JP2001097866A - Anti-helicobacter pylori agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an anti-helicobacter pylori agent containing a quinoline derivative having excellent anti-helicobacter pylori action as an active ingredient. SOLUTION: This anti-helicobacter pylori agent contains a quinoline derivative represented by the general formula (1) [R1 is hydrogen atom or methyl group; R2 is hydrogen atom or acetyl group; A is C(OH)HCH=CH, (CH2)n ((n) is an integer of 1-3), CH=CHCH2, CH=CHCH=CH or COCH2; B is hydrogen atom or (CH2)pCH3 ((p) is an integer of 2-10); W represents hydrogen atom or same or different 1-4 halogen atoms] as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anti-Helicobacter pylori containing a quinoline derivative which has a novel anti-Helicobacter pylori activity and is effective for the treatment of a disease which is considered to be caused by Helicobacter pylori infection. Agent.

[0002]

BACKGROUND OF THE INVENTION Helicobacter pylori is a microaerobic bacterium discovered in 1983 by Warren JR and Marshall B. et al. And has gastric ulcer, duodenal ulcer, gastritis,
It is considered one of the major causes of stomach cancer. Currently, treatment of various diseases caused by Helicobacter pylori includes, for example, bismuth, tetracycline, penicillin, cephalosporin, macrolide, quinolone, and nitroimidazole. Combination therapy using three or three agents,
Alternatively, a combination therapy of a proton pump inhibitor (for example, omeprazole or the like) and the above drug is performed.

However, in these treatment methods, 1)
The dosage is large and the administration period is long. 2) Side effects such as vomiting, diarrhea, and constipation appear. 3) The eradication rate is wide. 4)
There are problems such as the possibility of emergence of resistant bacteria. Also,
Many of the compounds of the present invention are known compounds (JP-A-2-256665, JP-A-3-128355,
J. Biol. Chem., 159, 725-750 (1945), J. Biol. Che.
m., 196, 321-330 (1952), Chem. Pharm. Bull., 15, 71
8-720 (1967), Bull.Korean Chem. Soc., 16, 1128-113
0 (1995)), Biosci. Biotech. Biochem., 60, 1510-151.
2 (1996), Biochem. Biophys. Acta., 1318, 291-298.
(1997)), however, no antibacterial action against Helicobacter pylori is known.

[0004]

An object of the present invention is to provide an excellent anti-Helicobacter pylori agent.

[0005]

The present inventors have conducted intensive studies on substances having an antibacterial action against Helicobacter pylori and found that the quinoline derivative of the present invention has an excellent antibacterial action against Helicobacter pylori. Was found. In addition, the compounds of the present invention are selectively effective against Helicobacter pylori and have very little effect on other bacteria.

That is, the anti-Helicobacter pylori agent according to the present invention has the following general formula (1):

Embedded image [Wherein R ₁ represents a hydrogen atom or a lower alkyl group;
R ₂ represents a hydrogen atom or —CO— (CH ₂ ) _m —CH ₃ (where m represents an integer from 0 to 12), and A represents —C (O
H) HCH = CH-, -C (OH) HC≡C-,-(C
H _{2) n} - (where n is an integer from 1 3), - CH
ＣＨCHCH ₂ —, —CH ＝ CHCH ＝ CH—, —CO—
CH ₂ — or —CH ₂ CH ＝ CH—, B is a hydrogen atom, — (CH ₂ ) _p —CH ₃ (where p represents an integer of 2 to 10), — (CH ₂ ) _q —COOH (where q is an integer of 1 to 8) or _{-CH 2 CH = C (CH 3} ) C
_{H 2 CH 2 CH = C (} CH 3) represents -CH _3, W represents a hydrogen atom, the same or different 1 to 4 halogen atoms, lower alkyl group or a lower alkyl group. Where A is an anti-Helicobacter pylori agent which W is an active ingredient the quinoline derivative represented by unless a hydrogen atom to represent a -CH ₂ CH = CH-.

Further, the present invention relates to (1) R of the general formula (1)
₁ represents a hydrogen atom or a methyl group, R ₂ represents a hydrogen atom or an acetyl group, and A represents —C (OH) HCH ＝ CH
_{-, - (CH 2) n} - ( where n is an integer from 1 3), - CH = CHCH 2 -, - CH = CHCH = CH
— Or —CO—CH ₂ —, B represents a hydrogen atom or — (CH ₂ ) _p —CH ₃ (where p represents an integer from 2 to 10), and W represents a hydrogen atom or the same or different 1 An anti-Helicobacter pylori agent containing as an active ingredient a quinoline derivative represented by 4 to 4 halogen atoms, (2) R _{1 in the} general formula (1) is a methyl group, R ₂ is a hydrogen atom, and A is —CH
_2- , B is-(CH ₂ ) p-CH ₃ (where p is 2 to 1)
A quinoline derivative in which W is a halogen atom, (3) R _{1 in the} general formula (1) is a methyl group, R ₂ is a hydrogen atom, A is —CH ₂ —, and B is —CH ₂ CH = C (CH
_{3) CH 2 CH 2 CH =} C (CH 3) quinoline derivative -CH _3, W is represented by a hydrogen atom or a halogen atom,
(4) R _{1 in the} general formula (1) is a methyl group, R ₂ is a hydrogen atom,
A is -CO-CH ₂ -, B is - (CH _{2) p} -CH ₃ (wherein p is an integer of 2 to 10), quinoline derivatives W is represented by a hydrogen atom or a halogen atom, (5 ) In the general formula (1), R ₁ is a methyl group, R ₂ is a hydrogen atom, and A is -CH =
CHCH ₂ —, B is — (CH ₂ ) _q COOH (where q represents an integer of 1 to 8), and quinoline derivatives in which W is a hydrogen atom or a halogen atom.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention are useful for treating or preventing various diseases caused by Helicobacter pylori. Applicable diseases include, for example, gastric ulcer, duodenal ulcer, gastritis, gastric cancer and the like.

As used herein, the term "lower alkyl" as a group or part of a group means any of a straight or branched chain having 1 to 6 carbon atoms. Specific examples include methyl,
Ethyl, n-propyl, iso-propyl, n-butyl, iso
-Butyl, t-butyl and the like. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The compound of the present invention represented by the general formula (1) has a tautomeric relationship with the quinolone derivative represented by the general formula (2), and the present compound is also included in the present invention. That is, the following general formula (2)

Embedded image Wherein R ₁ , A, B and W have the same meaning as described above. ].

Among the compounds represented by the general formula (1) or (2) of the present invention, many compounds are known compounds, and known methods (JP-A-2-256665,
JP-A-3-128355, J. Biol. Chem., 159, 725.
-750 (1945), J. Biol. Chem., 196, 321-330 (1952), Che
m. Pharm. Bull., 15, 718-720 (1967), Bull.
em.Soc., 16, 1128-1130 (1995), Biosci.Biotech.Bioche
m., 60, 1510-1512 (1996), Biochem. Biophys. Acta., 1318,
291-298 (1997)).

The compound represented by formula (1) or (2) of the present invention can be administered as a compound as it is, but is preferably provided as a pharmaceutical composition. The pharmaceutical composition containing the compound of the general formula (1) or the general formula (2) as an active ingredient can be administered orally or parenterally (for example, intravenously, intramuscularly, etc.) by an administration route,
It can be administered to humans or non-human animals.

Therefore, the compound according to the present invention is formulated into an appropriate dosage form depending on the administration route, and specifically, is mainly administered by intravenous injection,
Injections such as intramuscular injections, capsules, tablets, granules, powders,
Various oral preparations such as pills, fine granules, and roach tablets can be prepared.

These various preparations are commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, dissolution aids. , A preservative, a flavoring agent, a soothing agent, a stabilizing agent, and the like.

The non-toxic additives that can be used include:
For example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerin,
Examples include ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate.

The dose of the compound represented by formula (1) or (2) varies depending on the age, weight, condition or degree of disease of the patient. 0.1 mg to 1000 mg. The frequency of administration is once to several times a day. The method of administration may be either oral or parenteral.

The compounds of the present invention can be used not only alone, but also in combination with other agents. Such drugs include, for example, tetracycline drugs (eg, tetracycline, minocycline, etc.), penicillin drugs (eg, amoxicillin, etc.), cephalosporin drugs (eg, cefpodoxime, etc.), and macrolide drugs (eg, clarithromycin, erythromycin, etc.) ), Quinolones (eg, ofloxacin, tosfloxacin, etc.), nitroimidazoles (eg, metronidazole, tinidazole, etc.), proton pump inhibitors (eg, omeprazole, lansoprazole, etc.).

[0018]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Among the compounds of the present invention, compounds other than compound 2, compound 12, compound 19 and compound 37 are known compounds and can be synthesized according to the descriptions in the following documents or patent publications, respectively.

Specific examples of these compounds are shown in Tables 1 and 2.
It is as listed in.

[0021]

[Table 1]

[Table 2] D1: J. Biol. Chem., 159, 725-750 (1945) D2: JP-A-2-266665 D3: Chem. Pharm. Bull., 15, 718-720 (1967) D4: Bull. Korean Chem. Soc., 16, 1128-1130 (1995) D5: JP-A-3-128355 D6: Biosci.Biotech.Biochem., 60, 1510-1512 (1996) D7: Biochem.Biophys.Acta., 1318,291-298 (1997)

Example 1 (Compound 2) 6-Fluoro-3-methyl-2-nonyl-4-hydroxyquinoline ethyl 2-methyl-3-oxododecanoate 7.3
3 g and 3.81 g of 4-fluoroaniline in benzene (4
0 ml) to the solution was added 0.3 ml of BF ₃ .Et ₂ O, and the mixture was refluxed for 4 hours while distilling off the generated water. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, and then dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was distilled under reduced pressure to obtain 4.97 g of a condensate (148-150 ° C./0.25 m
mHg) was obtained as an oil. Diphenyl ether (2
0 ml) Under reflux, 4.97 g of a condensate was added, and the mixture was refluxed for 15 minutes. After cooling to room temperature, 20 ml of n-hexane was added and the precipitated solid was collected by filtration and washed with n-hexane to give 6-
3.24 g of fluoro-3-methyl-2-nonyl-4-hydroxyquinoline was obtained as a colorless solid.

NMR (CDCl ₃ ) 0.84 (t, J =
7.06 Hz, 3H), 1.17-1.83 (m, 14
H), 2.21 (s, 3H), 2.77 (t, J = 7.
92Hz, 2H), 7.32 (ddd, J = 9.01,
8.04, 2.92 Hz, 1H), 7.76-7.80.
(M, 1H), 7.98 (dd, J = 9.26, 2.9)
2Hz, 1H), 11.83-11.91 (m, 1
H).

Example 2 (Compound 12) 3-Methyl-2- (1-oxononyl) -4-hydroxyquinoline 2- (trans-1-hydroxy-2-nonenyl) -3
-Methyl-4-acetoxyquinoline (1 g) was allowed to stand at room temperature for 14 days, and then purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to give 2- (1-oxononyl) -3-methyl. -4
-400 mg of acetoxyquinoline were obtained. 2 obtained
178 mg of potassium carbonate was added to a solution of 400 mg of (1-oxononyl) -3-methyl-4-acetoxyquinoline, 20 ml of methanol and 2 ml of water, and the mixture was stirred at room temperature for 10 minutes. After neutralization with 1N hydrochloric acid, water was added, extracted with chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 3-methyl-2- (1-oxononyl)-.
280 mg of 4-hydroxyquinoline were obtained.

EIMS 299 (M ⁺ ) NMR (CDCl ₃ ) 0.89 (3H, t, J = 7H
z), 1.21-1.40 (10H, m), 1.78
(2H, q, J = 7 Hz), 2.50 (3H, s),
3.06 (2H, t, J = 7 Hz), 7.32 (1H,
t, J = 8 Hz), 7.37 (1H, d, J = 8H)
z), 7.62 (1H, ddd, J = 8, 7, 1H
z), 8.33 (1H, d, J = 8 Hz), 9.26
(1H, bs).

Example 3 (Compound 19) 2- (8-Carboxy-1-octenyl) -3-methyl-4-hydroxyquinoline Carboxyoctyltriamine was added to a solution of 60% NaH in 1.28 g of NaH2 and dimsyl anion prepared from 20 ml of DMSO. A solution of 7.76 g of phenylphosphine and 30 ml of DMSO was added at room temperature and stirred for 20 minutes. A solution of 4.22 g of 2-formyl-3-methyl-4-benzoyloxyquinoline and 30 ml of THF was added to the reaction solution under ice-cooling, and the solution was added at room temperature.
Stirred for hours. After adding 6N hydrochloric acid to adjust the pH to 4, water 25
0 ml was added, extracted with chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give 2- (8-carboxy-1-octenyl) -3-methyl-4-methyl-4-methyl-4-octenyl. 2.28 g of benzoyloxyquinoline were obtained. 1.15 g of the obtained 2- (8-carboxy-1-octenyl) -3-methyl-4-benzoyloxyquinoline, 20 ml of methanol,
A solution of 5 ml of water and 464 mg of KOH was stirred at room temperature for 1 hour. After 6N hydrochloric acid was added to adjust the pH to 3, water was added, extracted with chloroform, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to give 2- (8-carboxy-1-octenyl) -3-methyl-4-hydroxyquinoline (717 m).
g was obtained.

EIMS 313 (M ⁺ ) NMR (CD ₃ OD) 1.21-1.67 (10H,
m), 2.08, 2.18 (3H, each s),
2.28-2.39 (2H, m), 6.09-6.72
(2H, m), 7.30-7.37 (1H, m), 7.
54-7.67 (2H, m), 8.23 (1H, dd,
J = 8.7 Hz).

Example 4 (compound 37) 2- (4,8-dimethyl-3,7-nonadienyl) -3
-Methyl-4-hydroxyquinoline 2,3-dimethyl-4-hydroxyquinoline 200 m
g, THF (4 ml), n-butyllithium (1.36 ml, 1.7 M hexane solution) was added under ice cooling, and the mixture was stirred for 20 minutes. Geranyl bromide 25 was added to the reaction mixture under ice cooling.
1 mg was added and the mixture was stirred at room temperature for 5 hours. Water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 2- (4,8-dimethyl-3,7-nonadienyl) -3-methyl-4. -Hydroxyquinoline 2.2
8 g were obtained.

EIMS 309 (M ⁺ ) NMR (CDCl ₃ ) 1.54 (3H, s), 1.57
(3H, s), 1.65 (3H, s), 1.94-2.
05 (4H, m), 2.20 (3H, s), 2.42
(2H, q, J = 7 Hz), 2.79 (2H, t, J =
7 Hz), 5.03-5.07 (1H, m), 5.16
(1H, t, J = 7 Hz), 7.27 (1H, ddd,
J = 8, 7, 1 Hz), 7.41-7.43 (1H,
m), 7.52 (1H, ddd, J = 8, 7, 1H
z), 8.37 (1H, d, J = 8 Hz), 9.82
(1H, bs).

Test Example 1 Measurement of In Vitro Antibacterial Activity against Helicobacter pylori An evaluation compound was dissolved in dimethyl sulfoxide (DMSO) and diluted in two steps to a final concentration of 0.025 μg / ml to 100 μg / ml. The prepared evaluation compound was added to a heart infusion agar plate supplemented with 5% horse defibrinated blood to prepare an agar plate for measuring a minimum inhibitory concentration (MIC). Helicobacter pylori clinical isolates (stored in a state that can be sold to the Pharmaceutical Research Institute, Meiji Seika Co., Ltd.) are inoculated on a heart infusion agar plate supplemented with 5% horse defibrinated blood, and slightly aerobic with Campipack. Pre-culture at 37 ° C for 3 days under the conditions. Helicobacter pylori clinical isolates were collected from pre-cultured agar plates, suspended in physiological saline, and about 1 × 10 ⁶ CFU / ml.
Was prepared. About 5 μl of this bacterial solution was inoculated on an agar plate for MIC measurement using a microplanter. The inoculated agar plates were incubated at 37 ° C for 3 days (7
2 hours). After completion of the culture, the agar plate was observed, and the minimum concentration of the evaluation compound in which growth was not observed was defined as the minimum inhibitory concentration (MIC).

As a result, the MIC of compound 1 to compound 37
Is 3.13 μg / ml or less, and specific MIC values of five representative compounds are shown in Table 3.

[0032]

[Table 3]

Test Example 2 Measurement of In Vitro Antibacterial Activity Against Facultative Anaerobic Bacteria and Aerobic Bacteria The compound to be evaluated was dissolved in dimethylsulfoxide (DMSO) and adjusted to a final concentration of 0.025 μg / ml to 100 μg / ml. It was prepared by serial dilution. The prepared evaluation compound was added to a sensitivity disk agar agar plate to prepare an agar plate for MIC measurement. Various facultative anaerobic bacteria and aerobic bacteria were inoculated into sensitivity test broth and pre-cultured overnight at 37 ° C. This bacterial solution was diluted with physiological saline to a concentration of about 1 × 10 ⁶ CFU / ml. About 5 μl of this bacterial solution was inoculated on an agar plate for MIC measurement using a microplanter. 3 inoculated agar plates
Incubate at 7 ° C for 18 to 20 hours. After completion of the culture, the agar plate was observed, and the minimum concentration of the evaluation compound in which growth was not observed was defined as MIC.

As a result, Compounds 1 to 9 of the present invention were obtained from Staphylococcus aurus
eus) 209P JC-1, Escherichia coli (Esc)
MIC against facultative anaerobic bacteria and aerobic bacteria such as NIHJ JC-2 showed a value larger than 12.5 μg / ml.

Test Example 3 In Vitro Against Anaerobic Bacteria
Measurement of tro antibacterial activity The evaluation compound was dissolved in dimethyl sulfoxide (DMSO), and diluted in two steps to a final concentration of 0.025 µg / ml to 100 µg / ml to prepare. The prepared evaluation compound is added to a GAM agar plate to prepare an agar plate for MIC measurement. Inoculate each strain of anaerobic bacteria into GAM broth,
Under anaerobic conditions with a gas pack, the cells were cultured overnight at 37 ° C.
Using a GAM broth, this bacterial solution was added to about 1 × 10 ⁶ CF
The dilution was adjusted to U / ml. About 5 μl of this bacterial solution was inoculated on an agar plate for MIC measurement using a microplanter. The inoculated agar plate was subjected to anaerobic conditions as described above, 37
Incubate at 18 ° C for 18-20 hours. After completion of the culture, the agar plate was observed, and the minimum concentration of the evaluation compound in which growth was not observed was defined as MIC.

As a result, compound 7 of the present invention was obtained from Bacteroides fragiris ATCC2.
5285, Clostridium perfringens (Cl
ostridium perfringens) ATCC 3624, Fusobacterium varium ATCC
MIC against anaerobic bacteria such as 8501 is 100 μg
/ Ml.

[0037]

The compound of the present invention has an antibacterial activity against Helicobacter pylori and is effective as an agent for treating and preventing recurrence of gastric ulcer, duodenal ulcer, gastritis, gastric cancer and the like caused by Helicobacter pylori.

Claims (6)

[Claims] 1. A compound of the general formula (1) [Wherein R ₁ represents a hydrogen atom or a lower alkyl group;
R ₂ represents a hydrogen atom or —CO— (CH ₂ ) _m —CH ₃ (where m represents an integer from 0 to 12), and A represents —C (O
H) HCH = CH-, -C (OH) HC≡C-,-(C
H _{2) n} - (where n is an integer from 1 3), - CH
ＣＨCHCH ₂ —, —CH ＝ CHCH ＝ CH—, —CO—
CH ₂ — or —CH ₂ CH ＝ CH—, B is a hydrogen atom, — (CH ₂ ) _p —CH ₃ (where p represents an integer of 2 to 10), — (CH ₂ ) _q —COOH (where q is an integer of 1 to 8) or _{-CH 2 CH = C (CH 3} ) C
_{H 2 CH 2 CH = C (} CH 3) represents -CH _3, W represents a hydrogen atom, the same or different 1 to 4 halogen atoms, lower alkyl group or a lower alkyl group. Where A is an anti-Helicobacter pylori agent which W is an active ingredient the quinoline derivative represented by unless a hydrogen atom to represent a -CH ₂ CH = CH-. Wherein R ₁ represents a hydrogen atom or a methyl group, R ₂
Represents a hydrogen atom or an acetyl group, and A represents -C (OH)
HCH = CH -, - (CH 2) n- ( where n is from 1 to 3
Represents an _{integer), - CH = CHCH 2 -} , - CH = CH
CH = CH- or -CO-CH ₂ -, B stands hydrogen atom or _{- (CH 2) p -CH 3} ( wherein p 2 1
And W is a hydrogen atom or 1 to 4 identical or different halogen atoms.
The anti-Helicobacter pylori agent described in the above. (3) R ₁ is a methyl group, R ₂ is a hydrogen atom, and A is -C
H ₂ —, B is — (CH ₂ ) _p —CH ₃ (where p is 2 to 1)
A quinoline derivative represented by the general formula (1), wherein W represents a halogen atom. 4. R ₁ is a methyl group, R ₂ is a hydrogen atom and A is --C
H ₂ -, B is _{-CH 2 CH = C (CH 3} ) CH 2 CH 2 CH
= C (CH ₃₎ quinoline derivative represented by the general formula (1) representing -CH _3, W is a hydrogen atom or a halogen atom. 5. R ₁ is a methyl group, R ₂ is a hydrogen atom and A is —C
O-CH ₂ -, B is - (CH _{2) p} -CH ₃ (wherein p is an integer of 2 to 10), quinoline W is represented by the general formula (1) represents a hydrogen atom or a halogen atom Derivatives. 6. R ₁ is a methyl group, R ₂ is a hydrogen atom, and A is —C
A quinoline derivative represented by the general formula (1), wherein H = CHCH ₂ —, B is — (CH ₂ ) _q COOH (where q represents an integer of 1 to 8), and W represents a hydrogen atom or a halogen atom.