WO1996016656A1 - Condensed imidazole derivatives, their preparation and use - Google Patents

Abstract

An agent against a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides, antiulcerative agent, anti-stomach cancer agent and composition, which comprises a compound of the formula (I): A-X-R, wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; X is formula (a) in which n is an integer of 0 to 2, or -O-; and R is an optionally substituted hydrocarbon group, or a pharmaceutically acceptable salt thereof. A compound included in the formula (I) and its preparation and use are also provided.

Description

CONDENSED IMIDAZOLE DERIVATIVES, THEIR PREPARATION AND USE

TECHNICAL FIELD

The present invention relates to an imidazole derivative. Specifically, the present invention relates to an imidazole derivative having potent antibacterial activity particularly against bacteria belonging to the genus Helicobacter (e.g., Helicobacter pylori) or Campylobacter, and antibacterial, antiulcerative and anti-stomach cancer agents containing it. BACKGROUND OF THE INVENTION

Microorganisms that have a harmful effect in the digestive tract include Helicobacter pylori that is a gram-negative microaerophile belonging to the genus Helicobacter. It is suggested that Helicobacter pylori may be a major cause of the recurrence of gastritis, duodenal ulcer, gastric ulcer, etc.

In order to treat various diseases caused by Helicobacter pylori, combination chemotherapy has been conducted by using two preparations (i.e., a bismuth preparation and an antibiotic) or three preparations (i.e., a bismuth preparation, metronidazole (U.S. Patent No. 2,944,061) and tetracycline (disclosed in e.g., U.S. Patent No. 2,712,517) or amoxicillin (U.S. Patent No. 3,192,198)), etc. Metronidazole described above is an imidazole derivative having inhibitory activity against Helicobacter pylori, and has been used in combination with an antibiotic. The bismuth preparation, antibiotic, metronidazole, etc., have been administered orally.

However, the above bismuth preparation, antibiotic, metronidazole, etc., must be administered in a high dose per day to maintain its concentration sufficient to inhibit the growth of Helicobacter pylori at the growing site. This causes many problems such as side effects (e.g., vomiting, diarrhea).

Imidazo[1,2-b]pyridazine derivatives having a nitro group are disclosed in JP-A 47-20193, JP-A 49-62496, U.S. Patent No. 4,061,751, etc. However, these publications fail to disclose that the imidazo[1,2-b]pyridazine derivatives have antibacterial activity against microorganisms that have a harmful effect in the digestive tract (e.g., bacteria belonging to the genus Helicobacter). U.S. Patent No. 4,061,751 discloses anti-Fusobacterium necrophorum activity of the imidazo[1,2-b]pyridazine derivatives. However, Fusobacterium has no relation to diseases in the digestive tract caused by Helicobacter, etc. Fusobacterium is a strict aerobe and isolated from pus, wounds, sputum, etc. On the other hand, Helicobacter grows under microaerophilic conditions and lives in the human stomach. It is recognized that Helicobacter is associated with the onset of gastritis, gastric or duodenal ulcer and stomach cancer.

The main object of the present invention is to provide an imidazole derivative having potent antibacterial activity particularly against bacteria belonging to the genus Helicobacter (e.g., Helicobacter pylori) or Campylobacter, and antibacterial, antiulcerative and anti-stomach cancer agents containing it.

This object as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.

DISCLOSURE OF THE INVENTION

The present inventors have intensively studied to achieve the above objectives. As a result, they have found that a condensed imidazole derivative has potent antibacterial activity against bacteria that have a harmful effect in the digestive tract (e.g., bacteria belonging to the genus

Helicobacter such as Helicobacter pylori, and the genus

Campylobacter), and antiulcerative activity. After further studies based on this finding, the present invention has been accomplished.

The present invention provides an agent against a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides, which comprises a compound of the formula (I):

A-X-R ( I )

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; X is

in which n is an integer of 0 to 2, or -O-; and R is an optionally substituted hydrocarbon group, or a pharmaceutically acceptable salt thereof.

The present invention also provides a composition for treating a disease caused by a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides, which comprises a compound of the formula ( I ) as defined above or a pharmaceutically acceptable salt thereof.

The present invention also provides an antiulcerative agent comprising a compound of the formula (I) as defined above or a pharmaceutically acceptable salt thereof.

The present invention also provides an anti-stomach cancer agent (i.e., an agent for preventing or treating stomach cancer) comprising a compound of the formula (I) as defined above or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of the formula (IA'):

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; R' is a hydrocarbon group substituted with (i) an optionally substituted hydroxy group, (ii) an optionally esterified or amidated carboxyl group, (iii) an optionally substituted amino group or (iv) an optionally substituted aryl group; and n is an integer of 0 to 2, provided that when n is 0, R' is not an alkoxyalkyl group, or a salt thereof.

The present invention also provides a compound of the formula (IB'):

A-O-R'' (IB')

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; R'' is a hydrocarbon group which is substituted with a group of the formula:

in which Ra is an optionally substituted alkylcarbonyl group and Rb is a hydrogen atom or an alkyl group, or a salt thereof. The present invention also provides a method of producing a compound of the above formula (IA') which comprises reacting (i) a compound of the above formula (II'):

A-S-H (II')

in which A is of the same meaning as defined in the formula (IA'), or a salt thereof with a compound of the formula (III'):

Z-R' (III')

in which Z is a reactive group and R' is of the same meaning as defined in the above formula (IA'), or a salt thereof, or (ii) a compound of the formula (IV):

A-Z (IV)

in which all symbols are of the same meaning as defined above, or a salt thereof with a compound of the formula (V'):

H-S-R' (V)

in which R' is of the same meaning as defined above, or a salt thereof, and, if necessary, subjecting the resulting compound to an oxidation reaction.

The present invention also provides a method of producing a compound of the above formula (IB') which comprises reacting (i) a compound of the formula (II''):

A-O-H (II'')

in which A is of the same meaning as defined in the above formula (IB'), or a salt thereof with a compound of the formula: Z-R'' (III")

in which Z is a reactive group and R'' is of the same meaning as defined in the above formula (IB'), or a salt thereof, or (ii) a compound of the formula (IV):

A-Z (IV)

in which all symbols are of the same meaning as defined above, or a salt thereof with a compound of the formula:

H-O-R'' (V'')

in which R'' is of the same meaning as defined above, or a salt thereof.

The present invention also provides a composition which comprises a compound of the above formula (IA').

The present invention also provides a composition which comprises a compound of the formula (IB').

When the compounds represented by the above formulas contains an asymmetric carbon atom (i.e., chiral carbon atom), the optically active compounds and racemic mixtures thereof are also included in the scope of the invention.

Each symbol in the above formulas is explained in detail below.

The "lower alkyl" used herein means an alkyl group having 1 to 10 carbon atoms unless otherwise indicated.

The definition of A, R, R' and R'' in the formula (I), (IA') or (IB') is as follows. The "condensed imidazolyl groups" represented by A include, for example, condensed imidazolyl groups composed of imidazole and a 5- or 6-membered ring. Examples of the skeletons of the condensed imidazolyl groups include

etc. The above 5- or 6-membered ring is preferably a 5- or 6-membered aromatic heterocycle, more preferably a 6-membered aromatic heterocycle. The 5-membered aromatic heterocycles include, for example, 5-membered aromatic heterocycles having 1 or 2 nitrogen atoms, such as pyrrole, imidazole, pyrazole, etc. The 6-membered aromatic heterocycles include, for example, 6-membered aromatic heterocycles containing at least one nitrogen atom, oxygen atom or sulfur atom. Preferred examples of the 6-membered aromatic heterocycles include heterocycles having 1 to 3 nitrogen atoms, such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc. In particular, pyridazine is preferred. Preferred examples of the "condensed imidazolyl groups" include condensed imidazolyl groups containing 2 to 4 ring-constituting nitrogen atoms. Specific examples of the "condensed imidazolyl groups" include

etc. In particular, imidazo[1,2-b]pyridazin-6 or -7 or -8-yl, or imidazo[1,2-a]pyridin-5 or -6 or -7 or -8-yl is preferred. Imidazo[1,2-b]pyridazin-6-yl or imidazo[1,2-a]pyridin-5-yl is more preferred. Imidazo[1,2-b]pyridazin-6-yl is particularly preferred.

The number of the nitro group(s) on the imidazole ring of the "condensed imidazolyl group" represented by A is preferably 1 to 3, more preferably 1. Preferably, the nitro group is attached to a carbon atom that constitutes the imidazole ring.

The "condensed imidazolyl group having at least one nitro group on the imidazole ring" represented by A is preferably 2- or 3-nitroimidazo[1,2-b]pyridazin-6-yl, 2- or 3-nitroimidazo[1,2-a]pyridin-5-yl, etc., and more preferably 2- or 3-nitroimidazo[1,2-b]pyridazin-6-yl.

The "condensed imidazolyl group" represented by A may have a nitro group not only on the imidazole ring but also on the ring condensed with the imidazolyl group.

The "condensed imidazolyl group" represented by A may have a substituent other than a nitro group. The substituents include, for example, halogen atoms (e.g., chlorine, bromine, fluorine, iodine, etc.), a hydroxy group, a carboxyl group, an amino group, a sulfo group, a sulfamoyl group, a mono- or di-lower (C_1-10) alkylamino group, a lower alkylcarbonylamino group, a C_1-6 alkoxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, an optionally substituted lower alkyl group, a C_1-6 alkoxy group, an acyl group, etc.

The definitions of the above substituents are as follows.

The "mono- or di-lower alkyl amino groups" include, for example, an amino group substituted by one or two straight-chain or branched lower alkyl groups, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino, etc.

The "lower alkylcarbonylamino groups" include, for example, straight-chain or branched lower alkylcarbonylamino groups such as acetylamino, propionylamino, isopropionylamino, butyrylamino, etc.

The "C_1-6 alkoxycarbonyl groups" include, for example, straight-chain or branched C_1-6 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.

The "mono- or di-lower alkylcarbamoyl groups" include, for example, a carbamoyl group substituted by one or two straight-chain or branched lower alkyl groups, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc. The "lower alkyl group" of the "optionally substituted lower alkyl group" is preferably a straight-chain or branched C_1-6 alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

The substituents of the "optionally substituted lower alkyl groups" include, for example, halogen atoms (e.g., chlorine, bromine, fluorine, iodine), a hydroxy group, straight-chain or branched C_1-3 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a nitro group, a phenyl group optionally substituted by a halogen atom (e.g., chlorine, bromine, fluorine, iodine), etc.

Preferred examples of the "C_1-6 alkoxy groups" include straight-chain or branched C_1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, etc.

The "acyl groups" include, for example, acyl groups derived from organic carboxylic acids. Examples of the acyl groups include C_1-6 acyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. In particular, formyl is preferred.

Each of the "condensed imidazolyl groups" represented by A may have at least two same or different above-described substituents other than a nitro group. When the condensed imidazolyl group represented by

A has a substituent other than a nitro group, the substituent is attached to any one of the ring-constituting atom.

Preferably, the substituent is attached to a ring-constituting carbon atom.

The "hydrocarbon groups" of the "optionally substituted hydrocarbon groups" represented by R or the "hydrocarbon groups" represented by R' or R'' include, for example, C_1-10 hydrocarbon groups such as straight-chain or branched C_1-10 alkyl groups, straight-chain or branched C_2-10 alkenyl groups, C_2-10 alkynyl groups, C_3-10 cycloalkyl groups,

C_3-7 cycloalkenyl groups, C_5-7 cycloalkadienyl groups, C_1-4 alkyl groups substituted by C_3-6 cycloalkyl groups, etc. In particular, straight-chain or branched C_1-10 alkyl groups are preferred.

The "straight-chain or branched C_1-10 alkyl groups" include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl 1,1-diethylpropyl, 1-ethyl-1-methylpropyl, 1,1-dimethylpropyl, 1,1-diethylbutyl, etc. In particular, C_1-6 alkyl groups are preferred, and C_1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc., are more preferred.

The "straight-chain or branched C_2-10 alkenyl groups" include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc. In particular, C_2-4 alkenyl groups such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl, etc., are preferred.

The "C_2-10 alkynyi groups" include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. In particular, C_2-3 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, etc., are preferred.

The "C_3-10 cycloalkyl groups" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, etc.

The "C_3-7 cycloalkenyl groups" include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, etc. The "C_5-7 cycloalkadienyl groups" include, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, etc.

The "C_1-4 alkyl groups substituted by a C_3-6 cycloalkyl group" include, for example, C_1-4 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl isobutyl, tert-butyl, etc.) substituted by a C_3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.). Preferred examples thereof include cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, etc.

The substituents of the "optionally substituted hydrocarbon groups" represented by R or the "substituted hydrocarbon groups" represented by R' include (i) an optionally substituted hydroxy group (preferably, an optionally acylated hydroxy group), (ii) an optionally esterified or amidated carboxyl group, (iii) an optionally substituted amino group, (iv) optionally substituted heterocyclic groups, and (v) optionally substituted aryl groups. Preferred examples thereof include an optionally substituted hydroxy group, an optionally esterified or amidated carboxyl group, an optionally substituted amino group, and optionally substituted aryl groups. More preferred examples thereof include an optionally acylated hydroxy group, an optionally esterified or amidated carboxyl group and an optionally substituted amino group. In particular, an optionally acylated hydroxy group or optionally substituted amino group is preferred, and a hydroxy group or substituted amino group is particularly preferred.

The acyl groups of the "optionally acylated hydroxy groups" include, for example, acid residues (i.e., acyl groups derived from corresponding acids) such as optionally substituted carboxylic acid acyl groups, optionally substituted sulfonic acid acyl groups, an optionally substituted carbamoyl group, etc.

The carboxylic acid acyl groups include, for example, formyl, alkanoyl (alkylcarbonyl) groups, arylcarbonyl groups, alkyloxycarbonyl groups, aryloxycarbonyl groups, heterocycle-carbonyl groups, alkylthiocarbonyl groups, etc.

The alkyl groups of the optionally substituted alkanoyl (alkylcarbonyl) groups, optionally substituted alkyloxycarbonyl groups and optionally substituted alkylthiocarbonyl groups include, for example, straight-chain or branched C_1-6 alkyl groups (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), etc.

The aryl groups of the optionally substituted arylcarbonyl groups and aryloxycarbonyl groups include, for example, C_6-10 aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc), etc. The heterocyclic groups of the optionally substituted heterocycle-carbonyl groups include, for example, 5- or 6-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), etc

The sulfonic acid acyl groups include C_1-6 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), C_6-10 arylsulfonyl (e.g., benzenesulfonyl, toluenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), etc.

The above carboxylic acid acyl groups, sulfonic acid acyl groups and carbamoyl group may be substituted by 1 to 3 appropriate substituents such as a hydroxy group, a carboxyl group, an amino group optionally substituted by one or two C_{1 -6} alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), halogen atoms (e.g., chlorine, fluorine, bromine, etc.), etc.

The substituents of the "optionally substituted hydroxy group" include, for example, optionally substituted lower (C_1-6) alkyl groups (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), optionally substituted C_3-6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted aralkyl groups (e.g., benzyl, phenethyl, etc.), etc. The substituents of the optionally substituted lower (C_1-6) alkyl groups, optionally substituted C_3-6 cycloalkyl groups, optionally substituted aryl groups and optionally substituted aralkyl groups include halogen (e.g., fluorine, chlorine, bromine, etc.), etc.

The "optionally esterified carboxyl group" includes, for example, a carboxyl group and a carboxyl group esterified with a C_1-4 alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.), phenyl, benzyl, etc.

The "optionally amidated carboxyl group" includes a carboxyl group and a group represented by the formula:

wherein R¹ and R² are the same or different and are hydrogen or a C_1-6 alkyl group, and R¹, R² and the adjacent nitrogen atom may be joined together to form an optionally substituted nitrogen-containing heterocyclic group. The C_1-6 alkyl groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc. The nitrogen-containing heterocyclic groups formed by R₁, R₂ and the adjacent nitrogen atom include 4- to 7-membered nitrogen-containing heterocyclic groups which may contain, in addition to the nitrogen atom, 1 to 3 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., pyrrolidino, morpholino, thiomorpholino, piperazino, etc.). In particular, 6-membered nitrogen-containing heterocyclic groups which may contain, in addition to the nitrogen atom, another nitrogen atom are preferred.

The heterocyclic groups may have one to three substituents, preferably one substituent, at any possible position. The substituents include, for example, C_1-6 alkyl groups (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, etc.), C_2-6 alkenyl groups (e.g., vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.), C_2-6 alkynyl groups (e.g., ethynyl, 1-propyl, 2-propyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), C_3-6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C_6-10 aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), C_7-10 aralkyl groups (e.g., benzyl, phenethyl, etc.), an amino group, etc.

The substituents of the "optionally substituted amino group" include, for example, straight-chain or branched lower alkyl groups, optionally substituted lower cycloalkyl groups, optionally substituted aryl groups, optionally substituted aralkyl groups, acyl groups, an optionally esterified carboxyl group, etc. The substituents are the same or different. The number of the substituents is 1 to 2.

The lower alkyl groups include, for example, C_1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. The lower alkyl group may have 1 to 3 substituents at any possible position. Examples of the substituents include halogen (e.g., fluorine, chlorine, bromine, etc.).

The lower cycloalkyl groups include C_3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The aryl groups include C_6-10 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, etc.

The aralkyl groups include C_7-12 aralkyl groups such as benzyl, phenethyl, etc.

Each of the lower cycloalkyl groups, aryl groups and aralkyl groups may have 1 to 3 substituents at any possible position. Examples of the substituents include halogen (e.g., fluorine, chlorine, bromine, etc.), C_1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), etc.

The acyl groups include, for example, acid residues (i.e., acyl groups derived from corresponding acids) such as optionally substituted carboxylic acid acyl groups, optionally substituted sulfonic acid acyl groups, an optionally substituted carbamoyl group, etc.

The carboxylic acid acyl groups include, for example, formyl, alkanoyl (alkylcarbonyl) groups, arylcarbonyl groups, alkyloxycarbonyl groups, aryloxycarbonyl groups, heterocycle-carbonyl groups, alkylthiocarbonyl groups, etc.

The alkyl groups of the optionally substituted alkanoyl (alkylcarbonyl) groups, optionally substituted alkyloxycarbonyl groups and optionally substituted alkylthiocarbonyl groups include, for example, straight-chain or branched C_1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), etc.

The aryl groups of the optionally substituted arylcarbonyl groups and optionally substituted aryloxycarbonyl groups include, for example, C₆.₁₀ aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), etc.

The heterocyclic groups of the optionally substituted heterocycle-carbonyl groups include, for example, 5- or 6-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) (e.g., 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), etc.

The sulfonic acid acyl groups include, for example, C_1-6 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), C_6-10 arylsulfonyl (e.g., benzenesulfonyl, toluenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), etc.

Each of the above carboxylic acid acyl groups, sulfonic acid acyl groups and carbamoyl group may be substituted by 1 to 3 appropriate substituents such as a hydroxy group, a carboxyl group, an amino group optionally substituted by one or two C_1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), a halogen atom (e.g., chlorine, fluorine, bromine, etc.), etc.

The optionally esterified carboxyl groups include, for example, a carboxyl group and a carboxyl group esterified with a C_1-4 alkyl group (e.g., methyl, ethyl, propyl, butyl), phenyl, benzyl, etc.

The heterocyclic groups of the "optionally substituted heterocyclic groups" include 5- to 7-membered non-aromatic heterocyclic groups containing one sulfur atom, nitrogen atom or oxygen atom, and 5- or 6-membered non-aromatic heterocyclic groups containing 2 to 4 nitrogen atoms (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl, etc.), etc. Each of the heterocyclic groups may have 1 to 3 substituents at any possible position. Examples of the substituents include the above substituents of the "optionally substituted amino group", such as the straight-chain or branched lower alkyl groups, optionally substituted lower cycloalkyl groups, optionally substituted aryl groups, optionally substituted aralkyl groups, acyl groups, etc.

The aryl groups of the "optionally substituted aryl groups" include, for example, C_6-10 aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl, etc.), etc. Each of the aryl groups may have 1 to 3 same or different substituents at any possible position. Examples of the substituents include halogen atoms (e.g., chlorine, fluorine, bromine, etc.), C_1-3 alkoxy groups (e.g., methoxy, ethoxy, propoxy, etc.), C_1-3 alkyl groups (e.g., methyl, ethyl, propyl, etc.), etc.

R and R' are preferably a lower alkyl group branched at the α-position, a lower alkyl group substituted by a hydroxy group, or a lower alkyl group substituted by a substituted amino group.

The lower alkyl group of the lower alkyl group branched at the α-position is preferably a branched C_3-6 alkyl group.

The lower alkyl group of the lower alkyl group substituted by a hydroxy group is preferably a straight-chain lower alkyl group, more preferably a straight-chain C_1-4 alkyl group. The lower alkyl group of the lower alkyl group substituted by a substituted amino group is preferably a straight-chain lower alkyl group, more preferably a straight-chain C_1-6 alkyl group. The substituted amino group as the substituent of the lower alkyl group is preferably an amino group substituted by an acyl group. The acyl group is preferably an optionally substituted carboxylic acid acyl group, more preferably an optionally substituted lower alkylcarbonyl (alkanoyl) group. The substituent of the optionally substituted lower alkyl carbonyl group is preferably a halogen atom, etc.

In particular, when X is -S(O)_n-, the substituent of the hydrocarbon group represented by R or R' is preferably an optionally acylated hydroxy group, an optionally esterified or amidated carboxyl group, or an optionally substituted amino group.

When X is -S(O)_n-, R or R' is preferably, in particular, a C_1-10 alkyl group branched at the α-position, or a straight-chain C_1-10 alkyl group substituted with a hydroxy group.

When X is -O-, R or R' is preferably, in particular, a straight-chain C_1-10 alkyl group which is substituted with an amino group substituted with an acyl group.

The alkyl groups of the optionally substituted alkylcarbonyl groups represented by Ra include straight-chain or branched C_1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc. The substituents of the acyl group include halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxy, carboxy, or mono- or di-C_1-6 alkyl

(e.g., methyl, ethyl, propyl, butyl, etc.) amino.

Ra is preferably a C_1-6 alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, valeryl, etc.) which may be substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxy, carboxy, or mono- or di-C_1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) amino.

Rb is preferably a hydrogen atom or a C_1-6 alkyl (e.g., methyl, ethyl, propyl, butyl, etc.).

X is preferably -O-, especially, in terms of low toxicity of the compound.

n is preferably 0.

Preferred examples of the compound (I), (IA') or (IB') include:

6-[ (2R)-2-(trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2S)-2-(trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2R)-2-(N-methyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine, 6-[(2S)-2-(N-methyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2R)-2-(N-ethyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2S)-2-(N-ethyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[[1-(N-methyl-N-trifluoroacetylamino)cyclopentyl]-methyl]oxy-3-nitroimidazo[1,2-b]pyridazine (listed in Table 7 below as Compound 4-8), and

6-[2-(N-methyl-N-trifluoroacetylamino)ethyl]oxy-3-nitroimidazof1,2-b]pyridazine (listed in Table 7 below as Compound 4-12).

The present invention also relates to an antibacterial agent comprising a condensed imidazole derivative of the formula (α):

A-X-R''' (α)

wherein A and X are as defined above and R''' is an optionally substituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.

In the above formula (α), A and X are as defined above for the formula (I), (IA') or (IB').

The non-aromatic heterocyclic groups of the

"optionally substituted non-aromatic heterocyclic groups" represented by R''' include 5- to 7-membered non-aromatic heterocyclic groups containing one sulfur atom, nitrogen atom or oxygen atom, and 5- or 6-membered non-aromatic heterocyclic groups containing 2 to 4 nitrogen atoms. Examples of the non-aromatic heterocyclic groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, pyrrolinyl, imidazolidinyl, etc. Each of the heterocyclic groups may have 1 to 3 substituents at any possible position. Examples of the substituents include the substituents of the "optionally substituted amino group" as the substituent of the hydrocarbon group represented by R or R' described above.

When the compound of the formula (I), (IA'), (IB') or (ct) contain a basic or acidic group in the molecules, it can form salts with acids or bases. The kind of salt is not specifically limited. When a basic group is present in the molecule, salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, toluenesulfonic acid, methanesulfonic acid, etc. When an acidic group is present in the molecule, salts can be formed with an alkaline metal (e.g., sodium, potassium, etc.). In general, the above salts can be used as pharmaceutically acceptable salts. The compound of the formula (I'') (included in the formulas (I) and (IB')):

A-X'-R (I")

wherein X' is S or O and the other symbols are as defined above can be prepared by reacting a compound of the formula (II):

A-X'-H (II)

wherein each symbol is as defined above or a salt thereof with a compound of the formula (III):

Z-R (III)

wherein Z is a reactive group and R is as defined above or a salt thereof under the conditions described below, or reacting a compound of the formula (IV):

A-Z (IV)

wherein each symbol is as defined above or a salt thereof with a compound of the formula (V) :

H-X'-R (V)

wherein each symbol is as defined above or a salt thereof under the conditions described below.

The reactive group represented by Z may be a known reactive group. Examples of the reactive groups include halogen atoms (e.g., chlorine, bromine, fluorine, iodine, etc.), C_6-10 arylsulfonyloxy groups (e.g., benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), C_1-4 alkylsulfonyloxy groups (e.g., methanesulfonyloxy, etc.). Preferred examples of each definition other than Z in the formulas (II), (III), (IV) and (V) are the same as those described above for the formulas (I), (IA') and (IB').

This reaction is carried out in a solvent that does not hinder the reaction. The solvents include, for example, alcohols (e.g., methanol, ethanol, propanol, etc.), ethers

(e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), hydrocarbons (e.g., benzene, toluene, hexane, heptane, etc.), amides (e.g., dimethylformamide, etc.), dimethyl sulfoxide, etc.

If necessary, this reaction is carried out in the presence of a base. Such bases include, for example, organic bases such as 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc., inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc.

The reaction temperature is -50°C to 100°C, preferably about 0°C to 50°C.

The reaction time is normally about 1 to 48 hours, preferably about 5 to 10 hours. The amount of the compound of the formula (III) or (IV) to be used is about 1 to 10 mol, preferably about 1 to 3 mol, per mol of the compound of the formula (II) or (V).

The compound of the formula (I''') (included in the formulas (I) and (IA')):

A-X' '-R (I''')

wherein X'' is -SO- or -SO₂- and the other symbols are as defined above can be obtained by subjecting a compound of the formula (I''''):

A-S-R (I'''') wherein each symbol is as defined above to a per se known oxidation reaction.

This reaction is carried out in a solvent that does not hinder the reaction. The solvents include, for example, ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbons (e.g., benzene, toluene, hexane, heptane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., dimethylformamide, etc.), etc.

The oxidizing agents include, for example, m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, etc. The amount of the oxidizing agent to be used is about 1 to 5 mol, preferably about 1 to 2 mol, per mol of the compound of the formula (I''''). The reaction temperature is about 0 to 100°C, preferably about 0 to 30°C, and the reaction time is about 1 to 10 hours, preferably about 1 to 2 hours.

The compound of the formula (α) can be prepared in the same manner as that described above for the preparation of the compound of the formula (I), (IA') or (IB').

Because the compound of the formula (I) including the compound of the formula (IA'), (IB') or (α) or its salt has antibacterial activity and is of low toxicity, it can be used as an antibacterial agent against, for example, a bacterium belonging to the genus Helicobacter, Campylobacter, Peptostreptococcus (e.g., Peptostreptococcus anaerobius), Clostridium (e.g., Clostridium perfringens), Eubacterium (e.g., Eubacterium aerofaciens, Eubacterium alactolyticum, Eubacterium limosum), Bacteroides (e.g., Bacteroides fragilis, Bacteroides vulgatus), etc. In particular, the antibacterial agent of the invention exhibits antibacterial activity against, for example, bacteria that have a harmful effect in the digestive tract. The digestive tract includes, for example, stomach, duodenum, etc. The microorganisms that have a harmful effect in the digestive tract include, for example, bacteria belonging to the genera Helicobacter, Campylobacter (e.g., Campylobacter fetus, Campylobacter jejuni, Campylobacter mustelae, Campylobacter coli, etc.), etc. The antibacterial agent of the invention is particularly effective against bacteria belonging to the genus Helicobacter and Campylobacter, in particular Helicobacter pylori.

As described above, the antibacterial agent of the invention is effective in preventing or treating various diseases in the digestive system (e.g., duodenal ulcer, gastric ulcer, chronic gastritis, etc.) caused by bacteria that have a harmful effect in the digestive tract, in particular Helicobacter pylori.

In addition, the compound of the formula (I), (IA'), (IB') or (α) or its salt is also effective in preventing or treating an ulcer that is not caused by Helicobacter pylori, such as stress ulcer, and is thus effective as a novel antiulcerative agent in preventing or treating duodenal ulcer, gastric ulcer, etc.

Furthermore, the compound of the formula (I), (IA'),

(IB') or (α) or its salt is also effective in preventing or treating stomach cancer, and are useful as anti-stomach cancer agent.

The compound of the formula (I), (IA'), (IB') or (α) or a pharmaceutically acceptable salt thereof has low toxicity and can be used safely.

The antibacterial, antiulcerative or anti-stomach cancer agent of the invention can be administered orally or parenterally to mammals (e.g., humans, dogs, cats, etc.). In particular, oral administration is preferred. The antibacterial, antiulcerative, anti-stomach cancer agent or composition of the invention is preferably in the form of a pharmaceutical composition comprising a compound of the formula (I), (IA'), (IB') or (α) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, etc., described below.

The dosage forms for oral administration include, for example, tablets (including sugar-coated tablets, film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc.

The dosage forms for parenteral administration include, for example, injections, infusions, drip infusions, suppositories, etc.

The compound of the formula (I), (IA'), (IB') or (α) or a pharmaceutically acceptable salt thereof can be processed into the above dosage forms by per se known methods commonly used in the art. If necessary, the above dosage forms contain excipients, binders, disintegrators, lubricants, sweetening agents, surfactants, suspending agents, emulsions, etc., that are commonly used in the art to prepare the desired dosage forms.

For example, the above tablets may contain excipients, binders, disintegrators, lubricants, etc. The above pills and granules may contain excipients, binders, disintegrators, etc. The above powders and capsules may contain excipients, etc. The above syrups may contain sweetening agents. The emulsions and suspensions may contain suspending agents, surfactants, emulsifying agents, etc.

The excipients include, for example, lactose, sucrose, glucose, starch, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc. The binders include, for example, 5 to 10 W/W% starch solutions, 10 to 20 W/W% acacia or gelatin solutions, 1 to 5 W/W% tragacanth solutions, carboxymethyl-cellulose solutions, sodium alginate solutions, glycerin, etc. The disintegrators include, for example, starch, calcium carbonate, etc. The lubricants include, for example, magnesium stearate, stearic acid, calcium stearate, purified talc, etc. The sweetening agents include, for example, glucose, fructose, invertose, sorbitol, xylitol, glycerin, simple syrup, etc. The surfactants include, for example, sodium lauryl sulfate, polysorbate 80, sorbitan mono esters of fatty acids, polyoxyl 40 stearate, etc. The suspending agents include, for example, acacia, sodium alginate, carboxymethylcellulose, methylcellulose, bentonite, etc. The emulsifying agents include, for example, acacia, tragacanth, gelatin, polysorbate 80, etc.

In addition, the above dosage forms may contain colorants, preservatives, aromas, corrigents, stabilizers, thickening agents, etc., that are commonly used in the art. As described above, the compound of the formula (I), (IA'), (IB') or (α) or a pharmaceutically acceptable salt is stable, has low toxicity, and can be used safely. The daily dose of the compound of the formula (I), (IA'), (IB') or (ct) varies with the conditions and body weight of the subject, the kind of compound, the administration route, etc. In the case of oral administration, the daily dose for a human adult weighing 50 kg is suitably about 1 to 500 mg, preferably about 10 to 200 mg. The compound of the formula (I), (IA'), (IB') or (α) exhibited no toxicity in the range of the above dose.

The compound of the formula (I), (IA'), (IB') or ( a) or a pharmaceutically acceptable salt thereof can be administered in combination with other antibacterial agents and antiulcerative agents.

The antibacterial agents include, for example, macrolide antibacterial agents (e.g., clarithromycin, roxithromycin (Rulid), azithromycin, etc.), quinolone antibacterial agents (e.g., ofloxacin (Tarivid), tosufloxacin (Ozex), gulepafloxacin, balofloxacin, NM-441, T-3761, etc.), penicillin antibacterial agents (e.g., Flopenem, α-phenoxymethylpenicillin, phenethicillin, methicillin, oxacillin, ampicillin, amoxicillin, etc.), cephalosporin microbial agents (e.g., Flumax, cephalothin, cephaloridine, cefapirin, cephalexin, cefroxadine, cefotiam, cefuroxime, cefotiam hexetil, cefixime, cefteram pivoxil, ME 1207, etc.), etc.

The antiulcerative agents include, for example, drugs for peptic ulcer, such as proton pump inhibitors, histamine H₂ blockers, membrane-protecting type antiulcerativeative drugs, etc.

The proton pump inhibitors include, for example, benzimidazole compounds having antiulcerative activity, in particular, 2-[(pyridyl)-methylsulfinyl or methylthio]-benzimidazole derivatives or salts thereof. Examples thereof include 2-[2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridyl]-methylsulfinyl]benzimidazole (lansoprazole), 2-[(2-pyridyl)methylsulfinyl]benzimidazole (thimoprazole), 2-[2-(3,5-dimethyl-4-methoxypyridyl)methylsulfinyl]-5-methoxy-1H-benzimidazole (omeprazole), 2-[2-[4-(3-methoxypropoxy)-3-methylpyridyl]methylsulfinyl]-1H-benzimidazole sodium salt (E-3810), 2-[2-(3,4-dimethoxypyridyl)methylsulfinyl]-5-difluoromethoxy-1H-benzimidazole (pantoprasole), etc. The above benzimidazole compounds or salt thereof can be prepared by the methods described in JP-A 54-141783, JP-A 58-192880, JP-A 61-50978, JP-A 62-116576, JP-A 5-59043, etc., or modified methods thereof. Other examples of the proton pump inhibitors include, for example, 2-[[o-(isobutylmethylamino)benzyl]-sulfinyl]benzimidazole (leminone), 2-[(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulfinyl]-1H- benzimidazole sodium salts (TY-11345), 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-imidazo[4,5-b]pyridine (TU-199), etc.

The histamine H₂ blockers include, for example, 2-cyano-1-methyl-3-[2-[[5-methylimidazol-4-yl]methyl]thio]-ethyl]guanidine (cimetidine), N-[2-[[5-[(dimethylamino)-methyl]furfuryl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (ranitidine), (±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinylmethyl)-2-]pyridyl]oxy (z)-2-butenyl]acetamide (loctidine), etc.

The membrane-protecting type antiulcerative drugs include, for example, (Z)-7-[(1R,2R,3R)-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-3-methyl-5-oxocyclopentyl]-5-heptenoic acid (trimoprostil, Ulstar), 1-butyric acid-7-(L-2-aminobutyric acid)-26-L-aspartic acid-27-L-valine-29-L-alanine-1,7-carba-calcitonin (elcatonin), 3-ethyl-7-isopropyl-1-azulenesulfonate sodium (egualene sodium), etc.

The following examples, preparations and test examples further illustrate the invention in detail, but are not to be construed to limit the scope thereof. The term "room temperature" used hereinafter means about 15 to 25°C. Example 1

6-(Ethoxycarbonylmethylthio)-3-nitroimidazo[1,2-b]pyridazine

Sodium hydride (60%, 120 mg) was added to a solution of ethyl thioglycolate (360 mg) in dimethylformamide (10 ml) was added, and the mixture was stirred for 1 hour. 6-Chloro- 3-nitroimidazo[1,2-b]pyridazine (596 mg ) was added. After stirring for 2 days, dichloromethane (30 ml) was added, the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel. The desired compound was recrystallized from dichoromethane / diethyl ether to obtain colorless crystals

(287 mg, mp. 148-149°C).

Elemental analysis:

Calcd. for C₁₀H₁₀N₄O₄S: C,42.55; H,3.57; N,19.85 Found : C,42.46; H,3.52; N,20.04 Example 2

6-(2-Hydroxypropylthio)-3-nitroimidazo[1,2-b]pyridazine

1-Mercapto-2-propanol (582 mg) was added to a solution of sodium hydroxide (120 mg) in ethanol (25 ml), and the mixture was ice-cooled. 6-Chloro-3-nitroimidazo[1,2-b]pyridazine (596 mg) was added, and the mixture was heated at 50°C with stirring for 1 hour and then stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel. The desired compound was recrystallized from diethyl ether to obtain pale yellow crystals (607 mg, mp. 102-103°C).

Elemental analysis:

Calcd. for C₉H₁₀N_AO₃S: C,42.51; H,3.96; N,22.03 Found : C,42.24; H,3.98; N,22.26 Example 3

In the same manner as that described in Example 2, the compounds in Table 1 were obtained.

Example 4

6-(2-Acetyloxyethylthio)-3-nitroimidazo[1,2-b]-pyridazine

Acetic anhydride (1.5 ml) was added to a solution of 6-(2-hydroxyethylthio)-3-nitroimidazo[1,2-b]pyridazine (Compound No. 3-1) (240 mg) obtained in Example 3 in pyridine (3 ml) at 0°C, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cooled water and extracted with dichloromethane (50 ml). The organic layer was washed with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the crystals were washed with ether to obtain colorless crystals (210 mg, mp. 101-102°C).

Elemental analysis:

Calcd. for C₁₀H₁₀N₄O₄S: C,42.55; H,3.57; N,19.85 Found : C,42.71; H,3.34; N,19.87

Example 5

In the same manner as that described in Example 4, the compounds in Table 2 were obtained.

Example 6

6-(2-Methylsulfonyloxyethylthio)-3-nitroimidazo[1,2-b]pyridazine

Triethylamine (445 mg) and methanesulfonyl chloride (504 mg) were added to a solution of 6-(2-hydroxyethylthio)-3-nitroimidazo[1,2-b]pyridazine (Compound No. 3-1) (961 mg) obtained in Example 3 in dichloromethane (60 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated.

The residue was purified by column chromatography on silica gel, and the desired compound was recrystallized from dichloromethane / diethyl ether to obtain colorless crystals

(346 mg, mp. 151-153°C).

Elemental analysis:

Calcd. for C₉H₁₀N₄O₅S₂: C,33.96; H,3.17; N,17.60 Found : C,33.99; H,3.11; N,17.82 Example 7

6-(2-Hydroxypropylthio)-3-nitro-2-methylimidazo[1,2-b]pyridazine

In the same manner as that described in Example 2, the title compound was obtained as colorless crystals (358 mg; mp. 137-138°C) from 1-mercapto-2-propanol (213 mg) and 6-chloro-3-nitro-2-methylimidazo[1,2-b]pyridazine (425 mg).

Elemental analysis:

Calcd. for C₁₀H₁₂N₄O₃S: C,44.77; H_.4.51; N,20.88 Found : C,44.71; H,4.67; N,20.97

Example 8

6-(2-Hydroxypropylsulfonyl)-3-nitroimidazo[1,2-b]pyridazine

A solution of 6-(2-hydroxypropylthio)-3-nitroimidazo[1,2-b]pyridazine (254 mg) obtained in Example 2 in dichloromethane (15 ml) was ice-cooled, and a solution of m-chloroperbenzoic acid (474 mg) in dichloromethane (10 ml) was added dropwise. The mixture was stirred at 0°C overnight.

A saturated aqueous solution (10 ml) of sodium bicarbonate was added, and the mixture was stirred at room temperature for 15 minutes. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography on silica gel to obtain colorless crystals (150 mg, mp. 133-134°C).

Elemental analysis:

Calcd. for C₉H₁₀N₄O₅S: C,37.76; H,3.52; N,19.57

Found : C,37.84; H,3.53; N,19.71

Example 9

6-(Hydroxycarbonylmethylthio)-3-nitroimidazo[1,2-b]pyridazine

Sodium hydroxide (0.08 g) was added to a solution of 6-(ethoxycarbonylmetylthio)-3-nitroimidazo[1,2-b]pyridazine (2.82 g) obtained in Example 1 in methanol (100 ml), and the mixture was stirred at room temperature overnight. Dichloromethane (50 ml) and 1N hydrochloric acid (100 ml) were added, the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was washed with diethyl ether to obtain colorless crystals (2.12 g).

Elemental analysis:

Calcd. for C₈H₆N₄O₄S: C_.37.80; H,2.38; N,22.04 Found : C,37.70; H,2.61; N,22.14

Example 10

6-[(4-methylpiperazino)carbonyImethylthio]-3-nitroimidazo[1,2-b]pyridazine•HCl

Diethyl cyanophosphonate (618 mg ) and triethylamine (304 mg ) were added to a solution of 6-(hydroxycarbonylmethylthio)-3-nitroimidazo[1,2-b]pyridazine (763 mg ) obtained in Example 9 and N-methylpiperazine (300 mg) in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 2 hours. Dichloromethane (50 ml) and water (50 ml) were added, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from dichloromethane / diethyl ether to obtain colorless crystals (437 mg, mp. 249-251°C). The resulting crystals (336 mg ) were dissolved in dichloromethane, a 4N solution of hydrogen chloride in ethyl acetate was added, the solvent was evaporated, and the residue was washed with methanol and diethyl ether to obtain colorless solid (362 mg, mp. 249-251°C).

Elemental analysis:

Calcd. for C₁₃H₁₆N₆O₃S•HCl : C,41.88; H,4.60; N,22.54 Found : C,41.65; H,4.56; N,22.54

Example 11

In the same manner as that described in Example 10, the compounds in Table 3 were obtained.

Example 12

6-(2-Acetylaminoethylthio)-3-nitroimidazo[1,2-b]-pyridazine

Sodium hydride (60% in oil, 0.23g) was added to a solution of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (1.0 g) and cysteamine (0.4 g) in tetrahydrofuran (20 ml) at room temperature with stirring, and the mixture was stirred at room temperature for 2 hours. Methanol was added, and the mixture was extracted with ethyl acetate (20 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated. The oily compound (0.4 g) was dissolved in tetrahydrofuran (20 ml). Acetic anhydride (0.5 g) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml), washed with water and purified by column chromatography on silica gel to obtain colorless crystals (0.32 g, mp. 181-182°C).

Elemental analysis:

Calcd. for C₁₀H₁₁N₅O₃S: C,42.70; H,3.94; N,24.90 Found : C,42.71; H,3.80; N,24.70 Example 13

6-(2-Trifluoroacetylaminoethylthio)-3-nitroimidazo-[1,2-b]pyridazine

The oily compound (0.7 g) obtained in Example 12 was dissolved in tetrahydrofuran (15 ml). Trifluoroacetic anhydride (0.5 ml) was added, and the mixture was stirred at room temperature for 20 minutes. Thereafter, in the same manner as that described in Example 12, the title compound was obtained as colorless crystals (0.8 g, mp. 171-172°C).

Elemental analysis:

Calcd. for C₁₀H₈F₃N₅O₃S : C35.83; H,2.40; N,20.89 Found : C,36.19; H,2.59; N,20.60

Example 14

6-[2-(N-methyl-N-trifluoroacetylamino)ethylthio]-3-nitroimidazo[1,2-b]pyridazine

Sodium hydride (60% in oil, 60 mg ) was added to a solution of the compound (0.2 g) obtained in Example 13 and iodomethane (0.4 g) in tetrahydrofuran (6 ml), and the mixture was stirred at 40 to 50°C for 30 minutes. Water (30 ml) was added, and the mixture was extracted with ethyl acetate (20 ml), washed with water and purified by column chromatography on silica gel to obtain the title compound as colorless crystals (0.07 g, mp. 111-112°C).

Elemental analysis :

Calcd. for C₁₁H₁₀F₃N₅O₃S: C,37.83; H,2.89; N,20.05

Found : C,37.69; H,2.96; N,20.11

Example 15

6-[(2-Trifluoroacetylamino-1,1-dimethyl)ethylthio]-3-nitroimidazo[1,2-b]pyridazine

In the same manner as that described in Examples 12 and 13, the title compound was obtained as colorless crystals (0.27 g, mp. 184-185°C) using 6-chloro-3-nitroimidazo[1,2-b]pyridazine (0.5 g) and (2-amino-1,1-dimethyl)ethylmercaptane (0.37 g).

Elemental analysis: Calcd. for C₁₂H₁₂F₃N₅O₃S: C,39.67; H,3.33; N,19.28 Found : C,39.89; H,3.48; N,19.16

Example 16

6-[[2-(N-trifluoroacetyl-N-methyl)amino-1,1-dimethyl]ethylthio]-3-nitroimidazo[1,2-b]pyridazine

In the same manner as that described in Example 14, the title compound was obtained as colorless crystals (0.08 g, mp. 171-172°C) from the compound obtained in Example 15 (0.1 g).

Elemental analysis:

Calcd. for C₁₃H₁₄F₃N₅O₃S : C,41.38; H,3.74; N,18.56 Found : C,41.57; H,3.83; N,18.40

Reference Example 1

In the same manner as that described in Example 1, the compounds in Tables 4 and 5 were obtained.

Reference Example 2

6-[(2R)-(2-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine

Sodium hydride (60% in oil, 0.60 g) was added to a solution of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (2.2 g) and (R)-alaninol (1.0 g) in tetrahydrofuran (20 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, trifluoroacetic anhydride (2.0 ml) was added, the mixture was stirred at room temperature for 5 minutes, ethyl acetate was added, and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from isopropyl ether / ethyl acetate to obtain the title compound as pale yellow crystals (1.31 g, mp. 127-128°C).

Elemental analysis:

Calcd. for C₁₁H₁₀F₃N₅O₄: C,39.65; H,3.02; N,21.02

Found : C,39.84; H,2.71; N,20.75

Reference Example 3

In the same manner as that described in Reference Example 2, the compounds in Table 6 were obtained.

Reference Example 4

In the same manner as that described in Example 14, the compounds shown in Table 7 were obtained from the compounds obtained in Reference Examples 2 and 3.

Reference Example 5

6-[(2R)-(2-trifluorothioacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine

A solution of the compound (0.3 g) obtained in Reference Example 2 and Lawesson reagent (0.45 g) in toluene (15 ml) was heated with stirring at 100°C for 3 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel to obtain the title compound as yellow crystals (0.24 g, mp. 106-108°C).

Elemental analysis:

Calcd. for C₁₁H₁₀F₃N₅O₃S : C,37.83; H,2.89; N,20.05 Found : C,37.75; H,2.97; N,19.78

Reference Example 6

6-(2-Methoxycarbonylaminopropyl)oxy-3-nitroimidazo-[1,2-b]pyridazine

Sodium hydride (60% in oil, 0.30 g) was added to a solution of alaninol (0.5 g) in tetrahydrofuran (20 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, methoxycarbonyl chloride (2.0 ml) was added, the mixture was stirred at room temperature for 5 minutes, ethyl acetate was added, and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was recrystallized from isopropyl ether /ethyl acetate to obtain the title compound as colorless crystals (0.32 g, mp. 206-207°C).

Reference Example 7

In the same manner as that described in Reference Example 6, the compounds in Table 8 were obtained.

Reference Example 8

6-[(2R)-2-(N-ethyl-N-trifluoroacetylamino)propyl]-oxy-3-nitroimidazo[1,2-b]-pyridazine

Sodium hydride (60% in oil, 80 mg) was added to a solution of the compound (0.5 g) obtained in Reference Example

2 and ethyl iodide ( 0.5 ml ) in tetrahydrofuran (20 ml), and the mixture was stirred at 70°C for 6 hours. Water (30 ml) was added, and the mixture was extracted with ethyl acetate

(20 ml), washed with water and purified by column chromatography on silica gel to obtain the title compound as colorless crystals (0.24 g, mp. 79-80°C).

Elemental analysis:

Calcd. for C₁₃H₁₄F₃N₅O₄: C,43.22; H,3.91; N,19.38 Found : C,42.98; H,3.69; N.19.29 Reference Example 9

6-[(2R)-2-(N-benzyl-N-trifluoroacetylamino)propyl]-oxy-3-nitroimidazo[1,2-b]pyridazine

Sodium hydride (60% in oil, 100 mg ) was added to a solution of the compound (0.5 g) obtained in Reference Example

2 and benzyl bromide (0.3 g) in tetrahydrofuran (20 ml), and the mixture was stirred at 70°C for 15 hours. Water (30 ml) was added, and the mixture was extracted with ethyl acetate

(20 ml), washed with water and purified by column chromatography on silica gel to obtain the title compound as colorless crystals (0.14 g, mp . 105-106°C).

Elemental analysis:

Calcd. for C₁₈H₁₆F₃N₅O₄: C_.51.07; H,3.81; N,16.54 Found : C,51.13; H,3.82; N,16.29 Reference Example 10

6-[(2R)-2-(N-propyl-N-trifluoroacetylamino)propyl]- 3-nitroimidazo[1,2-b]pyridazine

Sodium hydride (60% in oil, 1.2 g) was added to a solution of 6-chloro-3-nitroimidazo[1,2-b]pyridazine (5.0 g) and (R)-alaninol (2.2 g) in tetrahydrofuran (100 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. Methanol was added, the mixture was extracted with ethyl acetate (20 ml), washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was crystallized from ethyl ether, and the crystals were collected by filtration. A solution of sodium cyanoborohydride (0.16 g) in ethanol (15 ml) was added dropwise to a solution of the crystallized compound (0.5 g), propionaldehyde (0.15 g) and acetic acid in ethanol (15 ml), and the mixture was stirred at room temperature for lTiour. Hydrochloric acid (1N) was added, the solvent was evaporated, an aqueous solution of sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate and dried. The solvent was evaporated, the residue was dissolved in tetrahydrofuran (10 ml), and trifluoroacetic anhydride (0.3 ml) was added. The solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml), washed with water and purified by column chromatography on silica gel to obtain the title compound as colorless crystals (0.17 g, mp. 89-90°C).

Elemental analysis:

Calcd. for C₁₄H₁₆F₃N₅O₄: C,44.80; H,4.30; N,18.66 Found : C,44.89; H,4.19; N,18.76 Reference Example 11

In the same manner as that described in Reference Example 10, the compounds in Table 9 were obtained.

The total amounts of the above components (1), ( 2 ) and (3) and 5 mg of the component (4) were mixed and granulated. The residual component (4) (5 mg) was added thereto, and the total amount of the mixture was filled into a gelatin capsule.

The total amounts of the above components (1), (2) and (3), 20 mg of the component (4) and 2.5 g of the component (5) were mixed and granulated. The residual components (4) (10 mg) and (5) (2.5 mg) were added to the granules, and the mixture was pressed to obtain tablets.

Test Example 1

Antibacterial activity against Helicobacter pylori Methods:

The compounds obtained in Examples and Reference Examples described above were used to determine their antibacterial activity by the following method (Agar Dilution method).

Each test compound was dissolved in dimethyl sulfoxide, and the solution was serially diluted (2-fold per dilution) with sterilized distilled water to prepare test samples. The culture medium used was Brucella agar to which 7% horse blood had been added. Each test sample (2 ml) thus prepared was mixed with Brucella agar (18 ml) to which 7% horse blood had been added. Thus, an assay plate was prepared.

The test microorganisms used were Helicobacter pylori strains NCTG 11637 and CPY 433. Each test microorganism was cultured with shaking at 37°C for 20 hours in Brucella broth to which 2.5% fetal bovine serum had been added, in a gas-packed jar containing CampyPak^TM (BBL^R Beckton

Dickinson Microbiology Systems).

Each microorganism solution (5 μl) adjusted to about 10⁶ CFU/ml with the same culture medium was inoculated in the assay plate. The microorganism was cultured at 37°C for 4 days in a gas-packed jar containing CampyPak ^TM and adsorbent cotton impregnated with water. After the culture, the growth of the microorganism strain was observed with the naked eye, and the minimum concentration in which the growth of the microorganism strain was not observed was made the MIC (minimum inhibitory concentration) of the test compound.

Using metronidazole (a known imidazole derivative having inhibitory activity against Helicobacter pylori) as a positive control, the MIC of metronidazole was determined in the same manner as that for the test compounds.

Results:

Table 10 shows the MICs of the test compounds and metronidazole (positive control).

The results show that the compound of the present invention has superior antibacterial activity to metronidazole.

Test Example 2

Screening for the inhibitory activity against

Helicobacter pylori

Methods:

Crj:ICR male mice of 5 weeks of age were fasted for

30 hours. Then, Helicobacter pylori CPY 433 F4 was inoculated in the stomach at 10 CFU per mouse. One week after the infection, the test compound (10 mg/kg) suspended in 0.5% methylcellulose was given orally once. The next day, the stomach of the infected mouse was removed and homogenated.

A 10-fold serially diluted solution of the homogenate was inoculated in a modified Skirrow medium to which active charcoal had been added. The culture was performed at 37°C for 4 days under microaerophilic conditions. The inhibitory activity against the bacterium was determined based on the presence of the bacterial growth. The results are shown in Table 11. The inhibitory ratio in the table indicates the ratio of the number of the cases where the bacterial growth was inhibited to the total number of the tested cases.

The results show that the compound of the present invention has superior inhibitory activity to metronidazole.

As described hereinabove, the compound of the formula (I), (IA'), (IB') or (α) or its salt is stable, and has low toxicity and potent antibacterial activity against microorganisms that have a harmful effect in the digestive tract (e.g., bacteria belonging to the genera Helicobacter such as Helicobacter pylori, Campylobacter) . The compound of the formula (I), (IA'), (IB') or (α) or its salt is therefore effective as an antibacterial agent in preventing or treating various diseases (e.g., duodenal ulcer, gastric ulcer, chronic gastritis, etc.) caused by the above bacteria. In addition, because Helicobacter pylori is also a major cause of the recurrence of ulcer, the compound of the formula (I), (IA'), (IB') or (α) or its salt is also effective in preventing the recurrence of ulcer as an antiulcerative agent. Furthermore, the compound (I), (IA'), (IB') or (α) or its salt is also effective as an antiulcerative agent in preventing or treating ulcer that is not caused by Helicobacter pylori, such as stress ulcer. In addition, the compound is also effective in treating or preventing stomach cancer.

The antibacterial agent of the invention provides desired antibacterial effects in a much lower dose than an effective dose of conventional antibacterial agents against microorganisms that have harmful a effect in the digestive tract (e.g., bacteria belonging to the genus Helicobacter such as Helicobacter pylori).

Claims

1. An agent against a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides, which comprises a compound of the formula

(I):

A-X-R (I)

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; X is

in which n is an integer of 0 to 2, or -O-; and R is an optionally substituted hydrocarbon group, or a pharmaceutically acceptable salt thereof.

2. An agent according to claim 1, wherein, when X is -O- or -S-, R is an optionally substituted hydrocarbon group except for a group of -(CH₂)_q-B in which B is a 5- or 6-membered heterocyclic group which may be a condensed ring and q is an integer of 1 to 4.

3. An agent according to claim 1, wherein the condensed imidazolyl group is an imidazo[1,2-b]pyridazinyl group.

4. An agent according to claim 1, wherein R is a hydrocarbon group which may be substituted with one selected from the group consisting of (i) an optionally substituted hydroxy group, (ii) an optionally esterified or amidated carboxyl group, (iii) an optionally substituted amino group, and (iv) an optionally substituted aryl group.

5. An agent according to claim 4, wherein the optionally substituted hydroxy group is an optionally acylated hydroxy group.

6. An agent according to claim 1, which is an agent against a bacterium belonging to the genus Helicobacter.

7. A composition for treating a disease caused by a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides, which comprises a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

8. An antiulcerative agent comprising a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

9. An anti-stomach cancer agent comprising a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

10. A method of preventing or treating an infection caused by a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides in a mammal which comprises administering to said mammal in need thereof an effective amount of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

11. A method of preventing or treating an ulcer in a mammal which comprises administering to said mammal in need thereof an effective amount of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

12. Use of a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an agent against a bacterium belonging to a genus selected from the group consisting of Helicobacter, Campylobacter, Peptostreptococcus, Clostridium, Eubacterium and Bacteroides or antiulcerative agent.

13. A compound of the formula (IA'):

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; R' is a hydrocarbon group substituted with (i) an optionally substituted hydroxy group, (ii) an optionally esterified or amidated carboxyl group, (iii) an optionally substituted amino group or (iv) an optionally substituted aryl group; and n is an integer of 0 to 2, provided that when n is 0, R' is not an alkoxyalkyl group, or a salt thereof.

14. A compound according to claim 13, wherein R' is a hydrocarbon group substituted with one selected from the group consisting of (i) an optionally acylated hydroxy group, (ii) an optionally esterified or amidated carboxyl group and (iii) an optionally substituted amino group.

15. A compound according to claim 13, wherein R' is a hydrocarbon group substituted with an optionally acylated hydroxy group.

16. A compound according to claim 13, wherein the condensed imidazoyl group is an imidazo[1,2-b]pyridazinyl group.

17. A compound according to claim 13, wherein R' is a hydrocarbon group substituted with a hydroxy group or an optionally substituted amino group.

18. A compound of the formula (IB'):

A-O-R'' (IB')

wherein A is a condensed imidazolyl group having at least one nitro group on the imidazole ring; R'' is a hydrocarbon group which is substituted with a group of the formula:

in which Ra is an optionally substituted alkylcarbonyl group and Rb is a hydrogen atom or an alkyl group, or a salt thereof.

19. A compound according to claim 18, wherein the condensed imidazolyl group for A is one selected from the group consisting of imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imiazo[1,5-a]pyridyl, imidazo[4,5-b]pyrazinyl, imidazo[1,5-a]pyrimidinyl, imidazo[1,2-d][1,2,4]triazinyl, imidazo[5,1-c][1,2,4]triazinyl, imidazo[1,5-b]pyridazinyl and 1H-imidazo[4,5-b]pyridyl; the hydrocarbon group for R'' is one selected from the group consisting of C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 cycloalkyl, C_3-7 cycloalkenyl, C_5-7 cycloalkadienyl, and C_1-4 alkyl substituted with C_3-6 cycloalkyl; Ra is a C_1-6 alkyl-carbonyl group which may be substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, carboxy and mono- or di-C_1-6 alkylamino; and Rb is a hydrogen atom or a C_1-6 alkyl.

20. A compound according to claim 18, wherein the condensed imidazolyl group is an imidazo[1,2-b]pyridazinyl group.

21. A compound according to claim 18, wherein the alkylcarbonyl group is an optionally substituted C_1-6 alkylcarbonyl group.

22. A compound selected from the group consisting of 6-[(2R)-2-(trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2S)-2-(trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-((2R)-2-(N-methyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2S)-2-(N-methyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2R)-2-(N-ethyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[(2S)-2-(N-ethyl-N-trifluoroacetylamino)propyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

6-[[1-(N-methyl-N-trifluoroacetylamino)cyclopentyl]-methyl]oxy-3-nitroimidazo[1,2-b]pyridazine, and

6-[2-(N-methyl-N-trifluoroacetylamino)ethyl]oxy-3-nitroimidazo[1,2-b]pyridazine,

or a salt thereof.

23. A method of producing a compound of claim 13 which comprises reacting (i) a compound of the formula (II'):

A-S-H (II')

in which A is of the same meaning as defined in claim 13, or a salt thereof with a compound of the formula (III'):

Z-R' (III') in which Z is a reactive group and R' is of the same meaning as defined in claim 13, or a salt thereof, or (ii) a compound of the formula (IV):

A-Z (IV)

in which all symbols are of the same meaning as defined above, or a salt thereof with a compound of the formula (V):

H-S-R' (V)

in which R' is of the same meaning as defined above, or a salt thereof, and, if necessary, subjecting the resulting compound to an oxidation reaction.

24. A method of producing a compound of claim 18 which comprises reacting (i) a compound of the formula (II''):

A-O-H (II'')

in which A is of the same meaning as defined in claim 18, or a salt thereof with a compound of the formula:

Z-R'' (III'')

in which Z is a reactive group and R'' is of the same meaning as defined in claim 18, or a salt thereof, or (ii) a compound of the formula (IV):

A-Z (IV)

in which all symbols are of the same meaning as defined above, or a salt thereof with a compound of the formula:

H-O-R'' (V')

in which R'' is of the same meaning as defined above, or a salt thereof.

25. A composition which comprises a compound of claim 13.

26. A composition which comprises a compound of claim 18.