JP2000212180A - Quinoline compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an anti-ulcer agent having a selective strong antibacterial activity against Helicobacter pylori and having few side effects, or an agent for preventing ulcer relapse relapse. SOLUTION: 2-Methyl-4-((3-methyl-4-
A pyridine compound exemplified by (2- (2- (2,2,2-trifluoroethoxy) ethoxy) ethoxy) -2-pyridyl) methoxy) quinoline or a pharmaceutically acceptable salt thereof solves the above problems. Was found.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel quinoline compound or a pharmaceutically acceptable salt thereof which has an excellent antibacterial activity selectively against Helicobacter pylori.

[0002]

2. Description of the Related Art Helicobacter pylori
pylori: H. pylori)
A Gram-negative bacterium isolated from the gastric mucosa of patients with active chronic gastritis (Warren, JR & Marshall BJ Lancet i
: 1273-1275, 1983). The bacterium is isolated at a higher rate than gastric and duodenal ulcer patients, and exhibits evidence of active gastritis evident from infection experiments with human volunteers (Morri
s, A. & Nicholoson G. Am. J. Gastroenterology 82
: 192-199 1987), and experimental animals infected with H. pylori also show symptoms of gastritis similar to humans. Recently, it has also been attracting attention as an important risk factor for gastric cancer (Parsonnet J. et al. N. Eng. J. Med.
325: 1127-1131, 1991).

Although the pathogenesis of gastric and duodenal ulcers caused by H. pylori has not been elucidated, it is thought that cytotoxicity of the background gastric mucosa caused by infection with this bacterium is one of the causes. Factors and the host's immune response are being examined. As a factor on the bacterial side, the cytotoxicity of ammonia caused by urease produced by the bacteria (Hazell SL,
Lee A. Lancet ii: 15-17, 1986), as well as a decrease in the ability of proteases and lipases to protect against aggressive factors due to degradation of the mucus layer (Sarosiek J. Slomiany A. & Slomiany B.
L. Scand. J. Gastroenterol. 23: 585-590, 1988),
Direct cytotoxicity by vacuolated cytotoxin (VacA Cag A) is known (Figura N. Guglielmetti
O., Rossolini A. et al. J. Clin Microbiol. 27:22
5 1989CoverT.L.Dooley CP & Blaser MJ Infect
ion and Immunity 58: 6031990 Cover TL & Blase
r MJJ Biol. Chem. 267: 10570, 1992). On the other hand, H. p
The fact that ylori infection stimulates the host immune system means that serum induces specific antibodies against H. pylori pathogens, and that H. pylori-infected gastric mucosa has inflammation such as polynuclear leukocytes, macrophages, and lymphocytes. It is clear from the infiltration of cells. Recently, remarkable enhancement of interleukin-8 production was observed in H. pylori-infected gastric mucosa,
It has been reported to migrate and activate polynuclear leukocytes (C
rabtree J.E.Wyatt JI Trejdosiewics LK et al.
J. Clin. Pathol. 47:61 1994). As described above, H. p
The pathogenesis of gastric mucosal injury caused by ylori infection is thought to be linked to the harmful factors of the bacteria and the immune response induced by persistent infection.

In recent years, the treatment of gastric and duodenal ulcers has made remarkable progress. However, there is a problem that recurrence is likely to occur due to reduction or discontinuation of the drug, and drug-resistant intractable ulcer disease. As the involvement of H. pylori in gastric and duodenal diseases has been pointed out, attempts to eradicate H. pylori by administering drugs that have antibacterial activity have been considered.
(Chiba N. et al. Am. J. Gastroenterology 87: 1716
-1727, 1992).

[0005] The fact that the elimination of H. pylori significantly suppresses the relapse and recurrence of peptic ulcers supports the relationship between the two.
ylori-positive peptic ulcers, regardless of their onset or recurrence, should be eradicated by using a gastric acid secretion inhibitor in combination with an antibacterial agent. "
The IH's unified opinion was issued. Recently, this bacterium has been set as Group 1 (reliable carcinogen) of WHO carcinogen classification as a cause of pathological conditions leading to gastric cancer development, and the relationship between the two has been widely recognized. In addition, it has been reported that the recurrence of gastric cancer was suppressed in patients who underwent gastrectomy for gastric cancer.

As for the antibacterial activity against H. pylori, amoxicillin and clarithromycin show good activity among the antibacterial agents. Although weak antibacterial activity is observed with proton pump inhibitors such as omeprazole, it is not observed with H2 receptor antagonists such as cimetidine and famotidine. However, the clinical effect of a drug exhibiting such antibacterial activity is weak when administered alone.

[0007] Against this background, eradication therapy has been energetically studied at present, but many problems still remain to establish complete eradication therapy. For example, classic triple therapy, which uses bismuth in combination with two antibacterial agents, has been studied mainly in Europe and the United States because of its high eradication effect.However, side effects such as diarrhea and central toxicity occur at a high rate. Bismuth has problems such as not being approved as an anti-ulcer agent in Japan. A treatment method with fewer side effects than this eradication method has been studied. Dual therapy using one antibacterial agent (such as amoxicillin or clarithromycin) in combination with a gastric acid secretion inhibitor, and two agents (amoxicillin, clarithromycin, or nitroimidazole) New triple therapy in combination with any two of the antibacterial agents) has been attempted. With dual therapy, the incidence of side effects is low,
The rate of eradication is lower than that of classical triple therapy. Amoxicillin cannot be used in patients with penicillin allergy. The failure rate of clarithromycin increases the rate of emergence of resistant bacteria.
Has a high disinfecting effect, but the problem is that the incidence of side effects is high. In any of these eradication methods, since a large amount of an antibacterial agent having antibacterial activity is used for bacteria other than H. pylori, it affects the intestinal bacteria and increases the incidence of diarrhea. Furthermore, it has been known that oral candidiasis and the like occur due to the effect on bacteria resident in the oral cavity in some patients, and a safe and reliable eradication method has not yet been established.

However, there are many reports describing the usefulness of eradication of H. pylori, and there is a consensus that the eradication healed intractable ulcers and suppressed the recurrence of ulcers.

[0009]

In view of the above points, there is a demand for an anti-ulcer agent having selective antibacterial activity against H. pylori and having few side effects. Needless to say, from the viewpoint of ulcer healing, a drug having both an antibacterial activity against H. pylori and a gastric acid inhibitory activity is more desirable.

Benzimidazole compounds having antibacterial activity against H. pylori are disclosed in JP-A-2-209809, JP-A-3-38523, and JP-A-3-4868.
0, JP-A-3-52887, JP-A-3-5
No. 2812, Japanese Patent Application Laid-Open No. H6-110049, International Publication WO92 / 12976, International Publication WO93 /
No. 24480, International Publication WO 95/11897, International Publication WO 95/34554,
-87629, International Publication WO98 / 04529, International Publication WO94 / 10164, and the like.

On the other hand, Japanese Patent Application Laid-Open No. 62-209 discloses that certain quinoline compounds are useful as agents for preventing and treating gastric diseases.
No. 062. However, it is not known that these compounds have an excellent antibacterial activity selective for H. pylori. Therefore, creation of a novel compound which is selective for H. pylori and has excellent antibacterial activity is desired.

[0012]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted various studies and found that H.py
The present inventors have found that the present invention has a selective and excellent antibacterial action against lori, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (I)

[0014]

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[Wherein R1 is hydrogen, halogen, nitro,
Represents cyano, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl. R2 represents hydrogen, alkyl, haloalkyl, acyloxyalkyl, alkoxyalkyl or hydroxyalkyl. R3 and R4 are the same or different and each represent hydrogen, halogen, or alkyl. X is O, S, S
O and SO ₂ are shown. B is O, S, SO, SO ₂ , NR5
Is shown. (In the formula, R5 represents hydrogen, alkyl, or acyl.) When D is D1-E, D1 represents a single bond, alkylene, alkylene having a substituent, or alkylene having oxo. E
Is an alkoxyalkyl, haloalkoxyalkyl, formula (a)

[0016]

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(Wherein R6 and R7 are the same or different and each has hydrogen, alkyl, cycloalkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoyl, mono-dialkylcarbamoyl, Phenylcarbamoyl, thiocarbamoyl, mono-dialkylthiocarbamoyl, phenylthiocarbamoyl which may have a substituent, phenylalkylcarbamoyl which may have a substituent, Phenylalkylthiocarbamoyl,
Represents phenyl which may have a substituent, aralkyl which may have a substituent or heteroarylalkyl which may have a substituent, or R6 and R7 are bonded and condensed with an adjacent nitrogen atom; May be formed, and the heterocyclic ring may have a substituent. )
Or equation (b)

[0018]

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(Wherein R8 is hydrogen, alkyl, acyl,
Carboxyalkyl, aralkyl which may have a substituent, Y represents methylene, O, S, SO, SO ₂ , and l and m each represent an integer of 0, 1-3. ) Is shown. When D is (LO) p- (MO) q-D2, L and M each have 2 to 1 carbon atoms which may have a substituent.
Represents 0 alkylene or vinylene, and p is 1 to 10
Represents an integer of 00, and q represents an integer of 0 to 1000. D
2 is hydrogen, alkyl, cycloalkyl, haloalkyl,
Phenyl which may have a substituent, aralkyl which may have a substituent, heteroarylalkyl which may have a substituent, or formula (c)

[0020]

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(Wherein G represents an alkylene which may have a substituent, and R6 and R7 are as defined above) or a pharmaceutically acceptable salt thereof.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION Specific examples of each group in the general formula (I) are as follows. In R1, examples of the halogen include chlorine, fluorine, bromine and iodine. Examples of the alkyl include alkyl having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl, decyl, dodecyl, octadecyl, and eicoisyl. 1-5 alkyl,
Particularly preferred is alkyl having 1 to 3 carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,
Pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, alkoxy having 1 to 20 carbons such as eicosyloxy are exemplified, preferably alkoxy having 1 to 5 carbons,
Particularly preferred is alkoxy having 1 to 3 carbon atoms. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl , Octadecyloxycarbonyl, eicosyloxycarbonyl and the like. Haloalkyl as trifluoromethyl, difluoromethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,3,3-trifluoropropyl, 1,1,
2,2-tetrafluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3
3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, hexafluoroisopropyl, 2,2,3,3,4,4,4
Examples thereof include haloalkyl having 1 to 10 carbon atoms such as -heptafluorobutyl, 2-chloroethyl, 3-chloropropyl, 2-bromoethyl, and 3-bromopropyl, preferably haloalkyl having 1 to 5 carbon atoms, and particularly preferably haloalkyl having 1 to 5 carbon atoms. 1
~ 3 haloalkyl. R1 is preferably hydrogen.

In R2, acyloxyalkyl means acetyloxymethyl, propionyloxymethyl,
Alkanoyloxyalkyl such as 2-acetyloxyethyl, 3-acetyloxypropyl, and 4-acetyloxybutyl, or benzoyloxymethyl, 2-benzoyloxyethyl, and a phenyl group containing halogen, alkyl, alkoxy, haloalkyl, hydroxy, nitro,
And benzoyloxyalkyl such as benzoyloxymethyl and 2-benzoyloxyethyl having 1 to 3 substituents selected from amino. Alkoxyalkyl is methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 2-ethoxyethyl,
Examples thereof include those in which alkoxy having 1 to 10 carbon atoms is bonded to alkyl having 1 to 10 carbon atoms, such as 3-ethoxybutyl. Hydroxyalkyl refers to hydroxyalkyl having 1 to 5 carbon atoms such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and 4-hydroxybutyl. Examples of the alkyl and haloalkyl are the same as those described above. R2 is preferably hydrogen or methyl, and particularly preferably methyl.

In R3 and R4, examples of the halogen and alkyl are the same as those described above. R3 is preferably 3-methyl, and R4 is preferably hydrogen.

R 5 in B is hydrogen, alkyl,
Acyl is exemplified. Examples of the alkyl include the same as those described above. Acyl includes alkanoyl or benzoyl having 1 to 5 carbon atoms such as acetyl, propionyl, isopropionyl, butyryl, pivaloyl, valeryl and the like.

Examples of the alkylene in D1 include alkylenes having 1 to 10 carbon atoms such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, and decamethylene. Examples of the substituent of the alkylene having a substituent include hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, carboxyl, carbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, Propylcarbamoyl, dipropylcarbamoyl and the like. The alkylene having oxo -CH ₂ CO -, - CH _{2
CH 2 CO -, - CH 2} CH 2 CH 2 CO -, - CH 2
Such as CH ₂ CH ₂ CH ₂ CO- and the like.

Examples of the alkoxyalkyl for E are the same as those described above. Haloalkoxyalkyl includes trifluoromethoxy, difluoromethoxy,
2-fluoroethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy, 2,3,3-trifluoropropoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy, 2,2 3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, hexafluoroisopropoxy, 2,2,3,3,4,4,4-heptafluorobutoxy, A haloalkoxyalkyl in which a haloalkoxy having 1 to 10 carbon atoms such as -chloroethoxy, 3-chloropropoxy, 2-bromoethoxy, or 3-bromopropoxy is substituted with an alkyl having 1 to 6 carbon atoms; Preferably, it is haloalkoxyalkyl substituted with haloalkoxy having 1 to 5 carbon atoms, particularly haloalkoxyalkyl substituted with haloalkoxy having 1 to 3 carbon atoms.

Examples of the alkyl, acyl, alkoxycarbonyl and hydroxyalkyl in R6 and R7 are the same as those described above. Phenyl which may have a substituent, aralkyl which may have a substituent, phenylcarbamoyl which may have a substituent, phenylthiocarbamoyl which may have a substituent, As the substituents of phenylalkylcarbamoyl which may have, phenylalkylthiocarbamoyl which may have a substituent or heteroarylalkyl which may have a substituent, halogen, alkyl,
There may be mentioned 1 to 3 groups selected from alkoxy, haloalkyl, hydroxy, nitro and amino. Cycloalkyl is a compound having 3 to 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
7 represents cycloalkyl. The phenylalkylcarbamoyl which may have a substituent is the aralkyl which may have a substituent substituted by carbamoyl, and is benzylcarbamoyl, 1-phenylethylcarbamoyl, 2-phenylethylcarbamoyl, 3-phenylpropylcarbamoyl, 4-phenylbutylcarbamoyl, 6-phenylhexylcarbamoyl, 8-phenyloctylcarbamoyl and the like are shown. The phenylalkylthiocarbamoyl which may have a substituent is the aralkyl which may have a substituent substituted by thiocarbamoyl, and is benzylthiocarbamoyl, 1-phenylethylthiocarbamoyl, 2-phenyl Ethylthiocarbamoyl, 3-phenylpropylthiocarbamoyl, 4-phenylbutylthiocarbamoyl,
And 6-phenylhexylthiocarbamoyl, 8-phenyloctylthiocarbamoyl and the like. The heteroarylalkyl which may have a substituent refers to an alkyl having 1 to 4 carbon atoms substituted by a heteroaryl such as furyl, thienyl, pyridyl, pyrimidyl, etc.
-Thenyl, 3-thenyl, furfuryl, 3-furylmethyl, 2-, 3- or 4-pyridylmethyl, 2-pyrimidinylmethyl and the like. Aralkyl of aralkyl optionally having substituent (s) means benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 8-phenyl
1 to 1 carbon atoms substituted by phenyl such as phenyloctyl
Represents an alkyl of 8. Mono-dialkylcarbamoyl means N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N, N -Especially mono-dialkylcarbamoyl having 1 to 10 carbon atoms, such as diethylcarbamoyl. Mono-dialkylthiocarbamoyl means N-methylthiocarbamoyl, N, N-
Dimethylthiocarbamoyl, N-methylthiocarbamoyl, N, N-dimethylthiocarbamoyl, N-methylthiocarbamoyl, N, N-dimethylthiocarbamoyl,
In particular, mono-dialkylthiocarbamoyl having 1 to 10 carbon atoms, such as N-ethylthiocarbamoyl and N, N-diethylthiocarbamoyl. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylethyl, isopropoxycarbonylethyl, butoxycarbonylmethyl,
Isobutoxycarbonylethyl, tertiary butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, octyloxycarbonylmethyl, decyloxycarbonylmethyl, etc., and in particular, an alkoxycarbonyl having 2 to 10 carbon atoms is an alkyl having 1 to 4 carbon atoms. Are exemplified. As carboxyalkyl, carboxymethyl, 2-carboxyethyl,
Examples thereof include carboxyalkyl having 2 to 5 carbon atoms such as 3-carboxypropyl and 4-carboxybutyl. R
Examples of the optionally condensed heterocyclic ring formed by bonding 6, R7 together with an adjacent nitrogen atom include 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-alkyl-1
-Piperazinyl, 4-phenyl-1-piperazinyl, 4
-Substituted phenyl-1-piperazinyl, 4-aralkyl-
1-piperazinyl, 4-substituted aralkyl-1-piperazinyl, 4-acyl-1-piperazinyl, morpholino, thiomorpholino, isoindoline-2-yl, 1,2,2
3,4-tetrahydroisoquinolin-2-yl and the like are exemplified. Morpholino and thiomorpholino include alkyl,
Carboxyl, hydroxyalkyl, alkoxycarbonyl and the like may be substituted, and the alkyl, aralkyl and acyl substituted at the 4-position of piperazine are the same as those described above, and the substituents of phenyl and aralkyl are halogen, Examples thereof include alkyl and alkoxy. An isoindoline ring and 1,2,3,4-
On the tetrahydroisoquinoline ring, halogen, alkyl, alkoxy, haloalkyl, hydroxy, nitro,
It may be substituted by any combination of 1 to 3 substituents selected from amino and oxo. Examples of the alkyl, acyl, carboxyalkyl, and aralkyl which may have a substituent in R8 are the same as those described above. P in D is preferably 1 to 10, and q is preferably 0 to 10. Examples of the alkylene having 2 to 10 carbon atoms which may have a substituent in L and M include ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octaene, excluding methylene among alkylenes of D1. Examples thereof include alkylene having 2 to 10 carbon atoms such as methylene, nonamethylene, and decamethylene. Hydroxy, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, carboxyl, carbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl and the like. Examples of the alkyl, cycloalkyl, haloalkyl, phenyl which may have a substituent, aralkyl which may have a substituent, and heteroarylalkyl which may have a substituent in D2 are the same as those described above. Is exemplified. Examples of the alkylene for G and the alkylene having a substituent are the same as those described above.

The pharmaceutically acceptable salts of the compounds of general formula (I) include hydrochlorides, hydrobromides, hydroiodides,
Sulfate, nitrate, phosphate, acetate, citrate, maleate, fumarate, malonate, malate, tartrate, succinate, methanesulfonate, benzenesulfonate, etc. Examples thereof include alkali metal salts such as acid addition salts, sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. The compounds of the present invention also exist as hydrates (hemihydrate, monohydrate, sesquihydrate and the like) and solvates, and these are also included in the present invention. When the compound of the formula (I) has an asymmetric carbon, at least two kinds of optical isomers exist. These optically active substances and their racemates are included in the present invention. Further, the present invention also includes cis and trans geometric isomers and mixtures thereof.

The compound of the general formula (I) can be produced as follows. Method General formula (II) obtained by a known method

[0031]

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Wherein each symbol is as defined above, and a compound represented by the general formula (III):

[0033]

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[Wherein W represents a reactive atom or group (eg, halogen or a sulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and other symbols are as defined above. is there. Or the acid addition salt thereof to give a compound represented by the general formula (I).

The compound of the general formula (II) and the compound of the general formula (II)
The reaction of the compound (I) with the compound is generally carried out in a reaction-inert solvent (water or methanol, ethanol, dimethylformamide or the like, or a mixed solvent thereof, preferably aqueous ethanol) in a base (sodium hydroxide, potassium hydroxide, In the presence of sodium hydride, potassium hydride, sodium methoxide, sodium carbonate, potassium carbonate, metallic sodium, triethylamine, pyridine and the like) at a temperature from about 0 ° C. to the boiling point of the solvent used, preferably 20 ° C.
C. to 80.degree. C. for about 10 minutes to 24 hours, preferably 30 minutes.
Progress in minutes to 7 hours. Examples of the acid addition salt of the compound of the general formula (III) include hydrochloride and hydrobromide.

Next, in the compound of the general formula (I), X, B,
Compounds wherein Y is SO or SO ₂ are those wherein X, B and Y are S
Which is produced by subjecting a compound of the general formula (I) to an oxidation reaction. As the oxidizing agent used for the oxidation reaction,
Metachloroperbenzoic acid, peracetic acid, trifluoroperacetic acid,
Permaleic acid, potassium superoxide, sodium bromite,
Sodium hypobromite, hydrogen peroxide and the like.
The reaction is usually a solvent inert to the reaction (water or dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or a mixed solvent thereof).
Medium, organic acids (formic acid, acetic acid, propionic acid, butyric acid, maleic acid, fumaric acid, malonic acid, succinic acid, benzoic acid, metachlorobenzoic acid, p-nitrobenzoic acid, phthalic acid, etc.)
In the presence of -70 ° C to the boiling point of the solvent used,
Preferably -50 ° C to room temperature, more preferably -20 ° C
０0 ° C. for about 5 minutes to 24 hours, preferably about 5 minutes to 20 hours, or a base (sodium hydroxide, potassium hydroxide, calcium hydroxide) in water or an alcoholic solvent such as ethanol, methanol or propanol. In the presence of an alkali hydroxide (eg, an alkali hydroxide) such as -70 ° C to the boiling point of the solvent used, usually at -50 ° C to room temperature, preferably at -20 ° C to 10 ° C for about 5 minutes to 24 hours, preferably 1 hour. From 10 hours.

In this case, a compound in which a compound having a nitrogen atom in the compound of the general formula (I) is N-oxidized may be synthesized.
Oxides are also included.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is racemic, for example, by fractional recrystallization of a salt with an optically active acid,
Alternatively, it can be divided into a desired optically active substance by passing through a column filled with an optically active carrier. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using an optically active raw material compound or the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

The compound of the general formula (I) according to the present invention comprises hydrochloric acid,
Hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, malonic acid, malic acid, tartaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, etc. To give the above-mentioned acid addition salt. Further, by reacting with sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or the like, a corresponding metal salt can be obtained. Further, when the obtained crystals of the compound of the present invention are anhydrous, a hydrate or a solvate can be obtained by treating the compound of the present invention with water, an aqueous solvent or another solvent.

The compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof selectively exhibit antibacterial activity against Helicobacter bacteria represented by H. pylori. It is effective for the prevention and treatment of various diseases such as gastritis and gastric ulcer caused. That is, the compound of the present invention and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter spp., Preventing recurrence of ulcer relapse, suppressing vomiting, Arsage Spepsia (Non-ulcer dyspep)
sia) and for the prevention and treatment of tumors (such as gastric cancer). In addition, the compound of the general formula (I) and a pharmaceutically acceptable salt thereof of the present invention are useful as preventive and therapeutic drugs for digestive diseases (gastric ulcer, duodenal ulcer, gastritis, diarrhea, colitis, etc.). Furthermore, it has properties such as low toxicity and stability against acids and the like.

Furthermore, the present invention relates to a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof and an anti-ulcer drug, preferably a proton pump, as seen in a two-drug and a new three-drug combination therapy. By using in combination with an inhibitor, or by using a compound of the present invention or a pharmaceutically acceptable salt thereof together with an anti-ulcer drug and an antibiotic or antiprotozoal,
Clearly superior eradication effect, anti-ulcer effect, and prevention of ulcer relapse and recurrence are obtained, which are superior to those obtained by using each drug alone.

The anti-ulcer drug used in the present invention together with the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes a proton pump inhibitor, a histamine H2 antagonist, a protective factor enhancer and the like. Can be Specific examples of the proton pump inhibitor include omeprazole, lansoprazole, pantoprazole, rabeprazole sodium and the like. Specific examples of the histamine H2 antagonist include cimetidine, ranitidine, famotidine, roxatidine and the like. Specific examples of protective factor enhancers include cetraxate hydrochloride, sucralfate, ecapapide, prostaglandin derivatives (mizoprostol,
Ornopro steel, etc.).

An antibiotic or an antiprotozoal is used together with the compound of the present invention or a pharmaceutically acceptable salt thereof and an anti-ulcer drug. Specific examples of antibiotics include, in particular, antibiotics such as amoxicillin, clarithromycin, ampicillin or prodrugs thereof. Specific examples of antiprotozoal drugs include metronidazole, tinidazole and the like. These drugs can preferably use a commercially available preparation.

[0044] The dosage is determined by age, body weight, general health condition,
It is appropriately selected according to sex, diet, administration time, administration method, excretion rate, combination of drugs, type and symptoms of gastritis / peptic ulcer of a patient, and the general formula (I) of the present invention having an anti-H. )) Or a pharmaceutically acceptable salt thereof is 0.1 to 50 mg / kg / day for an adult, preferably 0.1 to 50 mg / kg / day.
3 to 10 mg / kg / day can be administered. On the other hand, in the case of a proton pump inhibitor, the antiulcer drug used in combination is 0.01 to 10 mg / kg / day, preferably 0.1
~ 1.0 mg / kg / day. In the case of a histamine H2 antagonist, the dose is 0.1 to 100 mg / kg / day, preferably 1 to 10 mg / kg / day. In the case of a protective factor enhancer, 1.0 to 100 mg / kg / day, preferably 1 to 100 mg / kg / day
0 to 50 mg / kg / day is administered. The antibiotic used in combination is 0.1 to 100 mg / kg / day, preferably 5 to 30 mg / kg / day, and the antiprotozoal is 0.1 to 100 m / kg.
g / kg / day, preferably 1 to 10 mg / kg / day.

When the compound of the present invention is used as a medicament, the compound of the present invention may contain a pharmaceutically acceptable carrier (excipient, binder,
Disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.) to obtain a pharmaceutical composition, tablets, pills, powders, granules, capsules, troches, syrups, liquids, Emulsions, suspensions, injections (solutions, suspensions, etc.), suppositories,
It is formulated in a form suitable for oral or parenteral use as a formulation such as an inhalant, a transdermal absorbent, an eye drop, and an ointment.

In the case of a solid preparation, carriers include, for example, sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, tran gums , Gum arabic, gelatins, collagens,
Casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerin, polyethylene glycol, sodium hydrogen carbonate, magnesium stearate, talc and the like are used. In addition, tablets are tablets coated with normal skin as necessary, such as sugar-coated tablets,
Enteric-coated tablets, film-coated tablets, bilayer tablets, and multilayer tablets can be prepared.

In the case of a semisolid preparation, as a carrier, animal and vegetable oils (olive oil, corn oil, castor oil, etc.), mineral oils (vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, carnauba wax, For example, beeswax and the like, partially synthesized or totally synthesized glycerin fatty acid esters (such as lauric acid, myristic acid, and palmitic acid) are used. Examples of these commercially available products include Witepsol (manufactured by Dynamid Nobel), Pharmasol (manufactured by NOF Corporation) and the like.

In the case of a liquid preparation, examples of the carrier include sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol and ethyl alcohol. In particular, in the case of an injection, a sterile aqueous solution such as physiological saline, isotonic solution, or oily solution such as sesame oil or soybean oil is used. If necessary, a suitable suspending agent such as sodium carboxymethyl cellulose, a nonionic surfactant, and a solubilizing agent such as benzyl benzoate or benzyl alcohol may be used in combination.

The above-mentioned pharmaceutical composition may further contain an anti-ulcer drug or an anti-ulcer drug and an antibiotic or antiprotozoal.

[0050]

[0051]

EXAMPLES The present invention will be described below in more detail with reference to Examples, Formulation Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 2-chloromethyl-3-methyl-4- (2-morpholino
3.96 g of ethylthio) pyridine and 4-hydroxyquino
Dissolve 2.0 g of phosphorus in 30 mL of DMF, _TwoCO_Three
2.86 g was added, and the mixture was stirred at 60 to 70 ° C for 1 hour. Anti
After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. Ethyl acetate
After washing the water layer with water, it is dried over anhydrous magnesium sulfate,
The solvent was distilled off. The residue is purified by silica gel column chromatography.
Attached to the fee, CHCl_Three: Distilled at MeOH = 98: 2
Thereafter, ethanolic hydrochloric acid was added to obtain a hydrochloride. Coarse
The product was recrystallized from EtOH-MeOH to give 4-[[3-
Methyl-4- (2-morpholinoethylthio) -2-pyri
[Zill] methoxy] quinoline trihydrochloride white crystals 0.8
5 g were obtained. Melting point 142-145 [deg.] C./decomposition Example 2 2-chloromethyl-3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethy
Ruthio] pyridine / hydrochloride (1.0 g) and 4-hydroxyl
Dissolve 0.45 g of -2-methylquinoline in 30 mL of DMF
Let me know, K_TwoCO_ThreeAdd 0.4 g and heat at 60-70 ° C.
Stirred overnight. After the reaction, add water and extract with ethyl acetate.
did. After washing the ethyl acetate layer with water, anhydrous magnesium sulfate
After drying with a solvent, the solvent was distilled off. Silica gel residue
Chromatography, CHCl _Three: MeOH =
After distilling at 98: 2, it was crystallized by IPE. Rough body
Was recrystallized from IPE to give 2-methyl-4-[(3-methyl
-4- [2- [2- (2,2,2-trifluoroethoxy)
C) ethoxy] ethylthio] -2-pyridyl) methoxy
0.394 g of white crystals of [quinoline] were obtained. Melting point 77
-78 ° C

The following compounds were obtained in the same manner as in the above Examples. Example 3 4-({3-methyl-4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethylthio] -2
-Pyridyl @ methoxy) quinoline trihydrochloride. Melting point 77
-78 ° C Example 4 cis-4-([4- [2- (2,6-dimethylmorpholino) ethylthio] -3-methyl-2-pyridyl] methoxy) quinoline / 3 hydrochloride. Melting point 151-152 ° C / decomposition Example 5 2-methyl-4-[[3-methyl-4- (2-morpholinoethylthio) -2-pyridyl] methylthio] quinoline
Trihydrochloride. Melting point 195-198 [deg.] C./decomposition Example 6 4-({3-methyl-4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -2-].
Pyridyl {methoxy) quinoline trihydrochloride. Melting point 154
-156 ° C Example 7 2-Methyl-4-[[3-methyl-4- (2-morpholinoethoxy) -2-pyridyl] methoxy] quinoline · 3 hydrochloride. Melting point 141-143 [deg.] C. Example 8 2-methyl-4-[(3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethoxy {-2-pyridyl) methoxy] quinoline dihydrochloride. Melting point 142-144 ° C. Example 9 2-methyl-4- [(3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethylthio {-2-pyridyl) methylthio] quinoline dihydrochloride. Melting point 121-124 ° C / decomposition Example 10 4-([4- [2- (2-methoxyethoxy) ethylthio] -3-methyl-2-pyridyl] methoxy) -2-methylquinoline dihydrochloride. Melting point 145-148 [deg.] C./decomposition Example 11 4-[(4- {2- [2- (2-methoxyethoxy) ethoxy] ethylthio} -3-methyl-2-pyridyl) methoxy] -2-methylquinoline-2 Hydrochloride. Melting point 132
-134 [deg.] C / decomposition Example 12 4-{[2- (N-benzyl-N-methylamino) ethoxy-3-methyl-2-pyridyl] methoxy} -2-methylquinoline-3-hydrochloride. Mp 163-167 ° C Example 13 4-[[4- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy] ethylthio) -3-methyl-
2-pyridyl] methoxy} -2-methylquinoline dihydrochloride. Melting point 138-140 [deg.] C / decomposition Example 14 4-([4- [2- [2- [2- [2- (2-methoxyethoxy) ethoxy] ethoxy] ethoxy) ethylthio] -3-methyl-2-pyridyl. Methoxy) -2-methylquinoline dihydrochloride. Melting point 114-116 ° C / decomposition Example 15 4-[(4- {2- [2- (2- [2- [2- (2-methoxyethoxy) ethoxy] ethoxy] ethoxy) ethoxy] ethoxy] ethylthio] -3- Methyl-2-pyridyl) methoxy] -2-methylquinoline dihydrochloride. Melting point 114-
116 ° C./decomposition Example 16 4-{[4- (2- {2- [2- (2- [2- [2-
(2-methoxyethoxy) ethoxy] ethoxy] ethoxy) ethoxy] ethoxy] ethylthio) -3-methyl-
2-pyridyl] methoxy} -2-methylquinoline dihydrochloride. Melting point 100-102 ° C / decomposition Example 17 4-(｛4- [2- (2- ｛2- [2- (2- ｛2-
[2- (2-methoxyethoxy) ethoxy] ethoxy]
Ethoxy) ethoxy] ethoxy {ethoxy) ethylthio] -3-methyl-2-pyridyl {methoxy) -2-methylquinoline ¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.40 (s, 3H), 2.69 (s) , 3H), 3.21
(t, 2H), 3.37 (s, 3H), 52-3.56 (m, 2H), 3.64-3.66 (m, 26H),
5.43 (s, 2H), 6.89 (s, 1H), 7.15 (d.1H), 7.40 (t, 1H), 7.63
(t, 1H), 7.92 (d, 1H), 8.10 (d, 1H), 8.33 (d, 1H). Example 18 8-methoxy-2-methyl-4-[(3-methyl-4-
[2- [2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio} -2-pyridyl) methoxy] quinoline dioxalate. Melting point 120-122 ° C Example 19 8-cyano-2-methyl-4- [(3-methyl-4- [
2- [2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline. Melting point 93-95 [deg.] C Example 20 6-cyano-2-methyl-4- [(3-methyl-4- [
2- [2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline. Melting point 100-102 [deg.] C Example 21 6-methoxy-2-methyl-4-[(3-methyl-4-
[2- [2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline dioxalate. Melting point 105-107 ° C Example 22 ethyl 2-methyl-4- [(3-methyl-4- [2-
[2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline-6-carboxylate. Melting point 91-92 [deg.] C Example 23 ethyl 2-methyl-4-[[3-methyl-4- (2-morpholinoethylthio) -2-pyridyl] methoxy} quinoline-6-carboxylate. 148-149 ° C. Example 24 4-[[3-Methyl-4- (2-morpholinoethylthio) -2-pyridyl] methoxy] -2-quinolinemethanol. 160-161 ° C. Example 25 (4-[[3-Methyl-4- (2-morpholinoethylthio) -2-pyridyl] methoxy] -2-quinoline-2-
Ill) Methyl acetate. 112-113 ° C Example 26 2-methoxymethyl-4-[[3-methyl-4- (2-
Morpholinoethylthio) -2-pyridyl] methoxy] quinoline trihydrochloride. Melting point 145-146 ° C / decomposition Example 27 2-methyl-4- [(3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline-6-carboxylic acid. Mp 206-207 ° C. Example 28 2-Methyl-4-[[3-methyl-4- (2-morpholinoethylthio) -2-pyridyl] methoxy] quinoline-6
-Carboxylic acid dihydrochloride. Melting point 171-173 ° C / decomposition Example 29 2-methyl-4- [(3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline-7-carboxylic acid. Melting point 156-157 ° C Example 30 2-methyl-4- [(3-methyl-4- [2- [2-
(2,2,2-trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] quinoline-8-carboxylic acid. 134-135 ° C. Example 31 After adding 0.46 g of Na to 100 mL of EtOH,
-Hydroxyquinoline (1.45 g) was added, and the mixture was stirred at room temperature for 30 minutes. Next, 2-chloromethyl-3-methyl-4-
[[2- (2,2,2-trifluoroethoxy) ethoxy] ethylthio] pyridine / hydrochloride (3.64 g) was added, and
The mixture was stirred at the same temperature for 6 hours. After completion of the reaction, EtOH was distilled off, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the residue was distilled with CHCl ₃ : MeOH = 98: 2.
[[2- (2,2,2-Trifluoroethoxy) ethoxy] ethylthio] -2-pyridyl) methoxy] 0.064 g of white crystals of quinoline were obtained. 55-58 ° C

The compounds synthesized in the above examples are shown in the following table.

[0055]

[Table 1]

The medicament of the present invention can be prepared according to the following formulation examples. As the compound (I) of the present invention in a formulation example, 2-methyl-4-[(3-methyl-4
-[2- [2- (2,2,2-trifluoroethoxy)
Ethoxy] ethoxy {-2-pyridyl) methoxy] quinoline dihydrochloride (the compound of Example 8) is exemplified.

Formulation Example 1 A tablet containing 20 mg of compound (I) is prepared according to the following composition. Compound of Example 8 20 mg Corn starch 15 mg Lactose 57 mg Microcrystalline cellulose 25 mg Magnesium stearate 3 mg Total 120 mg After thoroughly mixing the compound of Example 8 with 20 parts, lactose 57 parts, microcrystalline cellulose 19 parts and corn starch 4 parts, corn starch 3 Kneaded well with the binder made in part. The kneaded mixture is sieved through 16 mesh and placed in an oven for 5 minutes.
After drying at 0 ° C., the mixture is sieved with 24 mesh. The kneaded powder thus obtained, 8 parts of corn starch, 6 parts of microcrystalline cellulose and 3 parts of magnesium stearate are mixed well, and the mixture is pressed into tablets each containing 20 mg of the active ingredient per tablet.

Formulation Example 2 1.0 mg of the compound of Example 8 and 9.0 m of sodium chloride
g in water for injection and filtered to remove pyrogens,
The filtrate is aseptically transferred to an ampoule, sterilized, and melt-sealed to give an injection containing 1.0 mg of the active ingredient. The medicament of the present invention can also be used in a combination therapy of two drugs and a new triple drug, in which case compound (I) and an anti-ulcer drug, or compound (I), an anti-ulcer drug and an antibiotic or antiprotozoal drug are used. It is sufficient that they coexist in the living body, and they may be combined into one agent, or may be separately formulated and administered to a patient simultaneously or separately.

The quinoline combination drug of the present invention is formulated, for example, as follows.

Formulation Example 3 (1) Omeprazole enteric coated tablet (available as Omeprazone tablet (trade name, manufactured by Yoshitomi Pharmaceutical Co., Ltd.)) (2) Capsule containing 20 mg of compound (I) and having the following formulation Agent Compound of Example 8 20 mg Corn starch 30 mg Lactose 63 mg Hydroxypropylcellulose 6 mg Magnesium stearate 1 mg Total 120 mg Formulations (1) and (2) can be administered to a patient simultaneously or separately.

Formulation Formulation Example 4 (1) Omeprazole enteric coated tablet (Omeprazone tablet (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.)) (2) Amoxicillin capsule (Amorin capsule (trade name, manufactured by Takeda Pharmaceutical Co., Ltd.) (3) Capsules of the following formulation containing 20 mg of compound (I) Compound of Example 8 20 mg Corn starch 30 mg Lactose 63 mg Hydroxypropylcellulose 6 mg Magnesium stearate 1 mg Total 120 mg Formulations (1), ( 2) and (3) can be administered to the patient simultaneously or separately.

Manufacturing Formulation Example 5 (1) Omeprazole enteric-coated tablet (Omeprazone tablet (trade name, available from Yoshitomi Pharmaceutical Co., Ltd.)) (2) Metronidazole internal tablet (Fragile internal tablet (trade name, Shionogi) (3) Capsules of the following formulation containing 20 mg of compound (I) Compound of Example 8 20 mg Corn starch 30 mg Lactose 63 mg Hydroxypropylcellulose 6 mg Magnesium stearate 1 mg Total 120 mg Formulation (1), (2) and (3) can be administered to a patient simultaneously or separately.

The pharmacological actions of these compounds of the general formula (I) of the present invention and pharmaceutically acceptable salts thereof can be confirmed by the following methods.

Experimental Example 1 In Vitro Antibacterial Activity Against H. pylori A clinical isolate (18 strains) cultured at 37 ° C. for 72 hours under microaerobic conditions using 5% horse serum was diluted with Brucella broth, A bacterial solution of several 106 cells / ml was prepared. The diluted bacterial solution was spot-inoculated on an agar plate containing a test compound in a two-fold dilution series using a microplanter, and cultured at 37 ° C. under 8% carbon dioxide for 3 to 4 days. The inhibitory concentration (MIC) was measured.

As a result, the MI of the compound of Example 8 of the present invention was
The C value is 0.012 μg / ml, especially H. pylori
Showed highly selective antibacterial activity.

[0066]

From the above results, the general formula (I) of the present invention can be obtained.
And its pharmaceutically acceptable salts are H. Pylori
It is considered to be effective for the prevention and treatment of various diseases such as gastritis and gastric ulcer caused by Helicobacter bacterium because it selectively exhibits antibacterial activity against Helicobacter bacterium represented by Helicobacter. That is, the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof are useful for preventing and treating various diseases caused by Helicobacter spp., Preventing recurrence of ulcer, Suppression of vomiting,
It is useful for the prevention and treatment of Non-ulcer dyspepsia, and for the prevention and treatment of tumors (such as gastric cancer).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/5377 A61K 31/535 606 C07D 401/14 213 C07D 401/14 213 413/14 213 413/14 213 (72) Inventor Hiroyuki Kitani 955, Komatsuri, Yoshitomi-cho, Yoshitomi-cho, Chikugami-gun, Fukuoka Inside the Kyushu Research Laboratory, Tomi Pharmaceutical Co., Ltd. Inside the research institute (72) Inventor Shuji Ehara 955, Koshiroku, Yoshitomi-cho, Chikugami-gun, Fukuoka Yoshitomi Pharmaceutical Co., Ltd. F-term in Kyushu Research Laboratory Co., Ltd. (reference) 4C063 AA01 AA03 BB08 CC14 CC15 CC54 DD12 EE01 4C086 AA02 AA03 BC28 BC30 BC73 GA07 GA08 GA09 NA05 NA14 ZA66 ZB35

Claims (1)

[Claims] 1. A compound of the general formula (I) [In the formula, R1 represents hydrogen, halogen, nitro, cyano, alkyl, alkoxy, hydroxy, alkoxycarbonyl, carboxyl or haloalkyl. R2 is hydrogen, alkyl, haloalkyl, acyloxyalkyl,
Represents alkoxyalkyl or hydroxyalkyl.
R3 and R4 are the same or different and each represent hydrogen, halogen, or alkyl. X represents O, S, SO, and SO _2. B represents O, S, SO, SO ₂ , and NR5. (In the formula, R5 represents hydrogen, alkyl, or acyl.) When D is D1-E, D1 represents a single bond, alkylene, alkylene having a substituent, or alkylene having oxo. E
Is an alkoxyalkyl, haloalkoxyalkyl, formula (a) (Wherein R6 and R7 are the same or different and each represents hydrogen, alkyl, cycloalkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoyl,
Dialkylcarbamoyl, optionally substituted phenylcarbamoyl, thiocarbamoyl, monodialkylthiocarbamoyl, optionally substituted phenylthiocarbamoyl, optionally substituted phenylalkylcarbamoyl, A phenylalkylthiocarbamoyl which may have a substituent, phenyl which may have a substituent, aralkyl which may have a substituent or heteroarylalkyl which may have a substituent, Alternatively, R6 and R7 may combine to form a heterocyclic ring which may be condensed with an adjacent nitrogen atom, and the heterocyclic ring may have a substituent. ) Or formula (b) (Wherein, R 8 represents hydrogen, alkyl, acyl, carboxyalkyl, aralkyl which may have a substituent,
Y represents methylene, O, S, SO, and SO _2, l, m is an integer of 0,1～3. ) Is shown.
When D is (LO) p- (MO) q-D2, L and M
Represents an alkylene or vinylene having 2 to 10 carbon atoms which may have a substituent, p represents an integer of 1 to 1,000, and q represents an integer of 0 to 1000. D2 is hydrogen, alkyl, cycloalkyl, haloalkyl, phenyl which may have a substituent, aralkyl which may have a substituent, heteroarylalkyl which may have a substituent, or a compound represented by the formula (c ) (Wherein G represents alkylene and alkylene having a substituent, and R6 and R7 are as described above) or a pharmaceutically acceptable salt thereof.