JPH0348680A - Antimicrobial agent - Google Patents

Abstract

PURPOSE:To obtain an antimicrobial agent containing a compound such as 2-[3-methyl-4-(1-methyl-2-piperidyl)methoxy-2-pyridyl]methylthio-1H-be nzimidazole as an active ingredient and effective against a bacterium belonging to the genus Campylobacter. CONSTITUTION:The antimicrobial agent containing a compound expressed by formula I [R<1> is H, halogen, alkyl, alkoxy, etc.; X is S, SO or SO2; R<2> and R<3> are H, halogen or alkyl; (n) is 0 or 1-8; L is N(R<4>)R<5> (R<4> and R<5> are H, alkyl, phenyl, aralkyl, etc., or R<4> and R<5> form heterocycle together with adjacent N), formula II (R6 is H, alkyl, etc.; Z is methylene, O or S; (l) and (m) are 0-3), etc.] or pharmaceutically permeable salt thereof. The antimicrobial agent is especially effective against a bacterium belonging to the genus Campylobacter which is a gram-negative and slightly aerobic bacterium.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an antibacterial agent, particularly an antibacterial agent having superior antibacterial activity against Campylobacter bacteria.

(Prior Art) The specifications of JP-A-1-6270, JP-A-1-79177, and International Publication No. WO 39100566 disclose compounds that have a gastric acid secretion suppressing effect and are useful as anti-ulcer agents.

[Problem to be solved by the invention]

Campylobacter, a Durham-negative microaerobic bacterium (
Bacteria of the genus Campy Iobacter were discovered as bacteria that cause diarrhea and miscarriage in livestock. Camplobac causes bacterial enteritis in humans.
terjejuni, Campylobacter
coli etc. are known.

On the other hand, in 1983, Warren and Marshall identified gastritis and Campylobacter pylor.
Since the association with Campylobacter pylori (Campylobacter pylori) infection was reported, many studies and reports have been published. In fact, Campylobacter pylori is frequently detected in chronic gastritis and antral gastritis tissue associated with gastric and intestinal ulcers.

At present, the relationship between the above lesions and Campylobacter pylori infection has not been clarified, but attempts have been made to administer antibiotics such as bacampicillin hydrochloride and ofloxacin to patients in order to eliminate Honda. ing. However, the eradication effect of vacambicillin hydrochloride is only 50%, and Honda has not yet achieved sufficient efficacy, as it is said that it is easy to acquire resistance to ofloxacin. Under these circumstances, there is a desire for the development of useful antibacterial agents that can be used to treat bacterial infections caused by Campylobacter pylori and the like.

(Means for Solving Problem J) In order to solve the above problem, the present inventors have conducted various studies and found that the above-mentioned publication, which has been known as an anti-ulcer agent based on its gastric acid secretion suppressing effect, The present invention was completed based on the unexpected discovery that the compound group described in 1.

That is, the present invention provides a group represented by the general formula (where R4 and R5 are the same or different and each represents hydrogen, alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, or acyl, or R4 and R5 are adjacent Combined with the nitrogen atom,
Indicates a group forming an optionally fused heterocycle. ), Formula: (1) [In the formula, R1 is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or) alkyl, X is SSO or SOz, R2 and R3 are the same or different and are hydrogen, /'t rogen or alkyl, n is O or an integer of 1 to 8, and is a group represented by the formula (where R6 is hydrogen, alkyl or acyl, Z is methylene, oxygen or sulfur, 1. are the same or different and represent O and an integer from 1 to 3),
or a group represented by the formula: (wherein R'' represents hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralxy, or alkoxyalkyl) or a pharmaceutically acceptable compound thereof. The present invention relates to an antibacterial agent characterized in that it contains a salt that can be used.

The antibacterial agent of the present invention is particularly effective against Durham-negative bacteria, especially microaerophilic bacteria, especially Campylobacter genus bacteria represented by Campylobacter pylori. Therefore, the present invention provides a method for preventing and treating infectious diseases in mammals including humans, which method comprises administering an effective amount of a compound represented by the general formula ([), or a pharmaceutically acceptable salt thereof. It is characterized by

In this specification, halogen refers to chlorine, bromine, fluorine, and iodine, and alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl,
Alkyl refers to alkyl having 1 to 20 carbon atoms such as hexyl, octyl, decyl, dodecyl, octadecyl, eicosyl, etc., and alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy,
Alkoxy having 1 to 20 carbon atoms such as pentyloxy, hexyloxy, octyloxy, decyloxy, dodecyloxy, octadecyloxy, and eicosyloxy, and alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy Alkoxy having 1 to 20 carbon atoms such as carbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl, octadecyloxycarbonyl, eicosyloxycarbonyl -carbonyl and haloalkyl are trifluoromethyl, 2,2.2-trifluoroethyl, 2,3.3-1
Haloalkyl having 1 to 4 carbon atoms such as lifluoropropyl, 1.1.2.2-tetrafluoroethyl, 2.2,3.3-tetrafluoropropyl, etc., and aralkyl include benzyl, 1-phenylethyl, 2. -phenylethyl, 3
-Phenyl-substituted alkyl having 1 to 8 carbon atoms such as phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, and 8-phenyloctyl, and acyl refers to carbon atoms such as acetyl, propionyl, isopropionyl, butyryl, pivaloyl, and valeryl. Number 1 to 5 alkanoyl or benzoyl, aryl refers to phenyl, naphthyl, etc. Substituted phenyl, substituent Ryl or substituted aralkyl has 1 to 3 halogen, alkyl, alkoxy, haloalkyl, hydroxyl group as a substituent. The optionally condensed heterocycle formed by a group selected from , nitro, and amino together with an adjacent nitrogen atom is ■-pyrrolidinyl, piperidino, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-aralkyl. -1-Piperazinyl, 4-substituted aralkyl-1-piperazinyl, 4-alkyl-1 homopiperazinyl, 4-acyl-1-homopiperazinyl, morpholino, thiomorpholino, 2-oxo-1-pyrrolidinyl, 2,4-dioxo-1-pyrrolidinyl ,2-oxo-1
-piperidinyl, isoindolin-2-yl, 1.2.
3.4-tetrahydroquinolin-1-yl, 1.2.3
．． 4-tetrahydroisoquinolin-2-yl (these isoindoline rings and 1.2.3. 1 to 4-tetrahydro(iso)quinoline rings selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl group, nitro, amino, oxo) Alkoxyalkyl refers to methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxodimethyl, phthoxymethyl, iso7
'Toxymethyl, tertiary butoxymethyl, pentyloxymethyl, hexyloxymethyl, octyloxymethyl, decyloxymethyl, dodecyloxymethyl, octadecyloxymethyl, eicosyloxymethyl, 2-
It means methoxyethyl, 3-methoxypropyl, 3-propoxypropyl, 4-methoxybutyl, 4-isopropoxybutyl, etc., respectively.

The compound of general formula (1) of the present invention may exist in various isomers. The present invention includes one of these isomers or a mixture of these isomers.

- Pharmaceutically acceptable salts of the compound of formula (1) include:
hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, citrate, maleate, fumarate, malonate, malate, tartrate, Acid addition salts such as succinate, methanesulfonate and -
IC formula () [In the formula, m is 1.2 or 4, and A'' is Li'Na
", K', Mg", Cat'", Ti'°, N'(
R)4 (herein, R is an alkyl having 1 to 4 carbon atoms) or C'' (N Hz)+, and the other symbols have the same meanings as above.] .

-i The compound of formula (1) can be prepared by a known method, for example, JP-A-1
It can be produced by the method described in JP-A-6270 and International Publication WO39100566.

Examples of the compounds of the present invention include the following compounds,
The present invention is not limited to these.

(1) 2-(3-methyl-4-(1-methyl-2
-piperidyl)methoxy-2-pyridyl)methylthio-
IH-benzimidazole (2) 2-(3-methyl-4-(3-morpholinopropoxy)-2-pyridyl]methylthio IH-henzimidazole (3) 2-(3-methyl-4-(2-piperidyl) ethoxy)-2-pyridylcomethylthio-I H-benzimidazole (4) 2-(3-methyl-4-(2-(2-oxo-1-pyrrolidinyl)ethoxy)-2-pyridyl]methylthio IH-benzimidazole (5) 2-
(3-methyl-4-(2-morpholinoethoxy)-2-
pyridyl]methylthio IH-penzimidazole (6) 2-(3-methyl-4-(3-piperidinopropoxy)-2-pyridylcomethylthio-1l+-benzimidazole (7) 5-methoxy-2-[3- Methyl-4=(2
-morpholinoethoxy)-2-pyridyl]methylthio IH-benzimidazole (8) 5-methoxy-2-[3-methyl-4-(2
-(N-benzyl-N-methylamino)ethoxy)-2
-pyridyl]methylthio IH-benzimidazole (9) 2-(3-methyl-4-(2-(N-methyl-N-(2-phenylethyl)amino)ethoxy)-
2-pyridyl]methylthio-IH-penzimidazole (10) 2-(3-methyl-4-(2-(N-methyl-N-(3-phenylpropyl)amino)ethoxy-2-pyridyl)methylthio-IH- Benzimidazole (11) 2- (3-methyl-4-(2-(N-
Benzyl-N-ethylamino)ethoxy)-2-bilicyl]methylthio-IH-benzimidazole (12) 2-(3-methyl-4-(2-(N-benzyl-N-propylamino)ethoxy)-2pyridyl ] Methylthio-IH-benzimidazole (13) 2-(3-methyl-4-(2-(N-methyl-N-(4-methylbenzyl)amino)ethoxy)-
2-pyridyl]methylthio-I H-benzimidazole (14) 2-13-methyl-4-(2-(N(4
-chlorobenzyl)-N-methylamino)ethoxy)-
2-pyridyl]methylthio IH-benzimidazole (15) 2-(3-methyl-4-(2-(N-(
4-bromobenzyl)-N-methylamino)ethoxy)
-2-pyridyl]methylthio IH-benzimidazole (16) 2-(3-methyl-4-(2-(1°2
．． 3.4-tetrahydroisoquinolin-2-yl)ethoxy)-2-pyridyl]methylthio IH-benzimidazole (17) 2-(3-methyl-4-(2-(N-benzyl-N-methylamino)ethoxy) -2-pyridyl]methylsulfinyl-IH-benzimidazole 2
Magnesium salt (18) 2-(3-methyl-4-(2-(N-methyl-N-(4-methylbenzyl)amino)ethoxy)
-2-pyridylcomethylsulfinyl-IH-benzimidazole A magnesium salt (19) 2-(3
-Methyl-4-(2-(N-(4-bromobenzyl)-
N-methylaminoethoxy)-2-pyridyl]methylsulfinyl-IH = benzimidazole, each magnesium salt (20)
゜2.3.4-tetrahydroisoquinolin-2-yl)
ethoxy)-2-pyridylcomethylsulfinyl-IH
-benzimidazole 2-magnesium salt (21) 2-(3-methyl-4-(2-(N-benzyl-N-methylamino)ethoxy)-2-pyridyl]methylsulfonyl-dazole (22) 2-(3 -Methyl-4-(2-(N-methyl-N-(4-methylhensyl)amino)ethoxy)-2-pyridylcomethylsulfonyl=I11-benzimidazole [Action and effect] The antibacterial agent of the present invention is particularly suitable for Duram It is effective against negative bacteria, especially microaerobic bacteria, especially Campylobacter genus bacteria represented by Campylobacter pylori.Therefore, the present invention is effective for preventing infectious diseases in dairy animals including humans. and used in therapy.

When the antibacterial agent of the present invention is used, for example, as an agent for treating or preventing bacterial infections, it usually contains a compound (N itself (i.e., free base) or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier). It is in the form of a pharmaceutical preparation that can be mixed with excipients, carriers, diluents, solubilizers, and other additives to produce capsules, tablets (including sugar-coated tablets and film-coated tablets), granules, injections, and infusions. In the case of oral administration, the dosage is about 0.01 to 30 nr/kr per day for adults, preferably 0.1 to 4 nr/kg, depending on the patient's symptoms, Needless to say, this may vary depending on age, drug tolerance, etc.

Experimental Example 1 The in vitro antibacterial activity of the active ingredient of the present invention against Campylobacter pylori was determined by the agar plate dilution method described below.

Using 5% horse serum, test bacteria were cultured for 72 hours under aerobic conditions at 37°C and diluted with Pulsella purus to obtain a bacterial count of approximately 10.
A bacterial solution of b cells/ml was prepared. Using a microplanter, the diluted bacterial solution was spot-inoculated on an agar plate containing a 2-fold diluted concentration series of the test compound, and after culturing for 2 days at ℃ under 10% di-acid and carbon dioxide, minimal growth inhibition was achieved. Concentration (M I
C) was measured.

The results are shown in Table 1.

MIC (μg/ml) of the test compound table From the above pharmacological data, the compounds of the present invention have excellent antibacterial activity and are useful as pharmaceuticals such as antibacterial agents.

〔implementation example〕

Hereinafter, the present invention will be specifically explained using production examples and formulation examples, but the present invention is not limited thereto.

Production example 2 of compound (22)-(3-methyl-4-(2-(N-methyl-N-(4
-Methylbenzyl)amino)ethoxy)-2-pyridyl]methylthio IH-penzimidazole9.22
g to ethanol 130n+1? Dissolve, add a solution of 4.2 g of sodium hydroxide and 65 ml of water, stir for 5 minutes, then add 9.2 g of 80% metachloroperbenzoic acid at below 5°C while cooling with ice, and stir at the same temperature for 4 hours. do. After the reaction is completed, the mixture is washed with an aqueous potassium carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with chloroform-methanol (49:1) to give 2-(3) with a melting point of 137-139°C (decomposition).
-Methyl-4-(2-(N-methyl-N-(4-methylbenzyl)amino)ethoxy)-2-pyridylcomethylsulfonyl-IH-henzimidazole is obtained.

Pharmaceutical Prescription Example ■ A tablet containing active ingredient 5■ is prepared by the following S composition.

Compound (1) 5■ Cornstarch 15nv Milk 11!
57mg Microcrystalline cellulose 40 ■ Magnesium stearate 3 ■ 120 ■ Sakotate Tokui A capsule containing 3 ■ active ingredients is prepared according to the following composition.

Compound (1) 3 ■ Cornstarch 30 ■ Lactose
61mg hydroxypropylcellulose 6■100m+r

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl or haloalkyl, X is S, SO or SO_2, R^2, R^3 is the same or different and represents hydrogen, halogen, or alkyl, n represents 0 or an integer of 1 to 8, and L is a group represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where, R^4 and R^5 are the same or different and each represents hydrogen, alkyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, or acyl;
Alternatively, it represents a group in which R^4 and R^5 are bonded together with adjacent nitrogen atoms to form an optionally fused heterocycle. ), formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A group represented by (where R^6 is hydrogen, alkyl or acyl, Z is methylene, oxygen or sulfur, l, m
are the same or different and represent 0 and an integer of 1 to 3. )
, or a group represented by the formula: -OR^7 (where R^7 is hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl,
Indicates alkoxyalkyl. ) is shown. ] or a pharmaceutically acceptable salt thereof.