JPH0820584A - Imidazole derivative and its use - Google Patents

Abstract

PURPOSE:To obtain the subject composition, having excellent antimicrobial activities, especially antimicrobial activities against bacteria such as Helicobacter pylori and useful for preventing or treating duodenal ulcer or gastric ulcer and preventing the relapse thereof. CONSTITUTION:This imidazole derivative of formula I (A' is a condensed imidazolyl having at least one nitro group on the imidazole ring; X is O or S; B is a 5- or a 6-membered heterocyclic ring which may form a condensed ring; m and n are each an integer of 0-4] or its salt, e.g. 6-[(imidazol-2-yl)thio]-3- nitroimidazo[1,2-b]pyridazine or its salt. The compound of formula I is obtained by reacting, e.g. a compound of formula II (Z is a reactive group) with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to imidazole derivatives. More specifically, the present invention relates to an imidazole derivative having excellent antibacterial activity, particularly strong antibacterial activity against Helicobacter pylori such as Helicobacter pylori, and an antibacterial agent and antiulcer agent containing the same. .

[0002]

[Background Art] [Problems to be Solved by the Invention] As ulcer therapeutic agents, antacids, anticholinergic agents, antigastrin agents,
Gastrointestinal hormone agents, anti-pepsin agents, histamine H ₂ receptor antagonists, tissue repair agents, mucosal protective agents, microcirculatory agents,
Proton pump inhibitors have been developed. In particular, among these therapeutic agents for ulcer, the development of histamine H ₂ receptor antagonists and proton pump inhibitors having a strong acid secretion inhibitory action has facilitated the treatment of ulcers.

However, these remedies for ulcers have a high recurrence rate of ulcers after discontinuation of medication, which remains a major problem to be solved at present. Helicobacter pylori is a Gram-negative microaerobic bacterium belonging to the genus Helicobacter, and has been suggested to be a major cause of recurrence of gastritis, duodenal ulcer, gastric ulcer and the like.

For the treatment of various diseases caused by Helicobacter pylori, at present, a two-drug combination of a bismuth preparation and an antibiotic, a bismuth preparation, metronidazole (US Pat. No. 2,944,061), and tetracycline (for example, US Pat. No. 2,712,517) are used. No.) or amoxicillin (U.S. Pat. No. 3,192,198) in combination with chemotherapy. The above metronidazole is an anti-Helicobacter
It is an imidazole derivative having a pylori action and is used in combination with antibiotics. These bismuth preparations, antibiotics, metronidazole, etc. are administered in the form of oral administration.

However, the above-mentioned bismuth preparations, antibiotics, metronidazole, etc. must be administered in a large amount per day in order to maintain a sufficient concentration at the growth site to prevent the growth of Helicobacter pylori, and There are many problems such as side effects such as vomiting and diarrhea.

Various compounds having an anti-Helicobacter pylori action have been reported. For example, JP-A-5-117268
Japanese Patent Publication discloses a pyridine derivative having an anti-Helicobacter pylori action, which is disclosed in European Patent (EP 0535).
528A1) discloses imidazole derivatives having anti-Helicobacter pylori activity. However,
These publications do not disclose a bicyclic fused imidazole compound having a nitro group. In addition, JP-A-49-70967, JP-A-3-505733, JP-A-51-125285,
JP-A-50-89370, JP-A-50-84570 and JP-A-3-173817 disclose imidazole derivatives. However, these publications do not disclose that they have antibacterial activity against Helicobacter spp.

[0007]

Means for Solving the Problems As a result of intensive studies in view of the above problems, the present inventors have found that they have an excellent antibacterial action, especially an excellent antibacterial action against Helicobacter pylori represented by Helicobacter pylori. Furthermore, they have found an imidazole derivative having an antiulcer effect in addition to an antibacterial effect, and completed the present invention.

That is, the present invention provides (1) the general formula (I ').

[0009]

Embedded image [In the formula, A'is a condensed imidazolyl group having at least one nitro group on the imidazole ring, X is an oxygen atom or a sulfur atom, and B is a 5- or 6-membered heterocyclic group which may form a condensed ring. And m and n each represent an integer of 0 to 4] or a salt thereof,
(2) B is a general formula (VI)

[0010]

[Chemical 9] [In the formula, R ₁ and R ₂ are each a hydrogen atom, a lower alkyl group which may have a substituent, an amino group which may have a substituent, or a carboxyl group which may have a substituent. Or R ₁ and R ₂ together with the carbon atom to which they are attached may form an aromatic ring which may contain a nitrogen atom, and the carbon to which R ₁ and R ₂ are attached. The bond between the atoms is a single bond or a double bond (in the case of a single bond, it means that two hydrogen atoms are added), Y
Is an oxygen atom, a sulfur atom or a formula

[Chemical 10] (In the formula, R ₄ represents a hydrogen atom or an alkyl group which may have a substituent), and is a 5-membered heterocyclic group. , (3) B is the general formula (VII)

[0011]

[Chemical 11] [Wherein R ₁ 'and R ₂ ' represent a hydrogen atom or a lower alkyl group respectively, or R ₁ 'and R ₂ ' may contain a nitrogen atom together with the carbon atom to which they are bonded. The bond between the carbon atoms to which R ₁ 'and R ₂ ' are bonded, which may form an aromatic ring, is a single bond or a double bond (in the case of a single bond, two hydrogens are added. R ₃ is a hydrogen atom, a hydrocarbon group or a heterocyclic group, and Y ′ is
Is an oxygen atom, a sulfur atom or a group

[Chemical 12] The imidazole derivative according to (1) above, which is a 6-membered heterocyclic group represented by the following formula, or (4) above, wherein the fused imidazolyl group has from 2 to 4 nitrogen atoms as ring-constituting atoms. Imidazole derivative of (5) A ′
Is a condensed imidazolyl group of imidazole and a 6-membered heterocycle, (6)
A'is an imidazole derivative described in (1) above, which is a fused imidazolyl group of imidazole and a 6-membered heterocycle containing a nitrogen atom, and (7) A'is imidazole and pyridine, pyridazine, pyrimidine, pyrazine or triazine. The imidazole derivative according to (1) above, which is a condensed imidazolyl group, and (8) A ′ is the imidazole derivative above described (1), which is a condensed imidazolyl group with imidazole and pyridine or pyridazine, and (9) A ′ is 2-
Or 3-nitroimidazo [1,2-b] pyridazine-6
An imidazole derivative according to (1) above, which is an -yl group;
(10) A ′ is 2- or 3-nitroimidazo [1,2
-A] pyridin-5-yl group, the imidazole derivative described in (1) above, (11) the imidazole described in (2) above, wherein R ₁ and R ₂ are each a lower alkyl group having a hydrogen atom or a substituent. Derivatives, (12) R ₁ and R ₂
(13) R ₁ and R ₂ wherein any one of the above is a lower alkyl group substituted with a mono- or di-lower (C _1-6 ) alkylamino group.
Are linear or branched alkyl groups each having 1 to 6 carbon atoms, and the imidazole derivative according to (2) above, (1
4) The imidazole derivative according to the above (1), wherein X is a sulfur atom, and (15) Y has the formula:

[Chemical 13] (In the formula, R ₄ represents a hydrogen atom or a lower alkyl group having a substituent), the imidazole derivative according to (2) above, (16) wherein m and n are both 0 (1 (17) 6-[(imidazol-2-yl) thio] -3-nitroimidazo [1,2-b] pyridazine or a salt thereof, (1).
The described imidazole derivative, (18) 6-[[1- (2
-Hydroxyethyl) imidazol-2-yl] thio]
-3-Nitroimidazo [1,2-b] pyridazine or a salt thereof, wherein the imidazole derivative is (1).
9) 6-[(4-dimethylaminomethylimidazole-
2-yl) thio] -3-nitroimidazo [1,2-b]
The imidazole derivative according to (1) above, which is pyridazine or a salt thereof, (20) general formula (I)

[0012]

Embedded image [In the formula, A represents an imidazol-1-yl or a fused imidazolyl group having at least one nitro group on the imidazole ring, and X, B, m and n have the same meanings as described above] Alternatively, an antibacterial agent (21) A containing a pharmaceutically acceptable salt thereof,
The antibacterial agent according to the above (20), which is a condensed imidazolyl group having at least one nitro group on the imidazole ring.
(22) The antibacterial agent according to (20), which exhibits an antibacterial activity against Helicobacter spp., (23) the antibacterial agent according to (20), which exhibits an antibacterial activity against Helicobacter pylori, and (24) the 20) An antiulcer agent comprising the imidazole derivative represented by the general formula (I) described above or a pharmaceutically acceptable salt thereof.

When the imidazole derivative represented by the above general formulas (I ') and (I) contains asymmetric carbon, an optically active compound and a racemic mixture are also included in the present invention. Details of each definition of the above general formulas (I ′) and (I) are as follows. General formulas (I ′) and (I)
In each definition of, “lower” means a group having 1 to 6 carbon atoms unless otherwise specified.

First, the definitions of A'and A will be described in detail. Examples of the “fused imidazolyl group” represented by A ′ or A include a fused imidazolyl group formed by condensing an imidazole and a 5- or 6-membered ring, in which the imidazole and the 6-membered ring are condensed. A fused imidazolyl group is preferred. Examples of 5- or 6-membered rings include carbocycles (eg,
Aromatic rings or alicycles), heterocycles (for example, heterocycles containing a nitrogen atom, an oxygen atom or a sulfur atom), etc., among them, heterocycles are preferable, and a heterocycle containing a nitrogen atom is more preferable. preferable. Preferred examples of the 5-membered carbocycle include cyclopentane and cyclopentene.
Preferred examples of the 6-membered carbocycle include cyclohexane, cyclohexene, benzene ring and the like. Preferred examples of the 5-membered heterocycle include heterocycles containing 1 to 2 nitrogen atoms such as pyrrole, imidazole, pyrazole, imidazolidine and imidazoline. Preferred examples of the 6-membered heterocycle include heterocycles containing 1 to 3 nitrogen atoms such as pyridine, pyridazine, pyrimidine, pyrazine, triazine and piperazine, of which pyridine and pyridazine are preferred.

The "fused imidazolyl group" is preferably a fused imidazolyl group having 2 to 4 nitrogen atoms as ring-constituting atoms. Specifically, examples of the "fused imidazolyl group" include imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, and imidazo [4,5- b] pyrazinyl, imidazo [1,5-a] pyrimidinyl, imidazo [1,2-d] [1,2,4] triazinyl, imidazo [1,5-d] [1,2,4] triazinyl, imidazo [ 5,1-c] [1,2,4] triazinyl, imidazo [5,1-f] [1,2,4] triazinyl, imidazo [1,5-b] pyridazinyl, 1H-purinyl, imidazo [1, 5-a] pyridyl, 1H-imidazo [4,5]
-B] Pyridyl and the like can be mentioned. Among these, as a preferable example, imidazo [1,2-b] pyridazine-6
Alternatively, a -7 or -8-yl group and imidazo [1,
2-a] pyridin-5 or -6 or -7 or -8-yl group can be mentioned, and an imidazo [1,2-b] pyridazin-6-yl group or imidazo [1,2-a] pyridin-5- can be mentioned. The yl group is more preferred, and imidazo [1,2-
Most preferred is b] pyridazin-6-yl group.

The number of nitro groups which the “fused imidazolyl group” represented by A ′ or A or the “imidazol-1-yl group” represented by A has on the imidazole ring is preferably 1 to 3, particularly 1 Is preferred. The nitro group is preferably bonded to a carbon atom constituting the imidazole ring. Examples of the “fused imidazolyl group having at least one nitro group on the imidazole ring” represented by A ′ or A include 2- or 3-nitroimidazo [1,2-b] pyridazin-6-yl group, 2-or 3-nitroimidazo [1,2-a] pyridin-5-yl group and the like are preferable, and 2
-Or 3-nitroimidazo [1,2-b] pyridazine-
A 6-yl group is more preferred. Further, the “fused imidazolyl group” represented by A ′ or A is a group other than on the imidazole ring,
That is, it may have a nitro group on the ring condensed with the imidazolyl group.

Preferred examples of the substituent other than the nitro group which the "fused imidazolyl group" represented by A'or A or the "imidazol-1-yl group" represented by A have are halogen atoms (for example, chlorine, bromine, Fluorine, iodine, etc.),
Hydroxyl group, carboxyl group, amino group, sulfo group, sulfamoyl group, mono- or di-lower alkylamino group, lower alkylcarbonylamino group, lower alkoxycarbonyl group, carbamoyl group, mono- or di-lower alkylcarbamoyl group, lower alkyl Group, lower alkoxy group,
Examples thereof include an acyl group.

The definition of the substituents other than the nitro group will be described in detail below. Preferable examples of the "mono- or di-lower alkylamino group" include linear or branched amino groups substituted by 1 or 2 lower alkyl groups, specifically, for example, methyl group. Amino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino and the like can be mentioned. Preferred examples of "lower alkylcarbonylamino group" include linear or branched lower alkylcarbonylamino groups, and specific examples include acetylamino, propionylamino, isopropionylamino, butyrylamino and the like. To be

Preferred examples of "lower alkoxycarbonyl group" include linear or branched lower alkoxycarbonyl groups, specifically, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Butoxycarbonyl,
Examples include isobutoxycarbonyl and the like. Preferred examples of “mono- or di-lower alkylcarbamoyl group” include:
Examples thereof include a carbamoyl group substituted with a linear or branched 1 or 2 lower alkyl group, and specific examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, Dibutylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and the like can be mentioned.

Preferable examples of "lower alkyl group" include linear or branched C _1-6 alkyl group, specifically, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-
Butyl, n-pentyl, n-hexyl and the like can be mentioned.
Preferred examples of the "lower alkoxy group" include linear or branched C _1-6 alkoxy groups, specifically, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy. ,
Hexyloxy and the like can be mentioned. Preferred examples of the “acyl group” include C _1-6 acyl groups, and specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Of these, formyl is particularly preferred.

"Imidazole-1" represented by A'or A
The “-yl group” or the “fused imidazolyl group” may have two or more of the above-mentioned substituents other than the nitro group, which are the same or different. As the substituent other than the nitro group which the “imidazol-1-yl group” represented by A has, a lower alkyl group is preferable. When the fused imidazolyl group represented by A ′ has a substituent other than a nitro group, the substituent may be bonded to any atom constituting the ring, but is bonded to a carbon atom constituting the ring. Is preferred.

Next, the definition of B will be described in detail.
In the definition of B, a preferable example of the “5-membered heterocyclic group which may form a condensed ring” is the general formula (VI)

[0023]

[Chemical 15] [In the formula, R ₁ and R ₂ are each a hydrogen atom, a lower alkyl group which may have a substituent, an amino group which may have a substituent, or a carboxyl group which may have a substituent. Or R ₁ and R ₂ together with the carbon atom to which they are attached may form an aromatic ring which may contain a nitrogen atom, and the carbon to which R ₁ and R ₂ are attached. The bond between the atoms is a single bond or a double bond (in the case of a single bond, it means that two hydrogen atoms are added), Y
Is an oxygen atom, a sulfur atom or a formula

Embedded image (In the formula, R ₄ represents a hydrogen atom or an alkyl group which may have a substituent), and a 5-membered heterocyclic group.

Further, a preferable example of the "6-membered heterocyclic group which may form a condensed ring" is represented by the general formula (VII)

[0025]

[Chemical 17] [Wherein R ₁ 'and R ₂ ' represent a hydrogen atom or a lower alkyl group respectively, or R ₁ 'and R ₂ ' may contain a nitrogen atom together with the carbon atom to which they are bonded. The bond between the carbon atoms to which R ₁ 'and R ₂ ' are bonded, which may form an aromatic ring, is a single bond or a double bond (in the case of a single bond, two hydrogens are added. R ₃ is a hydrogen atom, a hydrocarbon group or a heterocyclic group, and Y ′ is
Is an oxygen atom, a sulfur atom or a group

Embedded image And a 6-membered heterocyclic group represented by

Each definition of the above 5-membered heterocyclic group and 6-membered heterocyclic group will be described. In the definitions of R ₁ , R ₂ , R ₁ ′ and R ₂ ′, preferable examples of “lower alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms (eg, methyl, ethyl). , Propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), and a linear or branched alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.) is particularly preferable. In the definition of R ₁ and R ₂ , preferred examples of the substituent in the “lower alkyl group optionally having substituent (s)” are the same as the substituents that A or A ′ may have. Of these, mono- or di-lower alkylamino groups are particularly preferred.

In the definition of R ₁ and R ₂ , preferred examples of the substituent in the “amino group which may have a substituent” include alkyl, cycloalkyl, aryl, aralkyl, heterocyclic group and the like. . Preferred examples of the above-mentioned "alkyl group" include linear or branched C _1-6 alkyl groups (eg methyl, ethyl, n-propyl, iso-
Propyl, n-butyl, iso-butyl, tert-butyl,
n-pentyl, n-hexyl and the like), and a C _1-3 alkyl group is more preferable. Preferred examples of the “cycloalkyl group” include C _3-8 cycloalkyl groups (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.). Preferred examples of the above “aryl group” include:
C _6-12 aryl groups (eg, phenyl, naphthyl, biphenylyl, etc.) can be mentioned. Preferred examples of the above-mentioned "aralkyl group" include C _7-19 aralkyl group (eg, benzyl, phenethyl, benzhydryl, trityl, naphthylethyl, etc.). Preferred examples of the above-mentioned "heterocyclic group" include a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. Pyrrolidino, 2-oxopyrrolidino, pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl,
Isoxazolyl, isothiazolyl, thiazolyl, piperidino, piperidinyl, pyridyl, pyridazinyl, pyrazinyl, piperazinyl, pyrimidinyl, indolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,3
-Dioxolanyl, morpholino, morpholinyl and the like. These heterocyclic groups may form a bicyclic condensed ring group (eg 8-quinolyl, 8-purinyl etc.) with a 5- or 6-membered ring (eg benzene, pyridine, cyclohexane etc.). The alkyl, cycloalkyl, aryl, aralkyl, and heterocyclic groups may be further substituted with 1 to 3 appropriate substituents (eg, hydroxyl group, carboxy group, amino group which may be substituted with C _1-6 alkyl group, etc.). ) May be substituted.

In the definition of R ₁ and R ₂ , the substituent in the "amino group which may have a substituent" is preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group. In the definition of R ₁ and R ₂ , preferred examples of “a carboxyl group which may have a substituent” include a carboxyl group and derivatives of a carboxyl group such as esters and amides. Examples of the above-mentioned "esters" include alkyl esters, cycloalkyl esters, aryl esters, aralkyl esters, heterocyclic-substituted alkyl esters, and the like, and examples of the above "amides" include , Unsubstituted amides and mono- or di-
Examples include substituted amides. Examples of the substituent of the substituted amide include alkyl, cycloalkyl, aryl,
Examples thereof include aralkyl and alkyl substituted with a heterocycle, and these may be substituted with a carboxyl group or an amino lower alkyl group. Preferable examples of these alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups include the same ones as described above. When the above amides are disubstituted amides, they may form a ring with the nitrogen atom to which they are attached. Examples of such a ring include a 6-membered ring containing 1 to 2 nitrogen atoms (eg, pyridine, pyrazine, etc.), and the ring containing these nitrogen atoms include, for example, lower alkyl, aralkyl, etc. It may have a substituent.

As R ₁ or R ₁ ′, a hydrogen atom is preferable. R ₂ or R ₂ ′ is preferably a hydrogen atom or a lower alkyl group which may be substituted with a mono- or di-lower alkylamino group.

R₃In the definition of, "hydrocarbon group" is preferable
Examples include lower alkyl groups, aryl groups, aralkyl
Examples include hydrocarbon groups having 1 to 20 carbon atoms such as groups. this
Of these, aryl groups are particularly preferred. Above "Lower Al
A preferable example of the “kill group” is R ₁, R₂, R₁'And R₂To '
Is the same as the definition. As an example of the above "aryl group"
Is preferably an aryl group having 6 to 12 carbon atoms, which is preferable.
Examples are phenyl, tolyl, xylyl, cumenyl,
Mesityl, biphenylyl, naphthyl and the like can be mentioned. This
Among them, particularly preferable examples are phenyl and tri
And the like. Preferred examples of the above "aralkyl group"
Examples thereof include benzyl and phenethyl. R₃
In the definition of, as an example of “heterocyclic group”, R is₁Or R₂To
Are similar to those explained in the definition of substituents
Among them, preferred examples thereof include pyridylmethyi.
, Pyridylethyl, pyridyl, furfuryl and the like.
Be done.

In the definition of R ₄ , examples of the alkyl group in the “alkyl group which may have a substituent (s)” include a linear or branched C _1-8 alkyl group (eg methyl,
Ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, neopentyl, tert-butyl, etc.), and preferable examples thereof include a linear or branched C _1-3 alkyl group (for example, Methyl, ethyl, propyl, etc.).

R_FourIn the definition of "may have a substituent
Examples of the substituent of the “alkyl group” include an aromatic ring
Group, 1 to 3 hydroxyl groups, 1 to which may have a substituent
Examples thereof include three amino groups. In the above "aromatic ring group"
Examples of the aromatic ring include 1 to 3 nitrogen atoms
May be C_6-12Aromatic rings are mentioned, and specifically, for example
For example pyridine, pyridazine, pyrimidine, pyrazine, tri
Azine, quinoline, isoquinoline, benzene, naphthale
And the like. These C_6-12Aromatic ring is C _1-6A
Alkyl group (eg methyl, ethyl, propyl, isopropyl)
Pill, butyl, etc.), C_1-6Alkoxy group (eg Metoki
Ci, ethoxy, propoxy, butoxy, isopropoxy
Etc.), aromatic ring groups (eg phenyl, pyrazinyl etc.) etc.
It may be substituted. The above "may have a substituent
Examples of “amino group” include methylamino and ethylami
No, propylamino, dimethylamino, diethylami
No., methylbenzylamino, pyrrolidino, piperidino, etc.
Is mentioned.

In the definition of R ₄ , preferred examples of the substituent which the “alkyl group which may have a substituent (s)” have are:
A hydroxyl group is mentioned. R ₄ is preferably a hydrogen atom or a C _1-3 alkyl group which may have a substituent.

When R ₁ and R ₂ together with the carbon atom to which they are bound form an aromatic ring which may contain 1-2 nitrogen atoms, preferred examples of the aromatic ring formed are , 6-membered aromatic rings such as benzene, pyridine, and pyrazine. Among them, benzene is particularly preferable. Y is the formula

[Chemical 19] And a group represented by

Embedded image Is preferred. The 5- or 6-membered heterocyclic group represented by B, which may form a condensed ring, may optionally have a substituent. Examples of the substituent include those similar to the substituent which A or A ′ may have.

B is preferably a 5-membered heterocyclic group which may form a condensed ring. More preferably, B is a 5-membered heterocyclic group represented by the general formula (VI), and particularly in the general formula (VI), R ₁ is a hydrogen atom, a carboxyl group substituted with a lower alkyl group, Or expression

[0036]

[Chemical 21] (Wherein R ₅ represents a hydrogen atom, R ₆ represents a lower alkyl substituted with amino or carboxyl, or R ₅ and R ₆ further contain a nitrogen atom together with the nitrogen atom to which they are bonded. Optionally a 6-membered heterocycle may be formed, which heterocycle may be substituted with a lower alkyl group which may be substituted with phenyl), and R ₂ is A 6-membered aromatic ring which represents a hydrogen atom or a lower alkyl group which may be substituted with di-lower alkylamino, or which may contain a nitrogen atom in addition to the carbon atom to which R ₁ and R ₂ are bonded. And Y is an oxygen atom, a sulfur atom or a formula

[Chemical formula 22] (In the formula, R ₇ is a hydrogen atom or a hydroxyl group; a lower alkyl, a lower alkoxy or a phenyl group which may be substituted with phenyl; or a 6-membered heterocyclic group containing a nitrogen atom which may be condensed with a benzene ring. Substituents such as ~
A group represented by a group represented by C _1-8 alkyl group _optionally substituted by) is preferable.

Most preferably, B is of the general formula (VI)
Which is a 5-membered heterocyclic group represented by the formula (VI), in which R ₁ represents a hydrogen atom and R ₂ represents a hydrogen atom or a lower alkyl group substituted with a di (lower alkyl) amino group, And Y is the formula

[Chemical formula 23] (Wherein R ₇ 'represents a C _1-3 alkyl group substituted with a hydrogen atom or a hydroxyl group).

In the definitions of formulas (I ') and (I), X is preferably a sulfur atom. As m, an integer of 0 to 2 is preferable, and 0 is more preferable. As n, 0 is preferable. As a preferable example of the compound represented by the general formula (I ′) or (I), 6-[(imidazol-2-yl) thio] -3-nitroimidazo [1,2-b] pyridazine (Example 6) -3), 6-[[1-
(2-Hydroxyethyl) imidazol-2-yl] thio] -3-nitroimidazo [1,2-b] pyridazine (compound prepared in Example 9-8) or 6-[(4-
Dimethylaminomethylimidazol-2-yl) thio]
Examples thereof include -3-nitroimidazo [1,2-b] pyridazine (the compound produced in Example 11) and salts thereof.

The imidazole derivatives represented by the general formulas (I ′) and (I) [hereinafter, sometimes abbreviated as compounds (I ′) and (I), respectively] are groups having basicity in the molecule or When an acidic group is present, it can form a salt with an acid or base. The type of these salts is not particularly limited. Examples of the salt when a basic group is present include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphorus salt, and acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid. Examples thereof include salts with acids, organic acids such as toluenesulfonic acid and methanesulfonic acid. In addition, examples of the salt when an acidic group is present include salts with alkali metals (for example, sodium, potassium, etc.). The above-mentioned salts can be generally used as pharmaceutically acceptable salts.

The compound (I ') of the present invention can be produced, for example, by the following method. General formula (II ')

[0041]

[Chemical formula 24] [Wherein each symbol has the same meaning as defined above, and Z represents a reactive group] or a salt thereof and a compound represented by the general formula (III)

[0042]

[Chemical 25] [Wherein each symbol has the same meaning as described above] or a compound represented by the formula (IV ')

[0043]

[Chemical formula 26] [Wherein each symbol has the same meaning as defined above] or a salt thereof and the general formula (V)

[0044]

[Chemical 27] It can be produced by reacting a compound represented by [wherein each symbol has the same meaning as described above] or a salt thereof under the following reaction conditions.

In the definitions of the general formula (II ') and the general formula (V), as the reactive group represented by Z, a reactive group generally used in this field can be used. Preferable examples of the reactive group include, for example, a halogen atom (for example, chlorine, bromine, fluorine, iodine, etc.), C ₆ -C.
₁₀ arylsulfonyloxy group (for example, benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), C _1-
A C ₄ alkylsulfonyloxy group (eg, methanesulfonyloxy etc.) and the like can be mentioned.

Preferred examples in the respective definitions (excluding Z) of the general formulas (II '), (III), (IV') and (V) are the same as those in the general formula (I '). In this reaction, ethers (for example, diethyl ether, tetrahydrofuran,
Dioxane), halogenated hydrocarbons (eg dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbons (eg benzene, toluene, hexane, heptane, etc.), dimethylformamide, dimethylsulfoxide, etc. You can

If desired, this reaction can be carried out in the presence of a base. Examples of such a base include organic bases such as 4-dimethylaminopyridine, triethylamine, triethylenediamine and tetramethylethylenediamine, and For example, an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride,
Potassium hydride or the like is used.

In this reaction, the reaction temperature is about -50 ° C.
100 ° C is suitable, with about 0 ° C to 50 ° C being preferred. The reaction time is usually about 1 to 48 hours, preferably about 5 to 10 hours. When this reaction is carried out, 1 mol of the compound represented by the general formula (II ′) or (V) is used for the general formula (II
It is suitable to use about 1 to 10 molar amount of the compound represented by I) or (IV ′), preferably about 1 to 3 molar amount.

The reaction product synthesized in this reaction can be prepared by known means such as solvent extraction, liquid conversion, phase transfer, salting out, crystallization,
It can be isolated and purified by recrystallization, chromatography and the like. The compound (I ′) obtained by the above reaction can be converted into its salt, if desired, according to a conventional method commonly used in the art.

The salts of the starting compounds (II '), (III), (IV') and (V) used when producing the compound (I ') are the compounds (I'). The same salt as the salt can be applied. A raw material compound (II ′) used when producing the above compound (I ′),
(III), (IV ') and (V) can be synthesized by a method known per se, a method described in Examples below or a method analogous thereto, and the like.

The compound (I) of the present invention has, for example, the general formula (II)

[0052]

[Chemical 28] [In the formula, each symbol has the same meaning as above] and a compound or a salt thereof and the compound (III) or a salt thereof,
Or general formula (IV)

[0053]

[Chemical 29] [Wherein each symbol has the same meaning as defined above] or a salt thereof and the compound (V) or a salt thereof under the same reaction conditions as in the production method of the compound (I ′). It can be produced by reacting.

The compound (I) of the present invention or a salt thereof has an antibacterial action, particularly a strong antibacterial activity against Helicobacter spp. Represented by Helicobacter pylori. It is effective for the prevention or treatment of various gastrointestinal system-related diseases (for example, duodenal ulcer, gastric ulcer, chronic gastritis, etc.). Further, the compound (I) of the present invention or a salt thereof has an antibacterial action against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis, in addition to Helicobacter spp. Show.

Furthermore, the compound (I) of the present invention or a salt thereof is effective for the prevention or treatment of ulcers such as stress ulcers not caused by Helicobacter pylori, and is a novel anti-ulcer agent, duodenal ulcer and gastric ulcer. It is effective for the prevention or treatment of The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be orally or parenterally administered to mammals such as humans as an antibacterial agent and an antiulcer agent, and is generally orally administered. Administration is preferred.

Examples of dosage forms for oral administration include tablets (including sugar-coated tablets and film-coated tablets),
Pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions and the like can be mentioned. Examples of dosage forms for parenteral administration include injections, infusions, drops, suppositories and the like.

As a method for producing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof into the above dosage form, a production method known per se generally used in the art is applied. You can Further, in the case of producing the above-mentioned dosage form, if necessary, an excipient, a binder, a disintegrating agent, a lubricant, a sweetening agent, an interface which is usually used in the field of formulation in producing the dosage form. It can be produced by containing an activator, a suspending agent, an emulsifier and the like.

For example, when the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is prepared into tablets, an excipient,
It can be produced by containing a binder, a disintegrating agent, a lubricant, etc., and in the case of producing pills and granules, it may be produced by incorporating an excipient, a binder, a disintegrating agent, etc. it can. In addition, when manufacturing powders and capsules, excipients, etc.,
In the case of making a syrup, a sweetener and the like can be added, and in the case of making an emulsion and a suspension, a suspending agent, a surfactant, an emulsifier and the like can be added. Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like. Examples of the binder include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution,
1 to 5 wt% tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, glycerin and the like can be mentioned. Examples of the disintegrant include starch, calcium carbonate and the like. Examples of lubricants include magnesium stearate, stearic acid, calcium stearate,
Examples include refined talc. Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like. Examples of the surfactant include sodium lauryl sulfate and polysorbate 8
0, sorbitan monofatty acid ester, stearic acid polyoxyl 40 and the like. Examples of suspending agents include
Examples thereof include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like. Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.

Further, when the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is produced in the above-mentioned dosage form, if desired, a coloring agent, a preservative and a fragrance which are usually used in the field of formulation are used. , Flavoring agents, stabilizers, thickeners and the like can be added. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is stable and has low toxicity, and can be used safely. The daily dose varies depending on the patient's condition, weight, type of compound, administration route, etc., but in the case of oral administration, the daily dose for an adult is about 1 to about 5
00 mg is suitable and about 10 to about 200 mg is preferred. No toxicity is seen in the above dose range.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can also be administered in combination with other antibacterial agents and antiulcer agents. Hereinafter, the present invention will be described more specifically by showing Examples, Formulation Examples, and Test Examples, but it goes without saying that the present invention is not limited thereto.

Example 1 1- (Benzoxazol-2-yl) thioethyl-2
-Methyl-5-nitroimidazole preparation

[0062]

Embedded image (1) 2-Methyl-5-nitro-1- [2- (toluenesulfonyloxy) ethyl] imidazole 2-Methyl-5-nitro-1-imidazole ethanol (5.2 g), paratoluenesulfonic acid chloride (5. 7
g) and triethylamine (3.4g) were dissolved in dichloromethane (100ml) and stirred at 40 ° C overnight. After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off, ethyl ether was added to the residue, and the residue was collected by filtration to give 2-
Crystals of methyl-5-nitro-1- [2- (toluenesulfonyloxy) ethyl] imidazole (8.9 g) were obtained.

(2) 1- (Benzoxazol-2-yl) thioethyl-2-methyl-5-nitroimidazole sodium hydride (60% by weight content) (0.132 g)
Was added to dimethylformamide (10 ml) at room temperature for 1
The mixture was stirred for 0 minutes, 2-mercaptobenzoxazole (0.45 g) was further added, and the mixture was stirred at room temperature for 30 minutes. After stirring, 5-methyl-2-nitro-1- [2- (toluenesulfonyloxy) ethyl] imidazole (0.97
g) was further added, and the mixture was heated with stirring at 60 ° C. overnight. Then, water (100 ml) was added to the reaction solution, extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from dichloromethane / ethyl ether to give 1- (benz Oxazole-2
-Yl) Thioethyl-2-methyl-5-nitroimidazole (0.80 g) was obtained. Melting point 144-145 ° C. Elemental analysis: C ₁₃ H ₁₂ N ₄ O ₃ S Theoretical value: C 51.31 H 3.97 N 18.41 Actual value: C 51.15 H 4.04 N 18.34

Example 2 1- (Benzimidazol-2-yl) thioethyl-2
-Methyl-5-nitroimidazole preparation

[0065]

[Chemical 31] 2-Mercaptobenzimidazole (0.45 g) instead of 2-mercaptobenzoxazole (0.45 g)
g) was used and reacted with 2-methyl-5-nitro-1- [2- (toluenesulfonyloxy) ethyl] imidazole according to the method described in Example 1 to give the title compound (0.52 g). was gotten. Melting point 290-292 ° C. (decomposition) Elemental analysis: C ₁₃ H ₁₃ N ₅ O ₂ S.1 / 2H ₂ O Theoretical value: C 49.99 H 4.52 N 22.42 Actual value: C 50.31 H 4.48 N 22.71

Example 3 1- (Benzthiazol-2-yl) thioethyl-2-
Production of methyl-5-nitroimidazole

[0067]

Embedded image 2-Mercaptobenzthiazole (0.45 g) instead of 2-mercaptobenzoxazole (0.45 g)
2-methyl- according to the method described in Example 1
5-nitro-1- [2- (toluenesulfonyloxy)
The title compound (0.61 g) was obtained by reacting with ethyl] imidazole. Melting point 121 to 122 ° C. Elemental analysis: C ₁₃ H ₁₂ N ₄ O ₂ S ₂ Theoretical value: C 48.73 H 3.78 N 17.49 Actual value: C 48.71 H 3.79 N 17.42

Example 4 6- (Benzoxazol-2-yl) thio-3-nit
Production of Leuimidazo [1,2-b] pyridazine

[0069]

[Chemical 33] Sodium hydride (60% content) (0.132 g),
It was suspended in dimethylformamide (10 ml), 2-mercaptobenzoxazole (0.45 g) was added, and the mixture was stirred at room temperature for 10 minutes. After stirring, 6-chloro-3-nitroimidazo [1.2-b] pyridazine (0.60 g) was further added, and the mixture was heated with stirring at 120 ° C. for 10 hours. Then, water (100 ml) was further added, and the mixture was extracted with dichloromethane. After extraction, the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from dichloromethane to give 6- (benzoxazol-2-yl) thio-3-nitroimidazo [1,2- b] Pyridazine crystals (0.56 g) were obtained. Melting point 176-178 ° C Elemental analysis: C ₁₃ H ₇ N ₅ O ₃ S Theoretical value: C 49.84 H 2.25 N 22.35 Actual value: C 49.72 H 2.05 N 21.97

Example 5 6- (Benzimidazol-2-yl) thio-3-nit
Preparation of Leuimidazo [1.2-b] pyridazine

[0071]

Embedded image 2-Mercaptobenzimidazole (0.45 g) instead of 2-mercaptobenzoxazole (0.45 g)
The title compound (0.60 g) was obtained according to the method described in Example 4 using g). Melting point 283 to 285 ° C Elemental analysis: C ₁₃ H ₈ N ₆ O ₂ S Theoretical value: C 50.00 H 2.58 N 26.91 Actual value: C 50.13 H 2.41 N 26.73

Example 6 Using 6-chloro-3-nitroimidazo [1,2-b] pyridazine according to the method described in Example 4, the compounds shown in Table 1 were obtained.

[0073]

[Table 1]

Example 7 Using 5-chloro-3-nitroimidazo [1,2-a] pyridine according to the method described in Example 4, the compounds shown in Table 2 were obtained.

[0075]

[Table 2]

Example 8 1-Benzyl-2-[(3-nitroimidazo [1,2-
b] -Viridazin-6-yl) thio] imidazole.1
hydrochloric acid

[0077]

Embedded image 2-[(3-Nitroimidazo [1,2-b] -pyridazin-6-yl) thio] imidazole (262 mg) obtained in Example 6-3 was treated with sodium hydride (6%) (40 m).
g) in a suspension of dimethylformamide (20 ml) at 0 ° C.
And then stirred for 10 minutes. Benzyl bromide (170 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours, then water (100 ml) was added to the reaction solution, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography, the obtained solid was dissolved in dichloromethane, and an ethyl acetate solution of 4N hydrogen chloride (1 ml) was added. After distilling off the solvent, the residue was recrystallized from ethanol-ethyl ether,
1-benzyl-2-[(3-nitroimidazo [1,2-b] -viridazin-6-yl), mp 147-150 ° C.
Thio] imidazole · 1 hydrochloric acid colorless crystals (154 mg) were obtained. Elemental analysis: C ₁₆ H ₁₂ N ₆ O ₂ S.HCl Theoretical value: C 49.42 H 3.37 N 21.61 Actual value: C 49.11 H 3.27 N 21.64

Example 9 2-[(3-nitroimidazo [1, obtained in Example 6
Using 2-b] pyridazin-6-yl) thio] imidazole and following the method described in Example 8, the compounds shown in Table 3 were obtained.

[0079]

[Table 3]

[0080]

[Table 4]

Example 10 6- (Benzimidazol-2-yl) oxy-3-ni
Troimidazo [1,2-b] pyridazine

[0082]

Embedded image 2-hydroxybenzimidazole (0.8 g) and 6-
Sodium hydride (60%) (0.12 g) was added to a solution of chloro-3-nitroimidazo [1,2-b] pyridazine (0.6 g) in dimethylformamide (20 ml), and the mixture was stirred at room temperature for 2 days. After distilling off the solvent, the residue was washed with water, methanol and dimethyl sulfoxide, and the melting point was 322-3.
Colorless crystals (0.22 g) of 6- (benzimidazol-2-yl) oxy-3-nitroimidazo [1,2-b] pyridazine at 23 ° C were obtained. Elemental analysis: C ₁₃ H ₈ N ₆ O ₃ Theoretical value: C 52.71 H 2.72 N 28.37 Actual value: C 53.12 H 2.82 N 28.14

Example 11 6-[(4-Dimethylaminomethylimidazole-2-
Il) thio] -3-nitroimidazo [1,2-b] pyri
Dazin trihydrochloride

[0084]

Embedded image A 50% dimethylamine aqueous solution (990 mg) was cooled to 0 ° C., and acetic acid (1 ml) and 37% formaldehyde (1.2 g) were added thereto. 2-[(3-Nitroimidazo [1,2-b] pyridazin-6-yl) thio] imidazole (0.26 g) obtained in Example 6-3 was added to this solution.
Was added and the mixture was heated with stirring at 50 ° C. for 48 hours. 1 in the reaction solution
A normal aqueous sodium hydroxide solution (20 ml) was added, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate,
The solvent was evaporated, the residue was separated and purified by silica gel column chromatography, and an acetic acid ethyl ester solution of 4N hydrogen chloride (1 ml) was added thereto. The solvent was distilled off, and the precipitated crystals were suspended in dichloromethane and collected by filtration to give 6-[(4-dimethylaminomethylimidazol-2-yl) thio] -3-nitroimidazo having a melting point of 175-177 ° C. Colorless crystals (52 mg) of [1,2-b] pyridazine trihydrochloride were obtained. Elemental analysis: C ₁₂ H ₁₃ N ₇ O ₂ S.3HCl Theoretical value: C 33.62 H 3.76 N 22.87 Actual value: C 33.54 H 3.89 N 22.37

Example 12 5-Methyl-4- (4-methylpiperazinocarbonyl)
-2-[(3-nitroimidazo [1,2-b] pyridazi
(N-6-yl) thio] imidazole dihydrochloride

[0086]

[Chemical 38] 4-Carboxy-5-methyl-2-mercaptoimidazole (158 mg), N-methylpiperazine (100 mg)
A solution of triethylamine (100 mg) in dimethylformamide (10 ml) was added to diethyl cyanophosphate (196 m).
g) was added and stirred at 0 ° C. for 30 minutes. Water (5 ml) was added and the mixture was stirred at room temperature for 30 min, the solvent was evaporated, the precipitated solid was suspended in ether and collected by filtration (248 mg). This was subjected to the same operations as in Example 4 to obtain 5-methyl-4- (4-methylpiperazino) carbonyl-2-
[(3-Nitroimidazo [1,2-b] pyridazine-6
-Yl) Thio] imidazole (30 mg) was converted to the hydrochloride salt, 5-methyl-4- (4-methylpiperazinocarbonyl) -2-[(3-nitroimidazo [1,2], mp 194-196 ° C. A colorless crystal (43 mg) of -b] pyridazin-6-yl) thio] imidazole dihydrochloride was obtained. Elemental analysis: C ₁₆ H ₁₈ N ₈ O ₃ S.2HCl Theoretical value: C 43.79 H 4.36 N 25.53 Actual value: C 43.92 H 4.43 N 25.32

Example 13 4- (4-benzylpiperazinocarbonyl) -5-methyi
Le-2-[(3-nitroimidazo [1,2-b] pyrida
(Din-6-yl) thio] imidazole dihydrochloride

[0088]

[Chemical Formula 39] Using 4-carboxy-5-methyl-2-mercaptoimidazole and following the method described in Example 12, melting point 17
4- (4-benzylpiperazinocarbonyl) -5-methyl-2-[(3-nitroimidazo [1,
2-b] pyridazin-6-yl) thio] imidazole
Colorless crystals of the dihydrochloride were obtained. Elemental analysis: C ₂₂ H ₂₂ N ₈ O ₃ S.2HCl.1 / 2H ₂ O Theoretical value: C 47.15 H 4.50 N 19.99 Actual value: C 46.89 H 4.71 N 19.51

Example 14 4-[(5-amino-1-carboxy) pentylamino
Carbonyl] -5-methyl-2-[(3-nitroimidazole
Zo [1,2-b] pyridazin-6-yl) thio] imida
Sol dihydrochloride

[0090]

[Chemical 40] Using 4-carboxy-5-methyl-2-mercaptoimidazole (316 mg) and N [epsilon] -tert-butoxycarbonyl lysine tert-butyl ester (604 mg) according to the method described in Example 12, 4-[(5 -Tert-Butoxycarbonylamino-1-tert-butoxycarbonyl) pentylaminocarbonyl] -5-methyl-2-[(3-nitroimidazo [1,2-b] pyridazin-6-yl) thio] imidazole (402 mg) Got This compound (2
11 mg) was dissolved in trifluoroacetic acid (5 ml) and left at room temperature for 30 minutes. Trifluoroacetic acid was distilled off, dissolved in acetonitrile (10 ml), and concentrated hydrochloric acid (0.105 ml)
Was added. The solvent was distilled off, and the precipitated crystals were suspended in ethyl ether and collected by filtration to give a melting point of 178-18.
4- (5-amino-1-carboxy) pentylaminocarbonyl-5-methyl-2-[(3-nitroimidazo [1,2-b] pyridazin-6-yl) thio] imidazole di-salt vinegar at 0 ° C Colorless crystals of salt (187 mg) were obtained. Elemental analysis: C ₁₇ H ₂₀ N ₈ O ₅ S.2HCl theoretical value C 39.16 H 4.25 N 21.49 measured value C 39.31 H 4.19 N 21.17

Example 15 4-[(1,2-dicarboxy) ethylaminocarbonyl
L] -5-methyl-2-[(3-nitroimidazo [1,
2-b] pyridazin-6-yl) thio] imidazole
Monohydrochloride

[0092]

Embedded image Using 4-carboxy-5-methyl-2-mercaptoimidazole and aspartic acid ditertiary butyl ester,
According to the method described in Examples 12 and 14, melting point 1
4-[(1,2-dicarboxy) ethylaminocarbonyl] -5-methyl-2-[(3-nitroimidazo [1,2-b] pyridazin-6-yl) thio] imidazole at 70-172 ° C. Colorless crystals of the monohydrochloride were obtained. Elemental analysis: C ₁₅ H ₁₃ N ₇ O ₇ S.HCl theoretical value C 38.17 H 2.78 N 20.78 measured value C 38.01 H 2.54 N 20.92

Formulation Example 1 Capsule (1) Compound obtained in Example 9-8 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg The above (1), ( The whole amount of (2) and (3) was mixed with 5 mg of (4), and then the mixture was granulated, and the rest of (4) (5 mg) was added thereto, and the whole was encapsulated in a gelatin capsule.

Formulation Example 2 Tablet (1) Compound obtained in Example 9-8 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg The total amount of 1), (2) and (3) and 20 mg of (4)
And 2.5 mg of (5) were mixed and granulated, and the remaining (4) (10 mg) and (5) (2.5 mg) were added to the granules, and the mixture was pressure-molded to give tablets.

Test Example 1 Pairing with Helicobacter pylori
Antibacterial activity test (test method) Using the compounds synthesized in Examples 1 to 6, 9 and 10, the antibacterial activity of each was measured by the following method [agar dilution method]. A test sample was prepared by dissolving each test compound in dimethyl sulfoxide and serially diluting it twice with sterile distilled water. Using 7% horse blood supplemented Brucella agar as a medium, 2 ml of the prepared test sample was mixed with 7% horse blood supplemented Brucella agar 18 ml to prepare a measurement plate.

Helicobacter pylori strains NCTC11637 and CPY433 were used as test bacteria. Each test organism is
Using Brucella broth medium supplemented with 2.5% fetal bovine serum,
CampyPak ^TM (BBL ^R Beckton Dickinson Microbiology Sys
tems) was inserted in a gas pack jar and cultured at 37 ° C. for 20 hours with shaking. 5 microliters of each bacterial solution prepared to about 10 ⁶ CFU / ml in the same medium was inoculated on each measuring plate, and 37 ° C in a gas pack jar in which absorbent cotton containing CampyPak ^™ and water was inserted. Cultured for 4 days. After culturing, the growth of the strain is visually observed, and the minimum concentration at which the growth of the strain is not observed is the MIC value (minimum inhibitory concentration) of the test compound.
And As a positive control, metronidazole (a known imidazole derivative having an anti-Helicobacter pylori activity) was used, and the MIC value of metronidazole was determined by operating in the same manner as the test compound.

(Test Results) Test compounds (Examples 1 to 6,
Table 4 shows the results of the MIC values of the compounds synthesized in 9 and 10) and metronidazole (positive control).

[0098]

[Table 5] From Table 4, it is clear that in all strains of Helicobacter pylori used in the test, the compound of the present invention has stronger antibacterial activity than metronidazole.

[0099]

INDUSTRIAL APPLICABILITY The compound (I '), (I) or a salt thereof of the present invention has a strong antibacterial activity against Helicobacter spp. Represented by Helicobacter pylori. Therefore, when the compound (I ′), (I) or a salt thereof of the present invention is used, a desired antibacterial effect against Helicobacter spp. (Particularly Helicobacter pylori) can be obtained at a dose much lower than the effective dose of conventional antibacterial agents. Obtainable.

The compound (I ′), (I) or a salt thereof of the present invention has a strong antibacterial activity against Helicobacter spp. Typified by Helicobacter pylori and, therefore, is attributed to Helicobacter spp. As an antibacterial agent. Duodenal ulcer, gastric ulcer, is effective in the prevention or treatment of various diseases such as chronic gastritis, Helicobacter pylori is also a major cause of recurrent ulcer, the compound of the present invention (I '),
(I) or its salt is also effective for preventing recurrence of ulcer.

The compounds (I ′), (I) or salts thereof of the present invention are also effective against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis. It also has an excellent antibacterial effect. Therefore, the compound (I ′), (I) or a salt thereof of the present invention is also effective as an antibacterial agent for the prevention or treatment of various diseases caused by these bacteria.

Further, the compound (I '), (I) or a salt thereof of the present invention, in addition to the above-mentioned action, serves as an anti-ulcer agent for preventing or preventing ulcers such as stress ulcers not caused by Helicobacter sp. It is also effective for treatment. The compound (I '), (I) or a salt thereof of the present invention is stable and has low toxicity. That is, the present invention provides an excellent antibacterial agent and antiulcer agent without side effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 403/12 223 417/12 223 487/04 144 7019-4C 519/00 301

Claims (24)

[Claims] 1. A compound represented by the general formula (I ′): [In the formula, A'is a condensed imidazolyl group having at least one nitro group on the imidazole ring, X is an oxygen atom or a sulfur atom, and B is a 5- or 6-membered heterocyclic group which may form a condensed ring. And m and n each represent an integer of 0 to 4] or a salt thereof. 2. B is a compound represented by the general formula (VI): [In the formula, R ₁ and R ₂ are each a hydrogen atom, a lower alkyl group which may have a substituent, an amino group which may have a substituent, or a carboxyl group which may have a substituent. Or R ₁ and R ₂ together with the carbon atom to which they are attached may form an aromatic ring which may contain a nitrogen atom, and the carbon to which R ₁ and R ₂ are attached. The bond between the atoms is a single bond or a double bond (in the case of a single bond, it means that two hydrogen atoms are added), Y
Is an oxygen atom, a sulfur atom or the formula The imidazole derivative according to claim 1, which is a 5-membered heterocyclic group represented by the formula: wherein R ₄ represents a hydrogen atom or an alkyl group which may have a substituent. 3. B is represented by the general formula (VII): [Wherein R ₁ 'and R ₂ ' represent a hydrogen atom or a lower alkyl group respectively, or R ₁ 'and R ₂ ' may contain a nitrogen atom together with the carbon atom to which they are bonded. The bond between the carbon atoms to which R ₁ 'and R ₂ ' are bonded, which may form an aromatic ring, is a single bond or a double bond (in the case of a single bond, two hydrogens are added. R ₃ is a hydrogen atom, a hydrocarbon group or a heterocyclic group, and Y ′ is
Is an oxygen atom, a sulfur atom or a group The imidazole derivative according to claim 1, which is a 6-membered heterocyclic group represented by 4. The imidazole derivative according to claim 1, wherein the condensed imidazolyl group has 2 to 4 nitrogen atoms as ring-constituting atoms. 5. The imidazole derivative according to claim 1, wherein A ′ is a fused imidazolyl group of imidazole and a 6-membered heterocycle. 6. A compound according to claim 1, wherein A ′ is a fused imidazolyl group of imidazole and a nitrogen atom-containing 6-membered heterocycle.
The imidazole derivative described. 7. The imidazole derivative according to claim 1, wherein A ′ is a condensed imidazolyl group of imidazole and pyridine, pyridazine, pyrimidine, pyrazine or triazine. 8. The imidazole derivative according to claim 1, wherein A ′ is a condensed imidazolyl group of imidazole and pyridine or pyridazine. 9. A ′ is a 2- or 3-nitroimidazo [1,2-b] pyridazin-6-yl group.
The imidazole derivative described. 10. The imidazole derivative according to claim 1, wherein A ′ is a 2- or 3-nitroimidazo [1,2-a] pyridin-5-yl group. 11. The imidazole derivative according to claim 2, wherein R ₁ and R ₂ are each a hydrogen atom or a lower alkyl group having a substituent. 12. The imidazole derivative according to claim ₂ , wherein _one of R ₁ and R ₂ is a lower alkyl group substituted with a mono- or di-lower (C _1-6 ) alkylamino group. 13. R ₁ and R ₂ each have 1 to 6 carbon atoms.
The imidazole derivative according to claim 2, which is a straight-chain or branched alkyl group. 14. The imidazole derivative according to claim 1, wherein X is a sulfur atom. 15. Y is of the formula: The imidazole derivative according to claim 2, which is a group represented by the formula (wherein R ₄ represents a hydrogen atom or a lower alkyl group having a substituent). 16. The imidazole derivative according to claim 1, wherein both m and n are 0. 17. The imidazole derivative according to claim 1, which is 6-[(imidazol-2-yl) thio] -3-nitroimidazo [1,2-b] pyridazine or a salt thereof. 18. The imidazole derivative according to claim 1, which is 6-[[1- (2-hydroxyethyl) imidazol-2-yl] thio] -3-nitroimidazo [1,2-b] pyridazine or a salt thereof. . 19. The imidazole derivative according to claim 1, which is 6-[(4-dimethylaminomethylimidazol-2-yl) thio] -3-nitroimidazo [1,2-b] pyridazine or a salt thereof. 20. The general formula (I): [In the formula, A represents an imidazol-1-yl group having at least one nitro group on the imidazole ring or a fused imidazolyl group, and X, B, m and n have the same meanings as defined in the general formula (I ′). ] An antibacterial agent comprising an imidazole derivative represented by or a pharmaceutically acceptable salt thereof. 21. The antibacterial agent according to claim 20, wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring. 22. The antibacterial agent according to claim 20, which exhibits an antibacterial action against Helicobacter spp. 23. The antibacterial agent according to claim 20, which exhibits an antibacterial action against Helicobacter pylori. 24. An anti-ulcer agent comprising the imidazole derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to claim 20.