JPH09104640A - Gastric mucosa-adhesive composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject highly safe composition having anti-Helicobacter pylori activity. SOLUTION: This composition contains, as active ingredient, 0.1-95wt.% of a condensed imidazole derivative (salt) of the formula A-X-R [A is a condensed imidazolyl bearing at least one nitro group on the imidazole ring; X is a lone bond, a group of the formula ((n) is 0 2) or O; R is a (substituted) hydrocarbon] which is incorporated in a matrix composed of a polyglycerin fatty acid ester and/or lipid. This composition has virtually no side effects, being effective over a long time at low concentrations for eliminating Helicobacter pylori, thus being useful for treating diseases involved in digestive organs such as gastritis and digestive ulcer. Its dose is <=250mg per day in terms of the condensed imidazole derivative (salt).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anti-Helicobacter
The present invention relates to a gastrointestinal mucoadhesive composition containing a condensed imidazole derivative having H. pylori activity.

[0002]

2. Description of the Related Art Since Helicobacter pylori (hereinafter sometimes abbreviated as HP) was isolated in 1983, [Lancet, No. 1
Vol., P. 1273, 1983], attention has been paid to the relationship between Helicobacter pylori and gastritis and peptic ulcer. This is despite the fact that HP is not normally found in the mucous membranes of healthy people [APMIS, 96, 84, 19].
88], because the positive rate is high in cases of chronic gastritis or gastric ulcer [American Journal of Gastroente
rology), 82, 2283, 1987]. on the other hand,
H ₂ blockers and proton pump inhibitors (hereinafter PPI
The cure rate for gastric and duodenal ulcers has risen dramatically, but there are some refractory cases that do not show improvement despite appropriate treatment using these drugs. It's a problem. Report on these cases of refractory gastric ulcer (Nichisho, Vol. 89, 5
(P. 71, 1992), the positive rate of HP is remarkably high, and a decrease in mucus in the gastric mucosa which is considered to be due to the ammonia produced by HP is observed. In addition, persistent HP infection has been reported to delay the healing of ulcers or contribute to the recurrence of ulcers (Lancet, 335, 1233, 1990), New England Journal. ·of. Medicine (NewEngland J
ournal of Medicine), Volume 328, p. 308, 199.
3 years]. In addition, various drugs having anti-Helicobacter pylori activity have been administered to patients with gastric and duodenal ulcers. For example, amoxicillin, metronidazole, bismuth acetate, tetracycline, etc. are used alone or in combination as an antibacterial agent against Helicobacter pylori, but the dosage is considerably large (for example, amoxicillin 750 mg or metronidazole 500 mg- Since it is administered 3 times a day), it is often accompanied by side effects such as diarrhea, nausea and nausea. In order to reduce such side effects, for example, by making amoxicillin into a gastric mucoadhesive formulation, the retention time of amoxicillin in the stomach is extended, and amoxicillin is released from the retention site at an appropriate rate to obtain a medicinal component. Attempts have been made to reduce the side effects by making more effective use of the drug (WO 94).
/ 00112).

[0003]

However, the conventional gastric mucoadhesive preparations containing these drugs are not clinically satisfactory in terms of anti-Helicobacter pylori activity, side effects, duration of effect, etc. Development is desired.

[0004]

[Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted diligent studies to obtain a gastric mucoadhesive composition showing stronger anti-Helicobacter pylori activity and higher safety.

Embedded image The gastric mucosa-adhesive composition containing the condensed imidazole derivative or a salt thereof represented by the above shows an unexpectedly low dose, excellent anti-Helicobacter pylori activity, and clinically advantageous properties such as few side effects. I found out what I was doing. The present invention has been completed based on these findings.
That is, the present invention provides (1) a gastric mucosa-adhesive composition containing a condensed imidazole derivative (I) or a salt thereof, (2) a composition according to the above (1) containing a matrix composed of a polyglycerol fatty acid ester and / or a lipid. Thing, (3)
The composition according to (2) above, wherein the condensed imidazole derivative or a salt thereof is contained in a matrix, (4) the composition according to (1) above, which contains a substance that causes viscosity in water.
(5) The composition according to (2), wherein the matrix contains a substance that causes viscosity with water, (6) the composition according to (2), wherein the matrix is coated with a substance that causes viscosity with water.

(7) The composition according to (2) above, wherein the polyglycerin fatty acid ester is an ester of polyglycerin having a degree of polymerization of 2 to 20 and a fatty acid having 12 to 22 carbon atoms,
(8) The molecular weight of the polyglycerin fatty acid ester is about 20.
The composition according to (2) above, which is 0 to about 5000, (9)
The melting point of polyglycerin fatty acid ester is about 15 ° C to about 8 ° C.
The composition according to (2) above, which is 0 ° C., and (10) the polyglycerin fatty acid ester is behenic acid hexa (tetra) glyceride, stearic acid penta (tetra) glyceride, stearic acid mono (penta) glyceride, stearic acid penta (hexa). ) A composition according to (2) above, which is a glyceride, sesqui (hexa) glyceride stearate or mono (deca) glyceride stearate, and (11) polyglycerin fatty acid ester is selected from the polyglycerin fatty acid ester according to (10) above. The composition according to the above (2), which is a mixture of at least two or more, (12) The composition according to the above (2), wherein the lipid is a fat or oil or hydrogenated oil thereof, a wax, a higher saturated fatty acid, a higher alcohol or a hydrocarbon. And (13) the melting point of the lipid is from about 40 ° C to about 120 ° C. Composition, (14) The composition according to (2) above, wherein the lipid is carnauba wax, hydrogenated oil and / or microcrystalline wax, (15) The composition according to (2) above, wherein the matrix is carnauba wax, and (16) matrix. Is composed of carnauba wax and penta (tetra) glyceride stearate, (17) The composition according to (4), wherein the substance that causes viscosity in water is a polymer, and (18) the viscosity in water. The composition according to (4) above, wherein the resulting substance is an acidic polymer, (19) the composition according to (4) above, wherein the substance that causes viscosity in water is an acrylic acid polymer or a salt thereof.

(20) The composition according to the above (4), wherein the substance that causes viscosity in water is a cellulosic polymer, (21)
The composition according to (19) above, wherein the acrylic acid polymer has a molecular weight of about 200,000 to about 6,000,000, and (22) the acrylic acid polymer has a molecular weight of about 1 million to about 5 million (19). (23) The composition according to (1) above, wherein the hydrocarbon group is a C _1-10 alkyl group, and (24) the fused imidazolyl group has 2 to 4 nitrogen atoms as hetero atoms constituting the ring. The composition according to (1) above, which has atoms.
(25) General formula (I '):

Embedded image (Wherein A is a fused imidazolyl group having at least one nitro group on the imidazole ring, R ′ is a hydrocarbon group having a substituent, and n is an integer of 0 to 2) A gastric mucoadhesive composition containing a derivative or a salt thereof, wherein (26) the condensed imidazolyl group is:
The composition according to (25) above, which has 2 to 4 nitrogen atoms as ring-constituting heteroatoms, (27) the fused imidazolyl group is a fused group of imidazole and a 6-membered aromatic heterocyclic group, (25) ) The composition described above, and (28)
A is

Embedded image And (29) the composition according to (1) above, which is an anti-Helicobacter pylori agent. Examples of the condensed imidazole derivative used in the present invention include compounds represented by the above general formulas (I) and (I ′) [hereinafter, sometimes abbreviated as compounds (I) and (I ′), etc.] and the like. . Details of each definition of the general formulas (I) and (I ′) are as follows.

In the present specification, "lower alkyl" means an alkyl group having 1 to 10 carbon atoms, unless otherwise specified. The definitions of A, R and R'will be described below. Examples of the “fused imidazolyl group” represented by A include a fused imidazolyl group formed by condensing imidazole with a 5- or 6-membered ring. As an example of the skeleton of the condensed imidazolyl group, for example,

Embedded image

Embedded image

Embedded image

Embedded image And the like. The 5- or 6-membered aromatic ring is preferably a 5- or 6-membered aromatic heterocycle, more preferably a 6-membered aromatic heterocycle. Examples of the 5-membered aromatic heterocycle include 5-membered aromatic heterocycles containing 1 to 2 nitrogen atoms such as pyrrole, imidazole and pyrazole. Examples of the 6-membered aromatic heterocycle include 6-membered aromatic heterocycles containing a nitrogen atom, an oxygen atom or a sulfur atom, and among them, a heterocycle containing 1 to 3 nitrogen atoms is preferable, for example, Pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like can be mentioned. Pyridazine is particularly preferable.

Examples of the "fused imidazolyl group" include a fused imidazolyl group having 2 to 4 nitrogen atoms as ring-constituting atoms. Specific examples of this "fused imidazolyl group" include:

Embedded image

Embedded image And the like. Among these, as a preferable example,
And imidazo [1,2-b] pyridazin-6 or -7 or -8-yl group and imidazo [1,2-a] pyridin-5 or -6 or -7 or -8-yl group. 1,2-b] pyridazine-6-
An yl group or an imidazo [1,2-a] pyridin-5-yl group is more preferable, and an imidazo [1,2-b] pyridazin-6-yl group is most preferable.

The number of nitro groups on the imidazole ring of the "fused imidazolyl group" represented by A is preferably 1 to 3, and particularly preferably 1. The nitro group is preferably bonded to a carbon atom constituting the imidazole ring.
The “fused imidazolyl group having at least one nitro group on the imidazole ring” represented by A is 2- or 3-nitroimidazo [1,2-b] pyridazine-6-
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] pyridazin-6-yl group is more preferable. . In addition, a “fused imidazolyl group” represented by A
May have a nitro group not only on the imidazole ring but also on the ring fused with the imidazolyl group. The “fused imidazolyl group” represented by A may have a substituent other than the nitro group. Examples of the substituent include a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, a carboxyl group, an amino group, a sulfo group, a sulfamoyl group, a mono- or di-lower (C _1-10 ) alkylamino group. Group, lower alkylcarbonylamino group, C _1-6 alkoxycarbonyl group, carbamoyl group, mono- or di-lower alkylcarbamoyl group, optionally substituted lower alkyl group, C _1-6 alkoxy group, acyl Groups and the like.

The definition of the above substituents will be described below. Examples of the “mono- or di-lower alkylamino group” include linear or branched 1 or 2 lower (C
_1-6 ) An amino group substituted with an alkyl group can be mentioned, and specific examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, hexylamino, dimethylamino, diethylamino. Etc. Examples of the "lower alkylcarbonylamino group" include linear or branched lower alkylcarbonylamino groups, and specific examples include acetylamino, propionylamino, isopropionylamino, butyrylamino lower (C
_1-4 ) An alkylcarbonylamino group and the like can be mentioned.
Examples of the “C _1-6 alkoxycarbonyl group” include a linear or branched C _1-6 alkoxycarbonyl group, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, Examples thereof include butoxycarbonyl and isobutoxycarbonyl.

The "mono- or di-lower alkylcarbamoyl group" includes, for example, a carbamoyl group substituted with 1 or 2 linear or branched lower (C _1-6 ) alkyl groups, and specifically, Examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and the like. The "lower alkyl group" of the "lower alkyl group which may have a substituent (s)" is preferably a linear or branched C _1-6.
Examples of the alkyl group include, specifically, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso.
-Butyl, tert-butyl, n-pentyl, n-hexyl and the like can be mentioned. The "substituent" of the "lower alkyl group which may have a substituent (s)" is, for example, a halogen atom (eg, chlorine, bromine, fluorine, iodine), a hydroxyl group, a straight chain or branched C _1-3. Examples thereof include an alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a hydroxyl group, a nitro group, and a phenyl group which may be substituted with a halogen atom.

The "C _1-6 alkoxy group" is preferably a linear or branched C _1-6 alkoxy group,
Specifically, for example, methoxy, ethoxy, propoxy,
Examples include isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and the like. Examples of the “acyl group” include an acyl group derived from an organic carboxylic acid, and specifically, for example, formyl, acetyl,
Examples thereof include C _1-6 acyl groups such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl. Of these, formyl is particularly preferred. The “fused imidazolyl group” represented by A may have two or more of the above-mentioned substituents other than the nitro group, which are the same or different. 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 may be bonded to a carbon atom constituting the ring. Is preferred.

Examples of the "hydrocarbon group optionally having a substituent" represented by R or the "hydrocarbon group having a substituent" represented by _R'include , for example, a C _1-10 hydrocarbon group. To be Specifically, for example, a linear or branched C _1-10 alkyl group, a linear or branched C _2-10 alkenyl group, C
_2-10 alkynyl group, C _3-10 cycloalkyl group, C _3-7 cycloalkenyl group, C _5-7 cycloalkadienyl group, C
_Examples thereof include C _1-4 alkyl substituted with a _3-6 cycloalkyl group. Of these, a linear or branched C _1-10 alkyl group is preferable. Examples of the "linear or branched C _1-10 alkyl group" 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 and the like are preferable, and among them, a C _1-6 alkyl group is preferable, more preferably methyl, ethyl or propyl. , Isopropyl, butyl, isobutyl, tert-butyl, etc.
_{1-4 is} an alkyl group.

Examples of the "linear or branched C _2-10 alkenyl group" include 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 and the like, and among them, a _C2-4 alkenyl group such as vinyl, allyl, isopropenyl, 2-methyl-1-propenyl and the like is preferable. Examples of the “C _2-10 alkynyl group” include ethynyl, 1-propynyl, 2-
Propinyl, 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. And especially ethynyl, 1-propynyl,
A C _2-3 alkynyl group such as 2-propynyl is preferred.

Examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3,2,1] octyl, bicyclo [3,2,2] nonyl, bicyclo [ Examples include 3,3,1] nonyl, bicyclo [4,2,1] nonyl, bicyclo [4,3,1] decyl, and the like. Examples of the “C _3-7 cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Examples of the “C _5-7 cycloalkadienyl group” include 2,
4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadiene-
1-yl and the like. The "C _1-4 alkyl group substituted by C _3-6 cycloalkyl" is, for example, methyl, ethyl, propyl, isopropyl or butyl substituted by C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. , Isobutyl, te
Examples thereof include C _1-4 alkyl groups such as rt.-butyl, and preferably cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl,
Examples thereof include cyclohexylethyl and cyclohexylpropyl.

The “substituent” of the “hydrocarbon group optionally having a substituent” represented by R or the “hydrocarbon group having a substituent” represented by R ′ is, for example, (i) substituted Optionally substituted hydroxyl group (preferably acylated hydroxyl group), (ii) esterified or amidated carboxyl group, (iii) optionally substituted amino group, (iv) Examples thereof include a heterocyclic group which may be substituted, and (v) an aryl group which may be substituted. Suitable examples include a hydroxyl group which may be substituted, a carboxyl group which may be esterified or amidated, an amino group which may be substituted, and an aryl group which may be substituted. More preferable examples include a hydroxyl group which may be acylated, a carboxyl group which may be esterified or amidated, and an amino group which may be substituted. Of these, an acylated hydroxyl group and an optionally substituted amino group are preferable, and a hydroxyl group and a substituted amino group are particularly preferable.

Examples of the acyl group in the "optionally acylated hydroxyl group" include a carboxylic acid acyl group which may have a substituent, a sulfonic acid acyl group,
An acid residue such as carbamoyl (an acyl group derived from the corresponding acid) can be mentioned. Examples of the carboxylate acyl group include formyl, alkanoyl (alkylcarbonyl) group, arylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic carbonyl group and alkylthiocarbonyl group. Examples of the alkyl in alkanoyl (alkylcarbonyl), alkyloxycarbonyl and alkylthiocarbonyl which may have a substituent include, for example, a linear or branched C _1-6 alkyl group (eg, methyl, ethyl, n- Propyl, iso-propyl, n-butyl, iso-
Butyl, tert-butyl, n-pentyl, n-hexyl, etc.) and the like. Examples of the aryl in the arylcarbonyl group and the aryloxycarbonyl group which may have a substituent include C _6-10 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.) and the like.

The heterocyclic group in the optionally substituted heterocyclic carbonyl group is, for example, a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.). (Eg 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,3
4-thiazol-2-yl, 1-methyl-5-tetrazolyl, etc.) and the like. Examples of the acyl sulfonate group include C _1-6 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C _6-10 arylsulfonyl (eg, benzenesulfonyl, toluenesulfonyl, 1
-Naphthylsulfonyl, 2-naphthylsulfonyl, etc.) and the like. The above-mentioned carboxylic acid acyl group, sulfonic acid acyl group and carbamoyl are 1 to 3 appropriate substituents (eg, hydroxyl group, carboxyl group, amino optionally mono- or di-substituted by C _1-6 alkyl). It may be substituted with a group or a halogen atom (eg, chlorine, fluorine, bromine, etc.).

Examples of the substituent of "optionally substituted hydroxyl group" include optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, n-propyl, iso-propyl, n -Butyl, iso-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.), optionally substituted C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally substituted aryl group (eg, phenyl) , 1-naphthyl, 2-naphthyl, etc.), and an optionally substituted C _7-12 aralkyl group (eg, benzyl, phenethyl, etc.) and the like. As the substituent in the optionally substituted lower (C _1-6 ) alkyl, the optionally substituted C _3-6 cycloalkyl, the optionally substituted aryl group and the optionally substituted aralkyl group, , Halogen (eg, fluorine, chlorine, bromine, etc.) and the like.

The "optionally esterified carboxyl group" is, for example, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), a carboxyl group optionally substituted with phenyl, benzyl, etc. Is mentioned. Among the “optionally amidated carboxyl group”, the “amidated carboxyl group” is, for example, a compound represented by the formula:

Embedded image (In the formula, R ¹ and R ² are the same or different and represent hydrogen or a C _1-6 alkyl group, or R ¹ and R ² may form a nitrogen-containing heterocyclic group together with the adjacent nitrogen atom. , The heterocyclic group may have a substituent). Examples of the C _1-6 alkyl group include methyl, ethyl, n-propyl, iso-propyl, n-
Butyl, iso-butyl, tert-butyl, n-pentyl,
Examples include n-hexyl and the like. The nitrogen-containing heterocyclic group which R ¹ and R ² may form together with the adjacent nitrogen atom includes 1 to 3 hetero atoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to the nitrogen atom. Examples thereof include a 4- to 7-membered nitrogen-containing heterocyclic group (eg, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino). Of these, a 6-membered nitrogen-containing heterocyclic group which may further contain one nitrogen atom in addition to the nitrogen atom is preferable.

The heterocyclic group may have 1 to 3 (preferably 1) substituents at substitutable positions, and examples of the substituent include a C _1-6 alkyl group (eg, Methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso
-Butyl, tert-butyl, n-pentyl, n-hexyl etc.), C _2-6 alkenyl group (eg 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 group (eg, 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.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.), C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), C _7-10 aralkyl groups (eg, benzyl, phenethyl, etc.)), amino groups and the like.

The substituent of the "optionally substituted amino group" is, for example, a linear or branched lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, or a substituted An optionally substituted aryl group,
Examples of the optionally substituted aralkyl group, an acyl group, an optionally esterified carboxyl group, and the like,
These substituents may be the same or different and may be substituted by 1 or 2. Examples of the lower alkyl group include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl. To be The lower alkyl group may have 1 to 3 substituents at substitutable positions, and examples of the substituents include halogen (eg, fluorine, chlorine, bromine, etc.) and the like. Examples of the lower cycloalkyl group include C such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
_3-6 cycloalkyl group etc. are mentioned. Examples of the aryl group include C _6-10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl. Examples of the aralkyl group include C _7-12 aralkyl groups such as benzyl and phenethyl. The lower cycloalkyl group, aryl group and aralkyl group may have 1 to 3 substituents at substitutable positions, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, etc.). ), C _1-3
Alkoxy (eg, methoxy, ethoxy, propoxy, etc.) and the like can be mentioned.

Examples of the acyl group include an acid residue (acyl group derived from the corresponding acid) such as a carboxylic acid acyl group, a sulfonic acid acyl group and carbamoyl which may each have a substituent. To be Examples of the carboxylate acyl group include formyl, alkanoyl (alkylcarbonyl) group, arylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, heterocyclic carbonyl group and alkylthiocarbonyl group. Examples of the alkyl in alkanoyl (alkylcarbonyl), alkyloxycarbonyl and alkylthiocarbonyl which may have a substituent include, for example, a linear or branched C _1-6 alkyl group (eg, methyl, ethyl, propyl, (Isopropyl, butyl, isobutyl, sec.-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl etc.)
And the like. Examples of the aryl in the arylcarbonyl group and the aryloxycarbonyl group which may have a substituent include C _6-10 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.) and the like.

The heterocyclic group in the optionally substituted heterocyclic carbonyl group is, for example, a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.). (Eg 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4
-Thiazol-2-yl, 1-methyl-5-tetrazolyl, etc.) and the like. Examples of the acyl sulfonate group include C _1-6 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C _6-10 arylsulfonyl (eg, benzenesulfonyl, toluenesulfonyl, 1
-Naphthylsulfonyl, 2-naphthylsulfonyl, etc.) and the like. The above-mentioned carboxylic acid acyl group, sulfonic acid acyl group and carbamoyl are 1 to 3 appropriate substituents (eg, hydroxyl group, carboxyl group, amino optionally mono- or di-substituted by C _1-6 alkyl). It may be substituted with a group or a halogen atom (eg, chlorine, fluorine, bromine, etc.). Examples of the optionally esterified carboxyl group include a C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl etc.) and a carboxyl group optionally substituted with phenyl, benzyl and the like.

The heterocyclic group in the "optionally substituted heterocyclic group" is a 5- to 7-membered non-aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom or 2 to 4
5- or 6-membered non-aromatic heterocyclic group containing nitrogen atoms (eg,
Oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl,
Piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl and the like) and the like. The heterocyclic group may have 1 to 3 arbitrary substituents at substitutable positions, and examples of the substituent include a substituent of the above-mentioned “optionally substituted amino group”. In the same manner as those mentioned above, a linear or branched lower alkyl group, an optionally substituted lower cycloalkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an acyl group. Groups and the like.
Examples of the aryl group in the “optionally substituted aryl group” include C _6-10 aryl (eg, phenyl,
1-naphthyl, 2-naphthyl, etc.) and the like. The aryl group may have 1 to 3 identical or different substituents at any substitutable position, and examples of the substituent include a halogen atom (eg, chlorine, fluorine, bromine, etc.), C
Examples thereof include _1-3 alkoxy groups (eg, methoxy, ethoxy, propoxy, etc.) and C _1-3 alkyl groups (eg, methyl, ethyl, propyl, etc.).

As R or R ′, a lower alkyl group branched at the α-position, a lower alkyl group substituted with a hydroxyl group or a lower alkyl group substituted with a substituted amino group is preferable. The lower alkyl group in the lower alkyl group branched at the α-position is preferably a branched C _3-6 alkyl group. The lower alkyl group in the lower alkyl group substituted with a hydroxyl group is preferably a linear lower alkyl group, and particularly preferably a linear C _1-4.
And an alkyl group. As the lower alkyl group in the lower alkyl group substituted with the substituted amino group, a linear lower alkyl group is preferable, and a linear C _1-6 alkyl group is particularly preferable. The substituted amino group which is a substituent in the lower alkyl group is preferably an amino group substituted with an acyl group. The acyl group is preferably a carboxylate acyl group which may have a substituent, and more preferably an optionally substituted lower alkylcarbonyl (alkanoyl) group. The substituent in the optionally substituted lower alkylcarbonyl group is preferably a halogen atom or the like.

X is preferably --S-- or --O--.
Particularly when X is —S (O) _n — (n represents an integer of 0 to 2), the substituent in the hydrocarbon group represented by R or R ′ may be acylated. A hydroxyl group, a carboxyl group which may be esterified or amidated or an amino group which may be substituted is preferable. When X is —S (O) _n — (n is an integer of 0 to 2), R or R ′ is substituted with a C _1-10 alkyl group or hydroxyl group branched at the α-position. Particularly preferred are straight-chain C _1-10 alkyl groups. When X is —O—, R or R ′ is a linear C _1-10 alkyl group substituted with an amino group substituted with an acyl group,
Particularly preferred. From the viewpoint of low toxicity of the compound, X is preferably -O-. n is preferably 0.

Specific preferred examples of the compound represented by the general formula (I) include the following compounds: JP-A No. 4-4
7-20193 (e.g., 6-methoxy-3-nitroimidazo [1,2-b] pyridazine, 6-ethoxy-3-nitroimidazo [1,2-b] pyridazine, etc.), US Patents Compounds described in Japanese Patent No. 4061751 (eg, 6-propoxy-3-nitroimidazo [1,2-b])
Pyridazine etc.), 6-tert butylthio-3-nitroimidazo [1,2-b] pyridazine (hereinafter sometimes referred to as compound A), 6-[(2R) -2- (trifluoroacetylamino) propyl] Oxy-3-nitroimidazo [1,2
-B] pyridazine (hereinafter sometimes referred to as compound B), 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.

A compound represented by the formula (I) or an imidazole derivative [hereinafter, these may be simply referred to as a compound (I) or an imidazole derivative (I) including a compound represented by the general formula (I '). . ] Can form a salt with an acid or a base when a group having a basicity or a group having an acidity is present in the molecule. The type of these salts is not particularly limited. Examples of the salt when a basic group is present include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
Salts with inorganic acids such as phosphorus salts, acetic acid, tartaric acid, citric acid,
Examples thereof include salts with organic acids such as fumaric acid, maleic acid, 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 condensed imidazole derivative used in the present invention is described in JP-A-47-20193, US Pat. No. 40.
It can be produced by the method described in Japanese Patent No. 61751 or a method analogous thereto, or the method described below and the method of Reference Examples or a method analogous thereto. In the compound (I), general formula (I ″): AX′—R (I ″) (In the formula, X ′ represents a bond, S or O, and other symbols have the same meanings as above. ) Or a salt thereof,
General formula (II): AX′-H (II) (wherein the symbols have the same meanings as defined above) or a salt thereof and general formula (III): Z—R (III) (wherein Z represents a reactive group, the other symbols are the compounds represented by the above) or a salt thereof, or general formula (IV): AZ (IV) [wherein the symbols have the same meanings as described above] ] The compound or its salt represented by these, and the compound or its salt represented by general formula (V): H-X'-R (V) [In the Formula, the symbol is the same meaning as the above], and the following reaction conditions. It can be produced by reacting. In the definitions of general formula (II) and general formula (V), as the reactive group represented by Z, a well-known reactive group may be used. Examples of the reactive group include a halogen atom (eg, chlorine, bromine, fluorine, iodine, etc.),
C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), C
_1-4 alkylsulfonyloxy groups (eg, methanesulfonyloxy, etc.) and the like. Formula (II), (II
Preferable examples in each definition of I), (IV) and (V) (excluding Z) are the same as those described in the above general formulas (I) and (I ′).

This reaction is carried out in a solvent that does not inhibit the reaction. Examples of the solvent include alcohols (eg, methanol, ethanol, propanol, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride). Etc.), hydrocarbons (eg, benzene, toluene, hexane, heptane, etc.), amides (eg, dimethylformamide, etc.), dimethyl sulfoxide and the like. Also,
This reaction may be carried out in the presence of a base as the case requires, and examples of such a base include organic bases such as 4-dimethylaminopyridine, triethylamine, triethylenediamine and tetramethylethylenediamine, such as sodium hydrogen carbonate and carbonic acid. Inorganic bases such as potassium hydrogen, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride are used. In this reaction, the reaction temperature is about -50 ° C to 100 ° C.
C., preferably about 0 to 50.degree. The reaction time is usually about 1 to 48 hours, preferably about 5 to 10 hours.

When this reaction is carried out, the compound of the general formula (III) or (I
The amount of the compound represented by V) used is about 1 to 10 with respect to 1 mol of the compound represented by the general formula (II) or (V).
It is a molar amount, and it is preferable to use about 1 to 3 molar amount.
Among the compound (I), the general formula (I ''') A- X''- R (I''') ( wherein, X '' is -SO- or -SO ₂ - indicates, other symbols Is a compound of the above-mentioned meaning) is a compound represented by the general formula (I ″ ″) A—S—R (I ″ ″) (where the symbols are as defined above) It can be obtained by subjecting it to a reaction. This reaction is carried out in a solvent that does not inhibit the reaction. Examples of the solvent include ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbons (eg, benzene,
Examples thereof include toluene, hexane, heptane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform etc.), nitriles (eg, acetonitrile etc.), and amides (eg, dimethylformamide etc.). Examples of the oxidizing agent include metachloroperbenzoic acid, hydrogen peroxide, peracetic acid and the like. The amount of the oxidizing agent to be used is about 1-5 mol amount, preferably about 1-2 mol amount, relative to 1 mol of the compound represented by the formula (I ″ ″). The reaction temperature is about 0 to 100 ° C, preferably about 0 to 30 ° C. The reaction time is about 1 to 10 hours, preferably about 1 to 2 hours.

The composition of the present invention is a gastric mucoadhesive composition containing the condensed imidazole derivative (I) or a salt thereof. A gastric mucoadhesive composition containing a condensed imidazole derivative (I) or a salt thereof is attached to and / or retained in the stomach to release the condensed imidazole derivative at an appropriate rate to prolong the drug residence time, and particularly to have an antibacterial action. Any composition may be used as long as it exhibits and enhances the anti-Helicobacter pylori activity. Examples of such a composition preferably include those containing a matrix composed of polyglycerin fatty acid ester and / or lipid. For example, a substance that causes viscosity with polyglycerin fatty acid ester and water (hereinafter abbreviated as viscous substance). Gastric mucoadhesive matrix and the like. In addition to this, a gastric mucoadhesive matrix or the like prepared by mixing a substance that causes viscosity with lipid and water may be included. As the gastric mucoadhesive matrix, a viscous substance is dispersed in a matrix containing polyglycerin fatty acid ester and / or lipid, and a matrix containing polyglycerin fatty acid ester and / or lipid is coated with viscous substance. The thing etc. are preferable. The melting point of the gastric mucoadhesive matrix is, for example, about 30 to about 120 ° C., preferably about 40.
Is about 120 ° C.

As the polyglycerin fatty acid ester,
As long as it is an ester of polyglycerin and a fatty acid, it may be any of a monoester, a diester and a polyester. The polyglycerin fatty acid ester has characteristics that it does not exhibit polymorphism and has almost no interaction with the drug. Therefore, when coexisting with the drug, the drug hardly deactivates and is stable for a long period of time. Polyglycerin is "1
M (cyclic) to (m + 2) (straight / branched) in the molecule
Polyhydric alcohol having hydroxyl groups of (m-1) (m-1) (linear / branched) to m (cyclic) ether bonds "[" polyglycerin ester "edited by Sakamoto Yakuhin Kogyo Co., Ltd. (1986) May 2) p. 12] and may be linear or branched. For example, the following formula (VI)

Embedded image (In the formula, m represents the degree of polymerization and is an integer of 2 or more). n is usually 2 to 5
0, preferably 2 to 20, more preferably 2 to 10. Specific examples of the polyglycerin include, for example, diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, heptaglycerin, octaglycerin, nonaglycerin, decaglycerin, pentadecaglycerin, eicosaglycerin, triacontaglyserin and the like. No. Among these polyglycerins, for example, tetraglycerin, hexaglycerin, decaglycerin and the like are frequently used. Examples of the fatty acid include saturated or unsaturated fatty acids having 8 to 40 carbon atoms, preferably 12 to 22 carbon atoms. Examples of the fatty acid include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid, capric acid, and behenic acid. Among these fatty acids, stearic acid, oleic acid, lauric acid, linoleic acid, behenic acid and the like are preferable.

Specific examples of the polyglycerin fatty acid ester include, for example, behenic acid hexa (tetra) glyceride,
Caprylic acid mono (deca) glyceride, caprylic acid di (tri) glyceride, capric acid di (tri) glyceride, lauric acid mono (tetra) glyceride, lauric acid mono (hexa) glyceride, lauric acid mono (deca) glyceride, oleic acid Mono (tetra) glyceride, oleic mono (hexa) glyceride, oleic mono (deca)
Glyceride, oleic acid di (tri) glyceride, oleic acid di (tetra) glyceride, oleic acid sesqui (deca) glyceride, oleic acid penta (tetra) glyceride, oleic acid penta (hexa) glyceride, oleic acid deca (deca) glyceride, Linoleic acid mono (hepta)
Glyceride, linoleic acid di (tri) glyceride, linoleic acid di (tetra) glyceride, linoleic acid di (hexa)
Glyceride, stearic acid mono (di) glyceride, stearic acid mono (tetra) glyceride, stearic acid mono (hexa) glyceride, stearic acid mono (deca) glyceride, stearic acid tri (tetra) glyceride, stearic acid tri (hexa) glyceride, Sesqui (hexa) glyceride stearate, penta (tetra) glyceride stearate, penta (hexa) glyceride stearate, deca (deca) glyceride stearate, mono (tetra) glyceride palmitate, mono (hexa) glyceride palmitate, palmitate Mono (deca) glyceride, tri (tetra) glyceride palmitate, tri (hexa) glyceride palmitate, sesqui (hexa) glyceride palmitate, penta (tetra) palmitate
Examples thereof include glyceride, penta (hexa) palmitate glyceride, and deca (deca) palmitate glyceride. Examples of preferable polyglycerin fatty acid ester include behenic acid hexa (tetra) glyceride (for example, Riken Vitamin Co., Ltd., trade name Poem J-46B,
Or Sakamoto Yakuhin Kogyo Co., Ltd., trade name HB-310, stearic acid penta (tetra) glyceride (for example, Sakamoto Yakuhin Co., Ltd. trade name, PS-310 etc.), stearic acid mono (tetra) glyceride (For example, Sakamoto Yakuhin Kogyo Co., Ltd., trade name MS-310, etc.), stearic acid penta (hexa) glyceride (for example, Sakamoto Yakuhin Kogyo Co., Ltd., trade name PS-500, etc.), stearic acid sesqui (hexa) ) Glycerides (for example, Sakamoto Yakuhin Kogyo Co., Ltd., trade name SS-500 etc.), stearic acid mono (deca) glyceride or a mixture thereof and the like can be mentioned. The above-mentioned polyglycerin fatty acid ester is one kind or two kinds or more, preferably 2 kinds.
Or used as a mixture of three kinds.

The molecular weight of the polyglycerin fatty acid ester is usually about 200 to about 5000, preferably about 300.
It is about 2000, more preferably about 500 to about 2000. HLB of polyglycerin fatty acid ester [Hydrophile-lipophile balance)
Is usually 1 to 22, preferably 1 to 15, and more preferably 2 to 9. Targeted H by appropriately mixing two or more polyglycerin fatty acid esters having different HLBs
LB may be adjusted. By adjusting the HLB of polyglycerin fatty acid ester, the drug release and elution properties can be controlled. Polyglycerin fatty acid ester is
It can be appropriately selected depending on the forms of the drug, the viscous substance and the matrix, but is preferably room temperature (about 15 ° C)
The solid type is used in. The melting point of the polyglycerin fatty acid ester is, for example, about 15 to about 80 ° C, preferably about 30 to about 75 ° C, more preferably about 45 to 75 ° C. When two or more polyglycerin fatty acid esters are used as a mixture, they may be used in combination with liquid polyglycerin fatty acid ester as long as the gastric mucoadhesive matrix is solid at room temperature. When a polyglycerin fatty acid ester is used as the gastric mucoadhesive matrix, the amount of the polyglycerin fatty acid ester used is, for example, in terms of weight, about 0.01 to about 1 based on the drug in the composition.
It is 0000 times, preferably about 0.1 to about 1000 times.

As the lipid, a melting point of about 40 to about 120 ° C.,
It is preferably about 40 to about 90 ° C. Examples of the lipid include saturated fatty acids having 14 to 22 carbon atoms (for example, myristic acid, palmitic acid, stearic acid, behenic acid, etc.) or salts thereof (for example, sodium salt, potassium salt); higher carbon atoms having 16 to 22 carbon atoms. Alcohol (eg cetyl alcohol, stearyl alcohol, etc.);
Fatty acid glycerin ester which is a monoglyceride, diglyceride, triglyceride (for example, 1-monostearin, 1-monopalmitin, etc.) with the above-mentioned fatty acids; oils and fats (for example, castor oil, cottonseed oil, soybean oil, rapeseed oil, beef tallow, etc., Hydrogenated oils); waxes (eg, beeswax, carnauba wax, spermaceti, etc.); hydrocarbons (eg, paraffin, microcrystalline wax, etc.), phospholipids (eg, hydrogenated lecithin, etc.) and the like. Among these lipids, for example, oils and fats, waxes, saturated fatty acids having 14 to 22 carbon atoms, and 16 to 2 carbon atoms
2 higher alcohols, hydrocarbons and the like are preferable, and hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, carnauba wax, stearic acid, stearyl alcohol, microcrystalline wax and the like are more preferable. Carnauba wax is particularly preferred. When a lipid is used as the gastric mucosa-adhesive matrix, the amount of the lipid used is, for example, about 0.01 to about 10 with respect to the drug in the composition.
000 times, preferably about 0.1 to about 1000 times.
The polyglycerin fatty acid ester and the lipid may be mixed and used, and for example, polyglycerin fatty acid ester and waxes, and specifically, penta (tetra) stearic acid glyceride and carnauba wax are used.

The substance that produces viscosity with water (viscous substance) is not particularly limited as long as it exhibits viscosity with water and exhibits adhesiveness to the gastrointestinal mucosa and is pharmaceutically acceptable. Among them, a substance which swells with water and is significantly thickened is particularly preferable. Examples of the viscous substance include a polymer and a natural viscous substance. The polymer is 2
The viscosity of a 2% aqueous solution of the polymer at 0 ° C. is about 3 to
About 50,000 cps, preferably about 10 to about 30,000 cps
Those exhibiting ps, more preferably about 15 to about 30,000 cps are preferred. However, in the case of a polymer that thickens by neutralization, the viscosity of the 0.2% neutralized solution at 20 ° C. is about 100 to about 500,000 cps, preferably about 10
0 to about 200,000 cps, more preferably about 1,50
Polymers exhibiting 0 to about 100,000 cps are desirable.
The above polymer is preferably an acidic polymer, and examples thereof include a polymer having a carboxyl group, a sulfo group or a salt thereof. Particularly preferred is a polymer having a carboxyl group or a salt thereof.

Examples of the polymer having a carboxyl group or a salt thereof include acrylic acid polymers (including copolymers) having acrylic acid as a constituent monomer and salts thereof. Examples of the salt include monovalent metal salts such as sodium and potassium salts, and divalent metal salts such as magnesium salt and calcium salt. Examples of the acrylic acid-based polymer or a salt thereof include a polymer containing about 58 to about 63% by weight of a carboxyl group and having a molecular weight of about 200,000 to about 6,000,000, preferably about 1,000,000 to about 5,000,000. Preferred acrylic acid-based polymers or salts thereof include acrylic acid homopolymers and salts thereof. Such a polymer is described as a carboxyvinyl polymer in a foreign regulation (October 1986). Specific examples of the polymer include, for example, Carbomer [trade name: Carbopol (hereinafter referred to as Carbopol) The BF Goodrich Company] 940,
934, 934P, 940, 941, 974, 974
P, 1342 (NF XVII), Hibiswako 103, 104, 105 (Wako Pure Chemical Industries, Ltd.), N
OVEON AA1 [trade name of the BF Goodrich Company], calcium voricapofil (USPXXII) and the like. The polymer having a sulfo group or a salt thereof,
For example, curd run and the like can be mentioned. Examples of natural viscous substances include mucin, agar, gelatin, pectin, carrageenan, sodium alginate, locust bingham, xanthan gum, tragacanth gum, acacia, chitosan, pullulan, waxy starch, sucralfate, curdlan, cellulose and derivatives thereof (eg. , Cellulose sulfate, etc.) and the like.
Preferably, hydroxypropyl methylcellulose, hydroxypropyl-cellulose and the like can be mentioned.

The viscous substance used in the present invention is preferably an acrylic acid polymer or a salt thereof. These viscous substances may be used alone or in combination of two or more. The amount of the viscous substance used is, for example, about 0.005 to about 99% by weight in the gastric mucoadhesive matrix, and preferably,
It is about 0.5 to about 45% by weight, more preferably about 10 to about 30% by weight. For example, if the viscous material is dispersed in a matrix containing polyglycerin fatty acid esters or lipids, the viscous material will be about 0.005 to about 9 total weight.
5% by weight, preferably about 0.5 to about 30% by weight, more preferably about 5 to about 25% by weight, when the matrix is coated with a viscous substance, about 0.005 to about 95% by weight. %, Preferably about 0.5 to about 30% by weight, more preferably about 5 to about 25% by weight. As the gastric mucoadhesive matrix, for example, when a gastric mucoadhesive matrix prepared by mixing a polyglycerin fatty acid ester with a viscous substance or a gastric mucoadhesive matrix prepared by mixing a lipid with a viscous substance is used, the polyglycerin fatty acid The amount of the ester and the lipid used is, in terms of weight, about 0.01 to about 10,000 with respect to the drug in the composition.
Times, preferably about 0.1 to about 1000 times. Furthermore, a lipid containing the polyglycerin fatty acid ester may be contained in the matrix. As the lipid, one that is a water-insoluble substance that is acceptable in the formulation and that has an action of adjusting the dissolution rate of the drug is used, and examples thereof include the above-mentioned lipids.

When the lipid and the polyglycerin fatty acid ester are used in combination, the amount of the lipid and the polyglycerin fatty acid ester used may be in a range that does not impair the adhesion to the gastrointestinal mucosa. Polyglycerin fatty acid ester is about 0.01 to about 1000 against the drug
0 times, preferably about 0.1 to about 1000 times, the lipid is about 0.01 to the polyglycerol fatty acid ester in the composition.
To about 100 times, preferably about 1 to about 20 times. The gastric mucoadhesive composition may be used in combination with an appropriate amount of an organic acid in order to promote absorption of the drug. As the organic acid, for example, tartaric acid, citric acid, succinic acid, ascorbic acid, etc. are used.

Other antibacterial agents and anti-ulcer agents may be used in appropriate amounts in the gastric mucoadhesive composition. Examples of the antibacterial agent include macrolide antibacterial agents (eg, Clarice, Luride, azithromycin, etc.), quinolone antibacterial agents (eg, Talibid, Ozex, Grepafloxacin, Valofloxacin, NM-441, T-3761, etc.) , Penicillin-based antibacterial agents (eg, fropenem, amoxicillin (amorin, etc.), cephalosporin antibacterial agents (eg, flumax, etc.) and the like. Examples of the anti-ulcer agent include peptic ulcer therapeutic agents and the like, and specific examples include proton pump inhibitors, histamine H ₂ blockers, mucosal protective anti-ulcer agents and the like.

Examples of the proton pump inhibitor include benzimidazole compounds having antiulcer properties, particularly 2-[(pyridyl) -methylsulfinyl or methylthio] benzimidazole derivatives or salts thereof. As a specific example, 2- [2- [3-methyl-4- (2,2,2-trifluoroethoxy) pyridyl] methylsulfinyl] benzimidazole (lansoprazole), 2-[(2-
Pyridyl) methylsulfinyl] benzimidazole (timoprazole), 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 (pantoprazole) and the like can be mentioned. The above-mentioned benzimidazole compounds or salts thereof are described in, for example, JP-A-54-141783 and JP-A-58-19288.
No. 0, JP 61-50978, JP 62
It is manufactured by the methods described in JP-A-116576, JP-A-5-59043 and the like, and methods equivalent thereto. Furthermore, for example, 2-[[o- (isobutylmethylamino) benzyl] sulfinyl] benzimidazole (reminone), 2-[(4-methoxy-6,7,8,9-
Tetrahydro-5H-cyclohepta [b] pyridine-9
-Yl) sulfinyl] -1H-benzimidazole sodium salt (TY-11345), 5-methoxy-2-
[[(4-Methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -imidazo [4,5-b]
Pyridine (TU-199) and the like are also included.

Examples of histamine H ₂ blockers include 2-cyano-1-methyl-3- [2-[[(5-methylimidazole-4-yl) methyl] thio] ethyl] guanidine (cimetidine), N- [2 -[[5-[(dimethylamino) methyl] furfuryl] thio] ethyl] -N '
-Methyl-2-nitri-1,1-ethenediamine (ranitidine), (±) -2- (furfurylsulfinyl)-
N- [4- [4- (4- (piperidinylmethyl) -2-pyridyl] oxy (z) -2-butenyl] acetamide (loctidine), N-sulfamoyl-3-[(2-guanidinothiazol-4-yl) And methylthio] propionamide (famotidine). Examples of the mucosa-protective antiulcer drug include (z) -7-[(1R, 2R, 3R)-
2-[(E)-(3R) -3-hydroxy-4,4-dimethyl-1-octenyl] -3-methyl-5-oxocyclopentyl] -5-heptenoic acid (thymoprostil,
Ulster), 1-butylic acid-7- (L-2-
Aminobutyric acid) -26-L-aspartic acid-27-L-valine-29-L-alanine calcitonin (elcatonin), 3-ethyl-7-isopropyl-1-azulensulphonate sodium (egualen sodium), teprenone Etc.

Further, when the composition is solid, conventional additives used in the production of solid pharmaceutical preparations (eg, fine granules, granules, etc.) may be used. As the additive, for example, lactose, corn starch, talc, crystalline cellulose (such as Avicel), powdered sugar, magnesium stearate,
Excipients such as mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine; starch, sucrose, gelatin, gum arabic powder, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose,
Binders such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin; disintegrators such as carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium; anionic surfactants such as sodium alkylsulfate, polyoxyethylenesorbitan Nonionic surfactants such as fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives; surface active agents; magnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminum sulfate, magnesium metasilicate magnesium aluminate, silica Acid antacids such as magnesium aluminate and sucralfate, and mucosal protective agents;
Coloring agents; flavoring agents; adsorbents; preservatives; wetting agents; antistatic agents, disintegration extenders, and the like. The amount of these additives added is appropriately selected within a range that does not impair the adhesion to the mucous membrane.

The polyglycerin fatty acid ester and / or
Alternatively, the gastric mucoadhesive composition in which a viscous substance is dispersed in a lipid-containing matrix may be a polyglycerin fatty acid ester and / or a lipid, a viscous substance and a drug dispersed in the composition. As the dispersion method, a method known per se is adopted. The method for producing the gastric mucosa-adhesive composition is as follows. 1) When the gastric mucoadhesive composition is solid at room temperature, a method known per se is adopted as a method for producing the gastric mucoadhesive solid composition. For example, a method may be mentioned in which a polyglycerol fatty acid ester and / or a lipid is heated to a melting point or higher to be melted, a viscous substance and a drug are added simultaneously or separately and dispersed, and then cooled. The heating temperature is, for example, about 40
To about 150 ° C, preferably about 50 to about 110 ° C, more preferably about 50 to about 95 ° C. For the above-mentioned method, a conventional granulator may be used, and for example, it is preferable to make a spherical solid agent (eg, fine granule) by spray cooling, for example, spray chilling. The spray chilling is, for example, 10 to 6000 rpm, preferably 900 to 6000.
Rotation / minute, more preferably 1000 to 3000 rotations / minute, on a high-speed rotation disk at a constant flow rate, by dropping a mixture of a viscous substance and a drug dispersed in molten polyglycerin fatty acid ester and / or lipid. You can As the rotating disk, for example, a diameter of 5 to 100
A cm, preferably 10 to 20 cm smooth disk, such as an aluminum disk, can be used. The dropping rate of the molten mixture can be selected according to the desired particle size, but is usually about 2 to about 200 g / min, preferably about 5 to about 100 g / min. Since the granular material thus obtained is closer to a true sphere, a uniform coating film can be efficiently formed at the time of coating in a later step.

In addition to the above method, for example, a method in which a polyglycerol fatty acid ester and / or a lipid, a viscous substance and a drug are dispersed by kneading and granulated to prepare may be adopted. Examples of the solvent used at this time include a conventional solvent (eg, methanol, acetonitrile, chloroform, etc.). Further, the solid composition may be produced by using, for example, a melt granulation method. As the melt granulation method, polyglycerin fatty acid ester and / or lipid,
They are heated and melted in the vicinity of their melting point, for example, in a temperature range lower than the melting point by about 5 ° C., and subjected to a granulating process such as the above spray chilling to form fine particles, and the viscous substance and drug are heated at a desired temperature. However, a method of suspending it to form a gastric mucosa-adhesive matrix can be used. In this case, since the action of heat on the drug can be suppressed, even if the drug is a peptide, a protein, or the like, a solid composition can be easily obtained while suppressing the inactivation of the components. A solid composition in which a matrix containing a polyglycerin fatty acid ester and / or a lipid is coated with a viscous substance, provided that the solid composition is coated with a viscous substance, preferably a coating agent containing at least a viscous substance. Good. The coating agent may contain, in addition to the viscous substance, at least one component of the polyglycerin fatty acid ester, the lipid, and the water-insoluble polymer. In this case, if a viscous substance that is poorly compatible with the components in the solid composition described above or is incompatible is used, the solid composition can be coated with a film in which the viscous material is dispersed. Furthermore, the coating agent is
You may contain the said additive.

As the water-insoluble polymer, for example, hydroxypropylmethyl cellulose phthalate (JP 1
1), hydroxypropylmethyl cellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., carboxymethyl ethyl cellulose (manufactured by Freund Industries, CMEC, external regulation 1986), cellulose acetate trimellitate (manufactured by Eastman), cellulose Acetate phthalate (JP 11), ethyl cellulose (Asahi Kasei Co., Ltd., FMC), aminoalkyl methacrylate copolymer [made by Reem Pharma Co., product name Eudragit E100], aminoalkyl methacrylate copolymer (made by Reem Pharma Co., product Name
Eudragit RS, RN100L, RSPML, RN
100, RSPM), methacrylic acid copolymer L (manufactured by Reem Pharma Co., trade name Eudragit L10)
0), methacrylic acid copolymer L-D (manufactured by Reem Pharma Co., trade name Eudragit L-30-D-5)
5), methacrylic acid copolymer S (manufactured by Rehm Pharma Co., trade name Eudragit S-100), polyvinyl acetate phthalate [manufactured by COLORCON], trade name Eudragit NE30-D (Ream)
(Pharma Co.) and the like. One of these water-insoluble polymers is used, or a mixture of two or more thereof is used.

The amount of the viscous substance used in the coating agent is
About 0.005 to about 10 of the total solid content in the coating agent
It is 0% by weight, preferably about 0.05 to about 95% by weight, more preferably about 0.05 to about 30% by weight, and particularly preferably about 1 to about 10% by weight. When a viscous substance is used in combination with at least one component of a polyglycerin fatty acid ester, a lipid and a water-insoluble polymer as the coating agent, the viscous substance is about 0.005 to the entire solid content in the coating agent. About 95% by weight, preferably about 0.5 to about 30% by weight, more preferably about 5 to about 25%.
% By weight. Further, in the coating agent, two or more kinds of components selected from polyglycerin fatty acid ester, lipid and water-insoluble polymer may be used in combination. In this case, the total amount of polyglycerin fatty acid ester and / or lipid is 1 part by weight. And other ingredients are about 0.0001 ~
It is about 1000 parts by weight, preferably about 0.01 to about 100 parts by weight, more preferably about 0.01 to about 10 parts by weight.

The coating amount of the coating agent can be selected according to the kind of the solid composition, the desired adhesion to the mucous membrane and the like. The coating amount of the solid composition is, for example, about 0.1 to 30% by weight for tablets, preferably about 0.5 to 10% by weight, and 0.1 to 50% by weight for pills and granules.
It is preferably about 1 to 20% by weight, and in the case of fine granules, it is 0.
It is about 1 to 100% by weight, preferably about 1 to 50% by weight. When coating, if necessary, the commonly used additives may be added to the coating agent for coating, or the coating agent and the additives may be separately used for coating. The amount of the additive used is, for example, about 0.1 to about 70% by weight, preferably about 1 to about 50% by weight, more preferably about 20 to about 10% by weight based on the solid content of the coating agent.
It is about 50% by weight. As the coating method, a method known per se, for example, a pan coating method, a fluid coating method, a rolling coating method, and the like can be adopted. When the coating agent is a solution or dispersion containing water or an organic solvent, a spray coating method can also be employed. The amount of the water or organic solvent used is, for example, about 25 to about 99.
% By weight. The type of the organic solvent is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropyl alcohol; ketones such as acetone; and halogenated hydrocarbons such as chloroform, dichloromethane, and trichloroethane.

When a polyglycerin fatty acid ester and / or lipid is used in the coating agent, the polyglycerin fatty acid ester and / or lipid and, if necessary, other additives are melted by heating and mixed, and then mixed with water. After emulsification by spraying, the solid composition may be sprayed on the surface and dried to obtain a coating composition. Further, in a device such as a coating pan, a coating composition may be added to a solid composition preheated with warm air, and the solid composition may be melted and spread to form a coating composition. Solid compositions are typically about 2
The coating is performed at 5 to about 60 ° C, preferably about 25 to about 40 ° C. The time required for coating can be appropriately selected in consideration of the coating method, the characteristics and amount of the coating agent used, the characteristics of the solid composition, and the like. In the gastric mucoadhesive solid composition,
As long as the mucoadhesiveness of the viscous substance is ensured in the digestive tract, the solid composition may be further coated with a conventional gastric-soluble or water-soluble coating or the like, if necessary.

The form of the gastric mucoadhesive solid composition is as follows:
Examples thereof include fine granules, granules, pills, tablets in which the fine granules or granules are tableted, and capsules in which the fine granules or granules are filled. this house,
Fine granules and granules are preferred. The particle size distribution of the fine granules is, for example, 75% by weight or more of particles of 10 to 500 μm and 500 μm.
5% by weight or less of particles of m or more and 10% by weight or less of particles of 10 μm or less. The particle size distribution of the fine granules is preferably 105
.About.500 .mu.m particles 75% by weight or more, 500 .mu.m or more particles 5% by weight or less, 74 .mu.m or less particles 10% by weight or less. The particle size distribution of the granule is, for example, 500 to 1410.
90% by weight or more of particles of .mu.m and 5% by weight or less of particles of 177 .mu.m or less.

2) When the gastric mucoadhesive composition is liquid at room temperature, a method known per se is adopted as a method for producing the gastric mucoadhesive liquid composition. For example, a method of adding or dispersing a polyglycerin fatty acid ester and / or a lipid, a viscous substance and a drug, which are liquid at room temperature, to disperse or dissolve them at the same time may be mentioned. Examples of the form of the gastric mucoadhesive liquid composition include syrups, emulsions, suspensions, and capsules in which the syrups, emulsions, and suspensions are filled. The content ratio of the condensed imidazole derivative in the composition of the present invention is about 0.1 to about 95.
%, Preferably about 1 to about 95% by weight, more preferably about 10 to 95% by weight.

The composition of the present invention has little toxicity and is a mammal that retains Helicobacter pylori (eg, cats,
It is effective for the treatment of cattle, dogs, horses, goats, monkeys, humans, etc., and is extremely effective for the eradication of Helicobacter pylori held by these animals. Examples of such target diseases include gastritis and peptic ulcer. Of these, it is particularly effective in treating peptic ulcer. The gastric mucoadhesive composition of the present invention can be orally administered to mammals including humans. If desired, pharmacologically and pharmaceutically acceptable additives (for example, diluent,
Excipients, binders, disintegrating agents, coloring agents, stabilizers, etc.) can be mixed or formulated using these. The dose of the composition of the present invention varies depending on the dosage form, administration method, or type of drug to be administered.
In the present invention, the dose of the condensed imidazole derivative (I) or a salt thereof can be reduced to about 1/2 to 1/10 of that of the single administration. For example, the gastric mucoadhesive composition of the present invention is preferably 250 mg or less per day, more preferably 150 mg or less per day as a condensed imidazole derivative (I) or a salt thereof for an adult (body weight 50 kg) with peptic ulcer. A dose of (10 to 150 mg) shows clinically sufficient efficacy.

[0055]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Reference Examples, Examples and Experimental Examples, but these do not limit the present invention.

【Example】

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

Embedded image To a solution of thioglycolic acid ethyl ester (360 mg) in dimethylformamide (10 ml) was added 60% sodium hydride (120 mg), and the mixture was stirred for 1 hour. 6-chloro-3-nitroimidazo [1,2-b] pyridazine (5
96 mg) was added, and the mixture was stirred for 2 days and night, then dichloromethane (30
ml) was added and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and the target substance was dichloromethane /
Recrystallized from diethyl ether, melting point 148-149 ° C
287 mg of colorless crystals were obtained. Elemental analysis value: as C ₁₀ H ₁₀ N ₄ O ₄ S theoretical value: C: 42.55; H: 3.57; N:
19.85 Found: C: 42.46; H: 3.52; N:
20.04

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

Embedded image Sodium hydroxide (120mg) in ethanol (25ml)
In the solution, 1-mercapto-2-propanol (582 m
g) was added, and the mixture was ice-cooled, 6-chloro-3-nitroimidazo [1,2-b] pyridazine (596 mg) was added, and the mixture was stirred with heating at 50 ° C. for 1 hour and then at room temperature overnight. The solvent was distilled off, the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was separated and purified by silica gel column chromatography, and the desired product was recrystallized from diethyl ether to give a melting point of 102-10.
607 mg of pale yellow crystals at 3 ° C. were obtained. Elemental analysis value: C ₉ H ₁₀ N ₄ O ₃ S Theoretical value: C: 42.51; H: 3.96; N:
22.03 Found: C: 42.24; H: 3.98; N:
22.26

Reference Example 3 By the same procedure as in Reference Example 2, the compounds shown in [Table 1] were obtained.

[Table 1]

Reference Example 4 6- (2-Acetyloxyethylthio) -3-nitroimidazo [1,2-b] pyridazine

Embedded image 6- (2-hydroxyethylthio) obtained in Reference Example 3
Acetic anhydride (1.5 ml) was added at 0 ° C to a solution of -3-nitroimidazo [1,2-b] pyridazine (Compound No. 3-1) (240 mg) in pyridine (3 ml), and the mixture was stirred at room temperature overnight. Add the reaction mixture to ice water and add dichloromethane (50 ml).
The organic layer was washed with diluted hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were washed with ether to give 210 mg of colorless crystals having a melting point of 101-102 ° C. Elemental analysis value: as C ₁₀ H ₁₀ N ₄ O ₄ S theoretical value: C: 42.55; H: 3.57; N:
19.85 Found: C: 42.71; H: 3.34; N:
19.87

Reference Example 5 By the same procedure as in Reference Example 4, the compounds shown in [Table 2] were obtained.

[Table 2]

Reference Example 6 6- (2-Methylsulfonyloxyethylthio) -3-
Nitroimidazo [1,2-b] pyridazine

Embedded image 6- (2-hydroxyethylthio) obtained in Reference Example 3
-3-Nitroimidazo [1,2-b] pyridazine (Compound No. 3-1) (961 mg) in dichloromethane (60 m
l) Triethylamine (445 mg) and methanesulfonyl chloride (504 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography, and the desired product was recrystallized from dichloromethane / diethyl ether to give a melting point of 151-15.
There were obtained 346 mg of colorless crystals at 3 ° C. Elemental analysis value: C ₉ H ₁₀ N ₄ O ₅ S ₂ Theoretical value: C: 33.96; H: 3.17; N:
17.60 Found: C: 33.99; H: 3.11; N:
17.82

Reference Example 7 6- (2-hydroxypropylthio) -3-nitro-2
-Methylimidazo [1,2-b] pyridazine

Embedded image 1-mercapto-2-propanol (213 mg) and 6-
Chloro-3-nitro-2-methylimidazo [1,2-
b] Pyridazine (425 mg) was subjected to the same operation as in Reference Example 2 to obtain 358 mg of colorless crystals having a melting point of 137-138 ° C. Elemental _{analysis: C 10 H 12 N 4 O} 3 S and a theoretical: C: 44.77; H: 4.51 ; N:
20.88 Found: C: 44.71; H: 4.67; N:
20.97

Reference Example 8 6- (2-Hydroxypropylsulfonyl) -3-nitroimidazo [1,2-b] pyridazine

Embedded image A solution of 6- (2-hydroxypropylthio) -3-nitroimidazo [1,2-b] pyridazine (254 mg) obtained in Reference Example 2 in dichloromethane (15 ml) was ice-cooled to give metachloroperbenzoic acid (474 mg). Was added dropwise to a dichloromethane (10 ml) solution. The mixture was stirred at 0 ° C overnight, saturated aqueous sodium hydrogen carbonate solution (10 ml) was added, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 150 mg of colorless crystals having a melting point of 133-134 ° C. Elemental analysis value: C ₉ H ₁₀ N ₄ O ₅ S Theoretical value: C: 37.76; H: 3.52; N:
19.57 Found: C: 37.84; H: 3.53; N:
19.71

Reference Example 9 6- (Hydroxycarbonylmethylthio) -3-nitroimidazo [1,2-b] pyridazine

Embedded image Sodium hydroxide (0.08 g) was added to a solution of 6- (ethoxycarbonylmethylthio) -3-nitroimidazo [1,2-b] pyridazine (2.82 g) obtained in Reference Example 1 in methanol (100 ml), Stir overnight at room temperature. Dichloromethane (50 ml) and 1N hydrochloric acid (100 m
l) was added, the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, the residue was washed with diethyl ether,
2.12 g of colorless crystals were obtained. Elemental analysis value: as C ₈ H ₆ N ₄ O ₄ S theoretical value: C: 37.80; H: 2.38; N:
22.04 Found: C: 37.70; H: 2.61; N:
22.14

Reference Example 10 6-[(4-Methylpiperazino) carbonylmethylthio] -3-nitroimidazo [1,2-b] pyridazine.
HCl

Embedded image A solution of 6- (hydroxycarbonylmethylthio) -3-nitroimidazo [1,2-b] pyridazine (763 mg) and N-methylpiperazine (300 mg) obtained in Reference Example 9 in tetrahydrofuran (10 ml) was added to diethyl cyanophosphate. (618 mg) and triethylamine (304 mg) were added, 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 give 437 mg of colorless crystals having a melting point of 249-251 ° C. Of this, 336 mg was dissolved in dichloromethane, acetic acid ethyl ester of 4N hydrogen chloride was added, the solvent was distilled off, the residue was washed with methanol and diethyl ether, and a colorless solid with a melting point of 249-251 ° C. 36
2 mg were obtained. Elemental analysis value: as C ₁₃ H ₁₆ N ₆ O ₃ S.HCl theoretical value: C: 41.88; H: 4.60; N:
22.54 Found: C: 41.65; H: 4.56; N:
22.54

Reference Example 11 By the same operation as in Reference Example 10, the compounds shown in [Table 3] were obtained.

[Table 3]

Reference Example 12 6- (2-Acetylaminoethylthio) -3-nitroimidazo [1,2-b] pyridazine

Embedded image A solution of 6-chloro-3-nitroimidazo [1,2-b] pyridazine (1.0 g) and cysteamine (0.4 g) in tetrahydrofuran (20 ml) was stirred at room temperature with sodium hydride (60% in oil, 0.23 g) was added 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 to remove the solvent. This 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 min. Remove the solvent, dissolve in acetic acid ethyl ester (20 ml), wash with water,
Separation and purification by silica gel column chromatography gave 0.32 g of colorless crystals having a melting point of 181-182 ° C. Elemental analysis value: as C ₁₀ H ₁₁ N ₅ O ₃ S theoretical value: C: 42.70; H: 3.94; N: 2
4.90 Found: C: 42.71; H: 3.80; N: 2
4.70

Reference Example 13 6- (2-trifluoroacetylaminoethylthio)-
3-nitroimidazo [1,2-b] pyridazine

Embedded image The oily compound (0.7 g) obtained in Reference 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, the same operation as in Reference Example 12 was performed to obtain 0.8 g of colorless crystals having a melting point of 171-172 ° C. Elemental _{analysis: C 10 H 8 F 3 N} 5 O 3 S and a theoretical: C: 35.83; H: 2.40 ; N: 2
0.89 found: C: 36.19; H: 2.59; N: 2.
0.60

Reference Example 14 6- [2- (N-methyl-N-trifluoroacetylamino) ethylthio] -3-nitroimidazo [1,2-
b] pyridazine

Embedded image Sodium hydride (60% in oil, 60 mg) was added to a solution of the compound (0.2 g) obtained in Reference Example 13 and iodomethane (0.4 g) in tetrahydrofuran (6 ml).
The mixture was stirred at 0-50 ° C for 30 minutes. Add water (30 ml),
Extracted with ethyl acetate (20 ml), washed with water, separated and purified by silica gel column chromatography, melting point 1
0.07 g of colorless crystals of 11-112 ° C was obtained. Elemental _{analysis: C 11 H 10 F 3 N} 5 O 3 S and a theoretical: C: 37.83; H: 2.89 ; N: 2
0.05 Found: C: 37.69; H: 2.96; N: 2
0.11

Reference Example 15 6-[(2-trifluoroacetylamino-1,1-dimethyl) ethylthio] -3-nitroimidazo [1,2-
b] pyridazine

Embedded image Using 6-chloro-3-nitroimidazo [1,2-b] pyridazine (0.5 g) and (2-amino-1,1-dimethyl) ethyl mercaptan (0.37 g), Reference Examples 12, 1
By the same operation as in Example 3, 0.27 g of colorless crystals having a melting point of 184-185 ° C. were obtained. Elemental analysis value: C ₁₂ H ₁₂ F ₃ N ₅ O ₃ S theoretical value: C: 39.67; H: 3.33; N: 1
9.28 Found: C: 39.89; H: 3.48; N: 1.
9.16

Reference Example 16 6-[[2- (N-trifluoroacetyl-N-methyl) amino-1,1-dimethyl] ethylthio] -3-nitroimidazo [1,2-b] pyridazine

Embedded image The compound (0.1 g) obtained in Reference Example 15 was subjected to the same operation as in Reference Example 14 to give colorless crystals having a melting point of 171 to 172 ° C.
08 g were obtained. Elemental _{analysis: C 13 H 14 F 3 N} 5 O 3 S and a theoretical: C: 41.38; H: 3.74 ; N: 1
8.56 Found: C: 41.57; H: 3.83; N: 1
8.40

Reference Example 17 By the same procedure as in Reference Example 1, the compounds shown in [Table 4] and [Table 5] were obtained.

[0072]

[Table 4]

[Table 5]

Reference Example 18 6-[(2R)-(2-trifluoroacetylamino)
Propyl] oxy-3-nitroimidazo [1,2-b]
Pyridazine (Compound B)

Embedded image A solution of 6-chloro-3-nitroimidazo [1,2-b] pyridazine (2.2 g) and (R) -alaninol (1.0 g) in tetrahydrofuran (20 ml) was added to sodium hydride (60 ml) with stirring at room temperature. % In oil, 0.60 g) was added and the mixture was stirred at room temperature for 2 hours. Thereafter, anhydrous trifluoroacetic acid (2.0 ml) was added, the mixture was stirred at room temperature for 5 minutes, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer is dried over anhydrous magnesium sulfate,
The solvent was removed, and the residue was recrystallized from isopropyl ether / acetic acid ethyl ester to obtain 1.31 g of pale yellow crystals having a melting point of 127-128 ° C. Elemental analysis value: C ₁₁ H ₁₀ F ₃ N ₅ O ₄ Theoretical value: C: 39.65; H: 3.02; N: 2
1.02 found: C: 39.84; H: 2.71; N: 2
0.75

Reference Example 19 By the same procedure as in Reference Example 18, the compounds shown in [Table 6] were obtained.

[0075]

[Table 6]

Reference Example 20 The compounds obtained in Reference Examples 18 and 19 were used as Reference Example 1
By the same operation as in 4, the compounds shown in [Table 7] were obtained.

[0077]

[Table 7]

Reference Example 21 6-[(2R)-(2-trifluorothioacetylamino) propyl] oxy-3-nitroimidazo [1,2-
b] pyridazine

Embedded image Toluene solution (15 ml) of the compound (0.3 g) obtained in Reference Example 18 and Lawesson's reagent (0.45 g) was heated to 100 ° C. for 3 days.
After heating and stirring for an hour, the solvent was removed, and the residue was separated and purified by silica gel column chromatography to give a melting point of 106-
0.24 g of yellow crystals at 108 ° C. were obtained. Elemental _{analysis: C 11 H 10 F 3 N} 5 O 3 S and a theoretical: C: 37.83; H: 2.89 ; N: 2
0.05 Found: C: 37.75; H: 2.97; N: 1
9.78

Reference Example 22 6- (2-Methoxycarbonylaminopropyl) oxy-3-nitroimidazo [1,2-b] pyridazine

Embedded image Alaninol (0.5g) in tetrahydrofuran (20m
l) solution with sodium hydride (6
0% in oil, 0.30 g) was added and the mixture was stirred at room temperature for 2 hours. Then add methoxycarbonyl chloride (2.0 ml), stir for 5 minutes at room temperature, then add ethyl acetate.
It was washed with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was recrystallized from isopropyl ether / ethyl acetate to obtain 0.32 g of colorless crystals with a melting point of 206-207 ° C.

Reference Example 23 By the same procedure as in Reference Example 21, the compounds shown in [Table 8] were obtained.

[Table 8]

Reference Example 24 6-[(2R) -2- (N-ethyl-N-trifluoroacetylamino) propyl] oxy-3-nitroimidazo [1,2-b] pyridazine

Embedded image Sodium hydride (60% in oil, 80 mg) was added to a solution of the compound (0.5 g) obtained in Reference Example 18 and ethyl iodide (0.5 ml) in tetrahydrofuran (20 ml), and the mixture was stirred at 70 ° C for 6 hours. did. Water (30 ml) was added, the mixture was extracted with ethyl acetate (20 ml), washed with water, and then purified by silica gel column chromatography to give a melting point of 79.
0.24 g of colorless crystals at -80 ° C were obtained. Elemental _{analysis: C 13 H 14 F 3 N} 5 O 4 as a theoretical value: C: 43.22; H: 3.91 ; N: 1
9.38 Found: C: 42.98; H: 3.69; N: 1.
9.29

Reference Example 25 6-[(2R) -2- (N-benzyl-N-trifluoroacetylamino) propyl] oxy-3-nitroimidazo [1,2-b] pyridazine

Embedded image In a solution of the compound (0.5 g) obtained in Reference Example 18 and benzyl bromide (0.3 g) in tetrahydrofuran (20 ml),
Sodium hydride (60% in oil, 100 mg) was added, and the mixture was stirred at 70 ° C for 15 hr. Add water (30 ml),
Extracted with ethyl acetate (20 ml), washed with water, separated and purified by silica gel column chromatography, melting point 1
0.14 g of colorless crystals at 05-106 ° C were obtained. Elemental _{analysis: C 18 H 16 F 3 N} 5 O 4 as a theoretical value: C: 51.07; H: 3.81 ; N: 1
6.54 Found: C: 51.13; H: 3.82; N: 1.
6.29

Reference Example 26 6-[(2R) -2- (N-propyl-N-trifluoroacetylamino) propyl] -3-nitroimidazo [1,2-b] pyridazine

Embedded image A solution of 6-chloro-3-nitroimidazo [1,2-b] pyridazine (5.0 g) and R-alaninol (2.2 g) in tetrahydrofuran (100 ml) was added to sodium hydride (60% in oil, 1.2g),
Stir for 2 hours at room temperature. Methanol was added, the mixture was extracted with ethyl acetate (20 ml), washed with water and dried over anhydrous magnesium sulfate to remove the solvent. The residue is crystallized with ethyl ether and filtered off. A solution of this compound (0.5 g), propionaldehyde (0.15 g) and acetic acid (0.13 g) in ethanol (15 ml) was added dropwise with a solution of sodium cyanoborohydride (0.16 g) in ethanol (2 ml). Stirred at room temperature for 1 hour. Add 1N hydrochloric acid, remove the solvent,
Aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying, the solvent was removed, the residue was dissolved in tetrahydrofuran (10 ml), and trifluoroacetic anhydride (0.3 ml) was added. The solvent was removed, the residue was dissolved in acetic acid ethyl ester (20 ml), washed with water, and then purified by silica gel column chromatography to obtain 0.17 g of colorless crystals having a melting point of 89-90 ° C. Elemental _{analysis: C 14 H 16 F 3 N} 5 O 4 as a theoretical value: C: 44.80; H: 4.30 ; N: 1
8.66 Found: C: 44.89; H: 4.19; N: 1.
8.76

Reference Example 27 By the same procedure as in Reference Example 26, the compounds shown in [Table 9] were obtained.

[Table 9]

Example 1 Preparation of Gastric Mucoadhesive Composition Containing Condensed Imidazole Derivative 6-tert-Butylthio-3-nitroimidazo [1,2-b] pyridazine (ie Compound A) Behenic Acid as Polyglycerin Fatty Acid Ester (PGEF) Hexa (tetra) glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310) (84.7 g) was weighed and melted by heating at 85 ° C. 0.3 g of Compound A, and then acrylic acid polymer (Hibiswako 104, Wako Pure Chemical Industries, Ltd.) 1
5 g was added, and the mixture was stirred at 85 ° C. for 15 minutes for dispersion. Diameter 15 with molten mixture rotating at 1860 rpm
Spherical fine granules that pass through a 30-mesh screen and do not pass through a 80-mesh screen (hereinafter abbreviated as 30/80 mesh) are obtained by dripping at a rate of 10 g / min onto an aluminum disc of cm. Was given.

Example 2 Production of Gastric Mucoadhesive Composition Containing Compound A 84.7 g of carnauba wax (manufactured by Freund Sangyo Co., Ltd., trade name: Polishing Wax 103) was weighed as a lipid, and melted at 95 ° C. Compound A 0.3 g,
Next, 15 g of an acrylic acid polymer (Hibiswako 104, Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred and dispersed for 15 minutes while being kept at 95 ° C. 10 g of the molten mixture on a 15 cm diameter aluminum disc rotating at 1860 rpm
Spherical fine granules of 30/80 mesh were obtained by dropping at a rate of / min.

Example 3 Production of Gastric Mucoadhesive Composition Containing Compound A 84.7 g of hydrogenated castor oil (Freund Industrial Co., Ltd., trade name Labrix Wax 101) as a lipid was weighed to 95
It was melted by heating to ℃ 0.3 g of Compound A, and then an acrylic acid-based polymer (Wako Pure Chemical Industries, Ltd., Hibiswako 1
04) 15 g was added, and the mixture was stirred for 15 minutes while maintaining it at 95 ° C. to disperse it. The molten mixture was added dropwise to a 15 cm diameter aluminum disk rotating at 1860 rpm at a rate of 10 g / min to give 30/80 mesh spherical fine granules.

Example 4 Production of Gastric Mucoadhesive Composition Containing Compound A Microcrystalline wax (Nippon Seiso Wax Co., Ltd.) was used as a lipid.
Co., Ltd., trade name HI-MIC-1070) 84.7 g
Was weighed and melted by heating at 95 ° C. Compound A 0.
3 g, and then 15 g of an acrylic acid-based polymer (Hibiswako 104, Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 95 ° C. for 15 minutes for dispersion. Melt mixture at 1860 rpm
Spherical fine granules of 30/80 mesh were obtained by dropping at a rate of 10 g / min on an aluminum disc having a diameter of 15 cm and rotating.

Example 5 Production of Gastric Mucoadhesive Composition Containing Compound A Carnauba wax (manufactured by Freund Sangyo Co., Ltd., trade name: Polishing Wax 103) 69.7 g was weighed and heated to 95 ° C.
Was heated and melted. 0.3 g of Compound A, and then hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical)
Co., Ltd., trade name TC-5, 10.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 10.0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., Hibisu) Wako 104) 10.
0 g was sequentially added, and the mixture was stirred at 95 ° C. for 15 minutes for dispersion. The molten mixture was added dropwise to a 15 cm diameter aluminum disk rotating at 1860 rpm at a rate of 10 g / min to give 30/80 mesh spherical fine granules.

Example 6 Production of Gastric Mucoadhesive Composition Containing Compound A 62.7 g of carnauba wax (manufactured by Freund Corporation, trade name: Polishing Wax 103) and penta (tetra) glyceride stearate (Sakamoto Yakuhin Co., Ltd., 7.0 g of trade name PS-310) was weighed and melted by heating at 95 ° C. Compound A 0.3 g, followed by hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-5) 10.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 10. 0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., Hibiswako 104) 10.0 g
Were sequentially added, and the mixture was stirred at 15 ° C. for 15 minutes to disperse. Diameter 15 with molten mixture rotating at 1860 rpm
A 30/80 mesh spherical fine granules were obtained by dropping onto a cm aluminum disc at a rate of 10 g / min.

Example 7 Preparation of Gastric Mucoadhesive Composition Containing Compound A 90.0 g of hexa (penta) glyceride oleic acid (Sakamoto Yakuhin Co., Ltd., trade name PO-500) was weighed as polyglycerin fatty acid ester (PGEF). did. 0.3 g of Compound A, and then acrylic acid polymer (Wako Pure Chemical Industries, Ltd.
Hibiswako 104) (10.0 g) and added 3
The mixture was stirred for 0 minutes and dispersed to obtain a mucoadhesive liquid composition.

Example 8 Preparation of Gastric Mucoadhesive Composition Containing Compound A 90.0 g of oleic acid tetra (penta) glyceride (Sakamoto Yakuhin Co., Ltd., trade name PO-310) was prepared as polyglycerin fatty acid ester (PGEF). A 0.3g,
Then hydroxypropyl methylcellulose 2910
(Shin-Etsu Chemical Co., Ltd., trade name TC-5) 10.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 10.0 g,
Acrylic acid polymer (Wako Pure Chemical Industries, Ltd., Hibiswako
104) 10.0 g was sequentially added, and the mixture was stirred and dispersed for 30 minutes to obtain a mucoadhesive liquid composition.

Example 9 Production of Gastric Mucoadhesive Formulation Containing Compound B Carnauba wax (Freund Sangyo Co., Ltd., trade name Polishing Wax 103) 66 g and stearic acid penta (tetra) glyceride (Sakamoto Yakuhin Co., Ltd., trade name)
7.0 g of PS-310) was heated and melted at 95 ° C. Compound B (0.3 g) and then hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-
5) 8.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name: hydroxypropyl cellulose H type) 8.0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 10. 0 g was sequentially added, and the mixture was stirred at 95 ° C. for 15 minutes for dispersion. Diameter 15 with molten mixture rotating at 1860 rpm
A 30/80 mesh spherical fine granules were obtained by dropping it on a cm aluminum disk at a rate of 10 g / min.

Example 10 Production of Gastric Mucoadhesive Preparation Containing Compound B 66 g of hydrogenated rapeseed oil (Freund Sangyo Co., Ltd., trade name Lubriwax-103) and penta (tetra) glyceride stearate (Sakamoto Yakuhin Co., Ltd., trade name) Name PS-
310) 7.0 g was melted by heating to 90 ° C. Compound B (0.3 g) and then hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-5) 8.
0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 8.0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd.),
10.0 g of trade name Hibiswako 104) was sequentially added, and the mixture was stirred at 90 ° C. for 15 minutes for dispersion. 3 by dripping the molten mixture at a speed of 10 g / min onto a 15 cm diameter aluminum disc rotating at 1860 rpm.
A 0/80 mesh spherical fine granule was obtained.

Example 11 Production of Gastric Mucoadhesive Formulation Containing Compound B 60 g of hydrogenated castor oil (Freund Sangyo Co., Ltd., trade name Lubri Wax-101) and penta (tetra) glyceride stearate (Sakamoto Yakuhin Co., Ltd., trade name) Name PS-
310) 10.0 g was melted by heating to 95 ° C. Compound B (0.3 g) and then hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-5) 1
0.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name Hydroxypropyl cellulose H type) 10.0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 10.0 g Sequentially added, the mixture was stirred at 15O <0> C for 15 minutes for dispersion. Diameter 15 with molten mixture rotating at 1860 rpm
A 30/80 mesh spherical fine granules were obtained by dropping it on a cm aluminum disk at a rate of 10 g / min.

Example 12 Production of Gastric Mucoadhesive Formulation Containing Compound B 60 g of Microcrystalline Wax 1070 (Nippon Seiwa Co., Ltd., trade name HI-MIC-1070) and penta (tetra) glyceride stearate (Sakamoto Yakuhin Co., Ltd. ), 10.0 g of trade name PS-310) was melted by heating to 95 ° C. Compound B (0.3 g), followed by hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-5) 10.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 10.0 g Then, 10.0 g of an acrylic acid-based polymer (trade name: Hibiswako 104, Wako Pure Chemical Industries, Ltd.) was sequentially added, and the mixture was stirred at 95 ° C. for 15 minutes for dispersion. Melt mixture at 1860 rpm
10g on a 15cm diameter aluminum disk rotating at
Spherical fine granules of 30/80 mesh were obtained by dropping at a rate of / min.

Example 13 Production of Compound B-Containing Gastric Mucoadhesive Preparation 85.0 g of hexa (tetra) glyceride behenate (Sakamoto Yakuhin Co., Ltd., trade name HB-310) was heated and melted at 85 ° C. Compound B 0.3 g, followed by hydroxypropylmethyl cellulose 2910 (Shin-Etsu Chemical Co., Ltd., trade name TC-5) 5.0 g, hydroxypropyl cellulose (Nippon Soda Co., Ltd., trade name hydroxypropyl cellulose H type) 5.0 g. , 5.0 g of an acrylic acid-based polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) were sequentially added, and the mixture was stirred at 85 ° C. for 15 minutes for dispersion. 30/80 mesh spherical fine granules were obtained by dropping the molten mixture at a rate of 10 g / min onto a 15 cm diameter aluminum disk rotating at 1860 rpm.

Example 14 Production of Gastric Mucoadhesive Formulation Containing Compound B 70 g of hydrogenated castor oil (Freund Industrial Co., Ltd., trade name Lubriwax-101) and hexa (tetra) behenate
Glyceride (Sakamoto Yakuhin Co., Ltd., trade name HB-310)
10.0 g was melted by heating to 95 ° C., and Compound B 10.0
g, 10.0 g of an acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104), and 95 ° C
The mixture was kept for 15 minutes and stirred to disperse. 2 for the molten mixture
30/80 by dropping at a rate of 10 g / min on an aluminum disc with a diameter of 15 cm rotating at 400 rpm.
A spherical fine granule of mesh was obtained.

Example 15 Production of Gastric Mucoadhesive Formulation Containing Compound B Carnauba wax (Freund Sangyo Co., Ltd., trade name Polishing Wax 103) 70.0 was heated and melted at 95 ° C. to give Compound B 15.0 g, acrylic acid system Polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 1
5.0 g was added, and the mixture was stirred for 15 minutes while maintaining the temperature at 95 ° C. to disperse. The molten mixture was added dropwise to a 15 cm diameter aluminum disk rotating at 2400 rpm at a rate of 10 g / min to give 30/80 mesh spherical fine granules.

Example 16 Production of Gastric Mucoadhesive Formulation Containing Compound B 70.0 g of hydrogenated castor oil (Freund Industrial Co., Ltd., trade name Lubri Wax 101) was heated and melted at 95 ° C.,
Compound B 10.0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 20.0
g was added, and the mixture was stirred at 95 ° C. for 15 minutes to disperse. Diameter 1 of the molten mixture rotating at 2400 rpm
A 30/80 mesh spherical fine granules were obtained by dropping onto a 5 cm aluminum disc at a rate of 10 g / min.

Example 17 Production of Gastric Mucoadhesive Formulation Containing Compound B 60.0 g of hydrogenated castor oil (Freund Industrial Co., Ltd., trade name Labrix Wax 101) was heated and melted at 95 ° C.,
Compound B 30.0 g, acrylic acid-based polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 10.0
g was added, and the mixture was stirred at 95 ° C. for 15 minutes to disperse. Diameter 1 of the molten mixture rotating at 2400 rpm
A 30/80 mesh spherical fine granules were obtained by dropping onto a 5 cm aluminum disc at a rate of 10 g / min.

Example 18 Production of Gastric Mucoadhesive Formulation Containing Compound B 60.0 g of Microcrystalline Wax (Nippon Seiwa Co., Ltd., trade name HI-MIC-1070) was heated and melted at 95 ° C. to give Compound B 30. 0 g, acrylic acid polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 10)
4) 10.0 g was added, and the mixture was stirred at 15 ° C. for 15 minutes to disperse. 10 g / mol of molten mixture on a 15 cm diameter aluminum disc rotating at 2400 rpm
A 30/80 mesh spherical fine granule was obtained by dropping at a rate of minutes.

Example 19 Production of Gastric Mucoadhesive Formulation Containing Compound B 55.0 g of hydrogenated castor oil (Freund Industrial Co., Ltd., trade name Lubri Wax 101) was heated and melted at 95 ° C.,
Compound B 40.0 g, acrylic acid type polymer (Wako Pure Chemical Industries, Ltd., trade name Hibiswako 104) 5.0 g
Was added, and the mixture was stirred at 15O <0> C for 15 minutes to disperse. Diameter 1 of the molten mixture rotating at 2400 rpm
A 30/80 mesh spherical fine granules were obtained by dropping onto a 5 cm aluminum disc at a rate of 10 g / min.

Experimental Example 1 Crj: ICR mice (5 mice per group) that had been fasted for 30 hours were orally infected with Helicobacter pylori CPY 433 (10 ^7.3 bacteria / mouse), and 13 days after the infection, under feeding,
The compound A-containing mucoadhesive composition obtained in Example 5 was orally administered as Compound A in an amount of 3.0 mg / kg.
Twenty-four hours after administration, the stomach was excised, the crushed stomach wall was inoculated into a selective separation medium, and the cells were cultured under microaerobic conditions for 4 days, and the viable cell count was measured to determine the eradication rate (negative mouse / all mice). . as a result,
The mucoadhesive composition containing Compound A showed excellent anti-Helicobacter pylori activity with a sterilization rate of 80%.

Experimental Example 2 In the same manner as in Experimental Example 1, the compound A-containing mucoadhesive composition obtained in Example 6 under feeding was used as Compound A.3.
Oral administration was performed so that the concentration would be 0 mg / kg. Twenty-four hours after administration, the stomach was excised, the crushed stomach wall was inoculated into a selective separation medium, and the cells were cultured under microaerobic conditions for 4 days, and the viable cell count was measured to determine the eradication rate (negative mouse / all mice). . As a result, the compound A-containing mucoadhesive composition exhibited excellent anti-Helicobacter pylori activity with a sterilization rate of 75%.

Experimental Example 3 Crj: ICR mice fasted for 30 hours (4 mice per group) were orally infected with Helicobacter pylori CPY 433 (10 ^7.3 bacteria / mouse), and 13 days after feeding, in Example 9 under feeding. The obtained gastric mucosa-adhesive composition containing Compound B was orally administered as Compound B in an amount of 3.0 mg / kg. As a control experiment, a gastric mucoadhesive preparation (control) containing no compound B obtained in Control Example 1 below was orally administered. Twenty-four hours after administration, the stomach was excised, the crushed stomach wall was inoculated into a selective separation medium, and the cells were cultured under microaerobic conditions for 4 days, and the viable cell count was measured to determine the eradication rate (negative mouse / all mice). . As a result, no HP-negative was observed at all in the control administration group, whereas 3 out of 4 animals administered with the compound B-containing gastric mucoadhesive composition became HP-negative and excellent anti-HP with a sterilization rate of 75%. Showed action. Control Example 1 A gastric mucoadhesive preparation was produced in the same manner as in Example 9 except that Compound B was not included for use as a control.

Experimental Example 4 Crj: ICR mice fasted for 30 hours (1 group 3-5)
Orally infected with Helicobacter pylori TN2 (10 ^7.3 bacteria / mouse), and after 13 days under feeding Example 9
The compound B-containing gastric mucoadhesive preparation obtained in 1. was orally administered twice a day for 7 days so that the dose of Compound B was 3.0 and 1.0 mg / kg, respectively. As a control experiment, the gastric mucoadhesive preparation (control) containing no compound B obtained in Control Example 1 was orally administered every day in the same manner. 17 hours after the final administration, the stomach was excised, the crushed stomach wall was inoculated into the selective separation medium, and after culturing for 4 days under microaerobic condition,
The viable cell count was measured to determine the eradication rate (negative mouse / all mice). As a result, no HP negative was observed in the control administration group. On the other hand, of the group administered with the compound B-containing gastric mucoadhesive composition, 1 out of 4 animals at a dose of 0.3 mg / kg
The animals became HP negative and the eradication rate was 25%, 1.0 mg / k
In g, all cases became HP negative and showed a eradication rate of 100%.

[0108]

EFFECTS OF THE INVENTION The gastric mucoadhesive composition of the present invention has a remarkable effect on eradication of Helicobacter pylori at a very low concentration over a long period of time with almost no side effects, and has a gastrointestinal disease such as gastritis or digestibility. It is effective in treating ulcers.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/50 ADZ A61K 31/50 ADZ 31/505 ACJ 31/505 ACJ 31/53 31/53 31 / 535 31/535 31/54 31/54 47/32 47/32 Z 47/34 47/34 B 47/38 47/38 Z 47/44 47/44 B C07D 471/04 108 C07D 471/04 108A 108X 487/04 144 487/04 144 498/04 513/04 375 513/04 375 498/04 112Q

Claims (29)

[Claims] 1. General formula (I): A gastric mucoadhesive composition containing a condensed imidazole derivative represented by: or a salt thereof. 2. The composition according to claim 1, which contains a matrix composed of a polyglycerin fatty acid ester and / or a lipid. 3. The composition according to claim 2, wherein the condensed imidazole derivative or a salt thereof is contained in the matrix. 4. A substance containing a substance which causes viscosity in water.
A composition as described. 5. A composition according to claim 2, wherein a substance which causes viscosity with water is contained in the matrix. 6. A composition according to claim 2, wherein the matrix is coated with a water-viscosifying substance. 7. A polyglycerin fatty acid ester having a degree of polymerization of 2
The composition according to claim 2, which is an ester of polyglycerin having 20 to 20 and a fatty acid having 12 to 22 carbon atoms. 8. The composition according to claim 2, wherein the polyglycerin fatty acid ester has a molecular weight of about 200 to about 5,000. 9. The composition of claim 2 wherein the polyglycerin fatty acid ester has a melting point of about 15 ° C to about 80 ° C. 10. A polyglycerin fatty acid ester is behenic acid hexa (tetra) glyceride, stearic acid penta (tetra) glyceride, stearic acid mono (penta) glyceride, stearic acid penta (hexa) glyceride,
The composition according to claim 2, which is sesqui (hexa) glyceride stearate or mono (deca) glyceride stearate. 11. The composition according to claim 2, wherein the polyglycerin fatty acid ester is a mixture of at least two selected from the polyglycerin fatty acid ester according to claim 10. 12. Lipids are oils and fats or hydrogenated oils thereof, waxes,
The composition according to claim 2, which is a higher saturated fatty acid, a higher alcohol or a hydrocarbon. 13. The composition of claim 2 wherein the melting point of the lipid is from about 40 ° C to about 120 ° C. 14. A lipid comprising carnauba wax, hydrogenated oil and / or
The composition according to claim 2, which is also a microcrystalline wax. 15. The composition of claim 2 in which the matrix comprises carnauba wax. 16. The composition of claim 2 in which the matrix comprises carnauba wax and penta (tetra) glyceride stearate. 17. The composition according to claim 4, wherein the water-viscosity generating substance is a polymer. 18. The composition according to claim 4, wherein the water-viscosity generating substance is an acidic polymer. 19. The composition according to claim 4, wherein the substance that causes viscosity with water is an acrylic acid polymer or a salt thereof. 20. The composition according to claim 4, wherein the water-viscosity generating substance is a cellulosic polymer. 21. The composition according to claim 19, wherein the acrylic acid polymer has a molecular weight of about 200,000 to about 6 million. 22. The molecular weight of the acrylic acid polymer is about 100.
20. The composition of claim 19, which is between about 10 and about 5 million. 23. The composition according to claim 1, wherein the hydrocarbon group is a C _1-10 alkyl group. 24. The condensed imidazolyl group has 2 to 4 nitrogen atoms as hetero atoms constituting a ring.
A composition as described. 25. The general formula (I ′): (Wherein A is a fused imidazolyl group having at least one nitro group on the imidazole ring, R ′ is a hydrocarbon group having a substituent, and n is an integer of 0 to 2) A gastric mucoadhesive composition containing a derivative or a salt thereof. 26. The condensed imidazolyl group has 2 to 4 nitrogen atoms as hetero atoms constituting the ring.
The composition according to 5. 27. The fused imidazolyl group is imidazole and 6
26. The composition according to claim 25, which is a group condensed with a membered aromatic heterocyclic group. 28. A is 26. The composition of claim 25 which is 29. The composition according to claim 1, which is an anti-Helicobacter pylori agent.