
Melting point 115-118 ° C. IR (KBr) cm ^-1 : 3238 (NH), 1344, 1177 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.06 (1H, br s, NH), 7.99 (4H, s, Ar-H), 7.81 (2H, s, Ar-H), 6.96 (1H, s, Ar-H), 6.81 (1H, s, Ar-H). FAB ^- MS m / z: 337 (M) ⁺ , 338 (M + H) ⁺ , 339 (M + 2) ⁺ , 340 (M + 2 + H) ⁺

Example 13 Synthesis of N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide 3,5-bis (trifluoromethyl) aniline (115 mg, 0.50 mmol) was prepared. Dissolve in anhydrous pyridine (0.5 mL), add 3,5-dichlorobenzenesulfonyl chloride (135 mg, 0.55 mmol), stir at room temperature under argon atmosphere for 1.5 hours, TLC plate (ethyl acetate: hexane = 1: The completion of the reaction was confirmed in 4). 2N HCl solution was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic layer was washed with water (20 mL × 2) and saturated brine (20 mL), decolorized with activated carbon, dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure to obtain a white residue. This residue was isolated by flash column chromatography (ethyl acetate: hexane = 1: 8) to obtain the title compound (white solid). Yield 64%.
Melting point 110 ° C. IR (KBr) cm ^-1 : 3258 (NH), 1345, 1163 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 10.15 (1H, br s, NH), 8.02 (1H, t, J = 1.8 Hz, Ar-H), 7.86 (1H, s, Ar-H) , 7.78 (2H, d, J = 1.8 Hz, Ar-H), 7.67 (2H, s, Ar-H). FAB ^- MS m / z: 437 (M) ⁺ , 438 (M + H) ⁺ , 439 (M + 2) ⁺ , 440 (M + 2 + H) ⁺ , 441 (M + 4) ⁺ , 442 (M + 4 + H) ⁺

Example 14 Synthesis of 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide p-nitroaniline (276 mg, 2.0 mmol) was dissolved in anhydrous pyridine (1.5 mL), and 3,5-di- Chlorobenzenesulfonyl chloride (540 mg, 2.2 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 4). 2N HCl solution was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic layer was washed with water (20 mL × 2) and saturated brine (20 mL), decolorized with activated carbon, dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure to obtain a yellow residue. This residue was recrystallized from ethyl acetate / hexane to give the title compound (yellow plate crystals). Yield 69%.
Melting point 190-192 ° C. IR (KBr) cm ^-1 : 3298 (NH), 1335, 1174 (SO ₂ ). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ: 11.45 (1H, s, NH), 8.17 (2H, dd, J = 9.3 Hz, 2.2 Hz, Ar-H), 8.00 (1H, t, J = 2.0 Hz, Ar-H), 7.85 (2H, d, J = 2.0 Hz, Ar-H), 7.35 (2H, dd, J = 9.3 Hz, 2.2 Hz, Ar-H). FAB ^- MS m / z: 346 (M) ⁺ , 347 (M + H) ⁺ , 348 (M + 2) ⁺ , 349 (M + 2 + H) ⁺ , 350 (M + 4) ⁺ , 351 (M + 4 + H) ⁺

Example 15 Synthesis of 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide 4-amino-2,6-dichloropyridine (163 mg, 1. 0 mmol) was dissolved in anhydrous pyridine (4.0 mL), 3,5-bis (trifluoromethyl) benzenesulfonyl chloride (313 mg, 1.0 mmol) was added, and the atmosphere was replaced with argon, followed by stirring at 60 ° C. for 22 hours. The completion of the reaction was confirmed with a TLC plate (dichloromethane: methanol = 10: 1). After pyridine was distilled off and extracted with ethyl acetate (40 mL × 3), the ethyl acetate layer was washed with water (40 mL × 2) and saturated brine (40 mL). Furthermore, it dried with anhydrous magnesium sulfate and the solvent was depressurizingly distilled. Isolation was performed by flash column chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid (214 mg). This was recrystallized with a mixed solvent of dichloromethane / cyclohexane to obtain the title compound (white needle crystals, 102 mg). Yield 23%.
Melting point 167.0-168.0 ° C. IR (KBr) cm ^-1 : 3090 (NH), 1360, 1177 (SO ₂ ). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.54 (1H, s, Ar-H), 8.48 (2H, s, Ar-H), 7.12 (2H, s, Ar-H)

Example 16 Synthesis of N- (2 ′, 6′-dichloro-4′-pyridyl) -3,5-dichlorobenzenesulfonamide 4-amino-2,6-dichloropyridine (163 mg, 1.0 mmol) was converted to anhydrous pyridine (4.0 mL), 3,5-dichlorobenzenesulfonyl chloride (270 mg, 1.1 mmol) was added, and the atmosphere was replaced with argon, followed by stirring at 60 degrees for 18 hours. The completion of the reaction was confirmed with a TLC plate (ethyl acetate: hexane = 1: 1). After pyridine was distilled off and extracted with ethyl acetate (40 mL × 3), the ethyl acetate layer was washed with water (40 mL × 2) and saturated brine (40 mL). Furthermore, it dried with anhydrous magnesium sulfate and decolorized with activated carbon, and the solvent was depressurizingly distilled. This was recrystallized from methanol to obtain the title compound (white needle crystals, 50 mg). Yield 22%.
Melting point: 163.0-164.0 ° C. IR (KBr) cm ^-1 : 3080 (NH), 1351, 1174 (SO ₂ ). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.78 (2H, d, J = 2.0 Hz, Ar-H), 7.64 (1H, t, J = 2.0 Hz, Ar-H), 7.01 (2H, s , Ar-H)

Example 17 Production of Compound (II) (Production of Intermediate A)
After washing 60% sodium hydride (1 mmol) with hexane, anhydrous N, N-dimethylformamide (2 mL) is added, and then sulfonamide compound X (1 mmol) is added at room temperature. Commercially available methyl 4-chloro-4-oxobutyrate (1 mmol) is added and stirred at room temperature. After completion of the reaction, the reaction solution is poured into cold water and extracted with ethyl acetate, and then the organic layer is washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure to obtain a crude product. Intermediate A is obtained by column chromatography and recrystallization.
(Production of Compound (II))
In a mixed solvent of Intermediate A in tetrahydrofuran and water in a volume ratio of 3: 1, 1.5 equivalent of lithium hydroxide is added and stirred at room temperature. After completion of the reaction, the reaction solution is made weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, the organic layer is washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure to obtain a crude product, and the target compound is obtained by column chromatography and recrystallization.

Experimental example 1
(Activity evaluation)
About the compound obtained in the Example and vancomycin (vancomycin), the minimum inhibitory concentration (MIC) against MRSA and VRE was measured by the following method (in vitro test).
[MIC measurement method (two-step dilution method)]
(I) Preparation of two-step dilution series of compound solution 95 μL of liquid medium is added to the first row of a 96-well plate, and 50 μL is added to the second and subsequent rows. Add 5 μL of a 10 mg / mL compound in DMSO to the first row. Take 50 μL from the first row and add to the next well. Take 50 μL of the last 12th column and discard it.
(Ii) Preparation of Bacterial Solution The pre-cultured bacterial solution is diluted 1000 times, and shaken and cultured at 37 ° C. and 140 min ⁻¹ until OD ₆₂₀ (bacterial turbidity at UV wavelength of 620 nm) = 0.1 (this culture). The main culture is further diluted 1000 times.
(Iii) 50 μL of the bacterial solution prepared according to (ii) is seeded from the well with the lowest concentration (well in the 12th row) of the two-stage dilution series prepared according to (i) above. After culturing the plate at 37 ° C. for 20 hours, the minimum compound concentration at which no bacterial growth is visually observed is defined as MIC. Further, the degree of cloudiness of the plate is measured with a plate reader (595 nm), and the minimum compound concentration having a transmittance (absorbance) of less than 0.1 is defined as MIC (minimum growth inhibitory concentration of bacteria).
Finally, the MIC of the naked eye and the plate reader were compared, and the one with the larger value was adopted.
The results are shown in Table 4.

  From the results in Table 4, it was revealed that the compounds of the present invention have excellent antibacterial activity against MRSA and VRE. In particular, compounds 8 and 13 showed strong activity against both MRSA and VRE.

Experimental example 2
(Acute toxicity test)
Compounds 7 and 8 obtained in the examples were subjected to an acute toxicity test using mice (in vivo test). For each compound, 5 mice were given a single dose of 100 mg / kg body weight by intraperitoneal administration, and the body weight was measured for 2 weeks. Since no significant weight loss is seen in mice, it is considered that there is no toxicity at this concentration.

Experimental example 3
(Antimicrobial activity against clinical isolates)
Among the compounds obtained in the examples, some of the compounds that showed remarkable antibacterial activity were tested for antibacterial activity by the Disc method against clinical isolates isolated from patients at Okayama University Hospital. went. The Disc method is as follows. Overnight, the isolated bacteria are pre-cultured in normal bouillon medium (Eiken Equipment Co., Ltd.). After seeding 100 μL of the solution, it was spread over one surface using a conage rod, and seven sheets of 8 mm diameter filter paper were placed on the regular hexagon, and 10 μL of a 10 mg / mL test compound DMSO solution was added dropwise thereto. The plate was incubated overnight at 37 ° C. and the diameter of the resulting inhibition circle was measured. In addition, the thing with the diameter of the prevention circle of 15 mm or more was made effective.

  As a result, sulfadiazine and sulfamethoxazole, which are sulfa drugs, did not show antibacterial activity, whereas in this test compound, only 14 had low antibacterial activity against enterococci, both staphylococci and Antibacterial activity was demonstrated against enterococci.

  When the molecular structure of the compound of the present invention is compared with the molecular structure of the sulfa drug, the benzenesulfonamide structure is similar, but the compound of the present invention is characteristic of the sulfa drug and is an essential structure as a sulfa drug. The amino group located para to the upper sulfonyl group is missing. Based on this point and the above experimental results, it is suggested that the antibacterial activity of the compound of the present invention is based on a mechanism of action different from that of sulfa drugs.

  The antibacterial agent containing the compound (I) of the present invention and a salt thereof or a prodrug thereof can be used for various antibacterial applications, for example, for prevention and treatment of bacterial infections, particularly infections caused by MRSA and VRE. It is useful as a pharmaceutical product. The compound (II) and salts thereof of the present invention are useful as prodrugs such as compound (I) and salts thereof.

  This application is based on Japanese Patent Application No. 2007-073738 filed in Japan, the contents of which are incorporated in full herein.

Claims (23)

Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
Or a salt thereof or a prodrug thereof.   The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, or 1 to 1 carbon atoms which may be substituted with a halogen atom. The antibacterial agent according to claim 1, which is an alkoxy group, a nitro group or a cyano group. (1) (i) Ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A,
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) The antibacterial agent according to claim 1 or 2, wherein ring B is a benzene ring, m is 1, and the substitution position of Y is 4-position of phenyl represented by B. The compound of formula (I) is
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) The antibacterial agent according to claim 1, which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.   The antibacterial agent according to any one of claims 1 to 4, which is used for anti-staphylococci or anti-enterococci.   The antibacterial agent according to any one of claims 1 to 4, which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci.   The antibacterial agent according to any one of claims 1 to 6, wherein the antibacterial agent is a pharmaceutical product. Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
The antibacterial method including coexisting the compound shown by these, its salt, or its prodrug with an antibacterial treatment object.   The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, or 1 to 1 carbon atoms which may be substituted with a halogen atom. The method according to claim 8, which is an alkoxy group, a nitro group or a cyano group. (1) (i) Ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A,
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
(Ii) The method according to claim 8 or 9, wherein ring B is a benzene ring, m is 1, and the substitution position of Y is 4-position of phenyl represented by B. The compound of formula (I) is
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) 9. The method of claim 8, which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.   The method according to any one of claims 8 to 11, which is for anti-staphylococci or anti-enterococci.   The method according to any one of claims 8 to 11, which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci. Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
A method for preventing or treating a bacterial infection, comprising administering a compound represented by the above or a salt thereof or a prodrug thereof to an administration subject. Formula (I) for the manufacture of antibacterial agents:

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
Or a salt thereof or a prodrug thereof.   The substituents represented by X and Y are the same or different and each is an alkyl group having 1 to 3 carbon atoms which may be substituted with a halogen atom, a halogen atom, or 1 to 1 carbon atoms which may be substituted with a halogen atom. 16. Use according to claim 15, which is an alkoxy group of 3, a nitro group or a cyano group. (1) (i) Ring A is a benzene ring, n is 2, and the substitution position of X is 3-position and 5-position or 3-position and 4-position of phenyl represented by A,
(Ii) ring A is a benzene ring, n is 1 and the substitution position of X is the 4-position of phenyl represented by A, or
(Iii) ring A is pyridine, the group represented by A is 4-pyridyl, n is 2, and the substitution positions of X are the 2- and 6-positions of 4-pyridyl represented by A; and (2) (i) Ring B is a benzene ring, m is 2, and the substitution positions of Y are the 3rd and 5th positions of phenyl represented by B, or
The use according to claim 15 or 16, wherein (ii) ring B is a benzene ring, m is 1 and the substitution position of Y is 4-position of phenyl represented by B. The compound of formula (I) is
(1) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-chlorobenzenesulfonamide,
(2) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethoxybenzenesulfonamide,
(3) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-trifluoromethylbenzenesulfonamide,
(4) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-cyanobenzenesulfonamide,
(5) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -4-nitrobenzenesulfonamide,
(6) 3,5-bis (trifluoromethyl) -N- (3 ′, 4′-difluorophenyl) benzenesulfonamide,
(7) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(8) 3,5-bis (trifluoromethyl) -N- (3 ′, 5′-dichlorophenyl) benzenesulfonamide,
(9) 3,5-bis (trifluoromethyl) -N- (4′-trifluoromethylphenyl) benzenesulfonamide,
(10) 3,5-bis (trifluoromethyl) -N- (4′-nitrophenyl) benzenesulfonamide,
(11) N- (3 ′, 5′-dichlorophenyl) -4-trifluoromethylbenzenesulfonamide,
(12) 3,5-dichloro-N- (3 ′, 5′-difluorophenyl) benzenesulfonamide,
(13) N- {3 ′, 5′-bis (trifluoromethyl) phenyl} -3,5-dichlorobenzenesulfonamide,
(14) 3,5-dichloro-N- (4′-nitrophenyl) benzenesulfonamide,
(15) 3,5-bis (trifluoromethyl) -N- (2 ′, 6′-dichloro-4′-pyridyl) benzenesulfonamide, or (16) N- (2 ′, 6′-dichloro-4) 16. Use according to claim 15, which is' -pyridyl) -3,5-dichlorobenzenesulfonamide.   The use according to any one of claims 15 to 18, which is for anti-staphylococci or anti-enterococci.   The use according to any one of claims 15 to 18, which is for anti-methicillin-resistant Staphylococcus aureus or anti-vancomycin-resistant enterococci.   Use according to any of claims 15 to 20, wherein the antibacterial agent is a pharmaceutical product. Formula (I):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent, and n and m are the same or different and each represents an integer of 0 to 3.
However, when the substituent represented by Y is substituted at the para-position of the phenyl group or aromatic heterocyclic group represented by B, Y is a substituent other than an amino group. ]
And a composition containing the compound or a salt thereof, or a prodrug thereof, and that the composition can or should be used for antibacterial applications or prevention or treatment of bacterial infections Commercial package containing the described items. Formula (II):

[Wherein, ring A and ring B are the same or different and each represents a benzene ring or an aromatic heterocyclic ring having one or two nitrogen atoms as constituent atoms of the ring,
X and Y are the same or different and each represents a substituent.
n and m are the same or different and each represents an integer of 0 to 3; and R represents —CH ₂ OR ′ or —COR ′ (wherein R ′ represents 1 to 3 carbon atoms substituted with carboxy. Or an alkyl group having 1 to 3 carbon atoms substituted with amino). ]
Or a salt thereof.