KR100267059B1 - 3-vinylquinoline derivatives and pharmaceutically acceptable salts thereof - Google Patents

Abstract

The present invention relates to a quinoline derivative having a vinyl substituent at position 3 represented by the following formula (1), a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient, and 3-vinyl of the present invention. Since quinoline derivatives and salts thereof have a function of inhibiting gastric acid secretion in mammals, they may be usefully used as therapeutic agents for gastric ulcers.

In Formula 1, R ¹ , R ² , Ar, X, and n are as defined in the specification.

Description

3-vinylquinoline derivatives and pharmaceutically acceptable salts thereof

The present invention relates to a quinoline derivative having a vinyl substituent at position 3 represented by the following formula (1), a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition containing them as an active ingredient.

Formula 1

In the above formula,

R ¹ is hydrogen, C _1-6 alkyl; Hydroxy; Or C _1-6 alkoxy, hydroxy or hydroxymethyl substituted or unsubstituted with fluorine; ,

R ² represents hydrogen or methyl,

X represents phenyl, OR ³ , SR ³ , SOR ³ , NR ³ R ⁴ , OR ⁴ , CO ₂ R ⁴ ,

Wherein R ³ is phenyl, pyridine or benzyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl Thio, nitrile, amino, nitro, hydroxy or benzyloxy and the like,

R ⁴ represents hydrogen or C _1-6 alkyl,

Ar is halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylthio, nitrile, amino, nitro, hydroxy Or phenyl or pyridine substituted with benzyloxy and the like,

n represents 0 or 1;

Until now, as a gastric acid secretion inhibitor, benzimidazole derivatives containing pyridine, represented by omeprazole, have been widely used. Benzimidazole derivatives containing pyridine have an excellent effect of inhibiting gastric acid secretion, but have an irreversible mechanism of action. There have been reported problems of side effects such as thickening of the stomach wall.

On the other hand, quinoline derivatives are known to exhibit the effect of inhibiting gastric acid secretion in mammals, and many attempts have now been made to develop them as reversible gastric acid secretion inhibitors [European Patent Application No. 87-307824.0; U.S. Patent 5,362,743; PCT Application KR 94-29274; European Patent Application No. 89-301801.0; European Patent Application 89-301805.1; European Patent Application No. 89-301802.8; European Patent Application No. 88-306583.1; PCT Application KR 97-00074; Korean Patent Application No. 96-38314; Korean Patent Application No. 97-30692; Korean Patent Application No. 97-30693; J. Med. Chem., 1992, 35, 1845-1852; J. Med. Chem., 1992, 35, 3413-3422; J. Med. Chem., 1995, 38, 2748-2762.

In particular, substituted quinoline derivatives have been reported to exhibit potent gastric acid secretion inhibitory effects, but so far no quinoline derivatives having a vinyl substituent at position 3 have been reported.

In order to develop a novel gastric acid secretion inhibitor that solves the above problems, the present inventors prepared a novel quinoline derivative having a vinyl substituent at position 3 and a salt thereof, which reversibly suppress gastric acid secretion and exhibit an excellent gastric ulcer therapeutic effect. Was completed.

It is an object of the present invention to provide 3-vinyl quinoline derivatives represented by the formula (1), pharmaceutically acceptable salts thereof, their preparation methods and their use as therapeutic agents for gastric ulcers.

In order to achieve the above object, the present invention provides a novel quinoline derivative having a vinyl substituent represented by the formula (1), a pharmaceutically acceptable salt thereof, a method of preparing them, and a pharmaceutical composition for treating gastric ulcers containing them as an active ingredient. .

Hereinafter, the present invention will be described in detail.

The present invention provides a quinoline derivative of the formula (1) having a double bond introduced at position 3 of quinoline and a pharmaceutically acceptable salt thereof.

Formula 1

In the above formula,

R ¹ is hydrogen, C _1-6 alkyl; Hydroxy; Or C _1-6 alkoxy, hydroxy or hydroxymethyl substituted or unsubstituted with fluorine; ,

R ² represents hydrogen or methyl,

X represents phenyl, OR ³ , SR ³ , SOR ³ , NR ³ R ⁴ , OR ⁴ , CO ₂ R ⁴ ,

Wherein R ³ is phenyl, pyridine or benzyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl Thio, nitrile, amino, nitro, hydroxy or benzyloxy and the like,

R ⁴ represents hydrogen or C _1-6 alkyl,

Ar is halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylthio, nitrile, amino, nitro, hydroxy Or phenyl or pyridine substituted with benzyloxy and the like,

n represents 0 or 1;

In the compound of Formula 1

R ¹ is hydrogen, hydroxy, methoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy; R ² is hydrogen or methyl; X is phenyl, OR ³ , SOR ³ , NR ³ R ⁴ , OR ⁴ or CO ₂ R ⁴ , R ³ is phenyl, pyridine or benzyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, nitrile , Amino, nitro, hydroxy or benzyloxy and the like; R ⁴ is hydrogen or C _1-6 alkyl; Ar is 2-methylphenyl, 4-hydroxy-2-methylphenyl, 4-methoxy-2-methylphenyl or 4-fluoro-2-methylphenyl, n represents more preferred activity when 0 or 1,

R ¹ is methoxy; R ² is hydrogen or methyl; X is NR ³ R ⁴ , R ³ is phenyl, 2-pyridyl; R ⁴ is hydrogen; Ar is 2-methylphenyl, n is 1, showing the most preferable activity.

Pharmaceutically acceptable salts of the compound of formula (1) refer to conventional salts used pharmaceutically, and may be formed using a suitable organic or inorganic acid according to a general method. The various acids used for the preparation of salts include hydrochloric acid, sulfuric acid, formic acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid, citric acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid and ascorbic acid. , Carbonic acid, phosphoric acid, nitric acid, acetic acid, L-aspartic acid, lactic acid, vanillic acid and hydroiodic acid.

On the other hand, the present invention includes a prodrug (Prodrug) of the compound of formula (1). In general, such prodrugs are functional derivatives of the compound of formula (I), which must be easily changeable in order to enter a living body and exhibit efficacy. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the existing literature (Design of Prodrug, ed. H. Bundgaard, 1985).

If the compound corresponding to the present invention has at least one asymmetric center, enantiomers may be present, and if it has two or more asymmetric centers, diastereoisomers may be present. Such isomers and mixtures thereof are included within the scope of the present invention.

In addition, the present invention provides a method for preparing the quinoline derivative of Formula 1, the compound of the present invention can be prepared as shown in Scheme 1.

In Scheme 1, R ¹ , R ² , Ar, X and n are as defined in Formula 1.

Production method of the present invention by the reaction scheme 1,

1) chlorination of a compound of formula (III) to obtain a compound of formula (IV) (first step),

2) reacting a compound of formula (IV) with an aryl amine compound of formula (V) to obtain a compound of formula (VI) (second step) and

3) reacting a compound of formula (VI) with a compound of formula (iii) to obtain a compound of formula 1 (formula (I)) having a vinyl substituent at position 3 (step (3)).

Synthesis of the compound used in the present invention used a method known in the literature (Heterocyclic Compounds, Quinolines, Vol 32, Part 1), wherein R ¹ and R ² are as defined in the formula (1).

The compound of formula (III) of Scheme 1, which is a starting material in the preparation method of the present invention, is synthesized by introducing iodine at position 3 of quinoline by a known method using the compound of formula (2) as a starting material (Synthesis, 1977). , 865).

R ¹ and R ² in Chemical Formula ² are as described in Chemical Formula 1.

The manufacturing method of each step of the present invention will be described in detail below.

In the scheme 1, the compound of formula (III) is chlorinated using phosphoryl chloride (POCl ₃ ), thionyl chloride (SOCl ₂ ), phosphorus pentachloride (PCl ₅ ), etc. to synthesize the compound of formula (IV). do. In this reaction, 1 to 10 equivalents of chlorination reagents can be used. As the reaction solvent, 1,2-dichloroethane, methylene chloride, or the like can be used, and the reaction can be carried out in a stock solution without a solvent.

Next, the aryl amine of formula (V) and the compound of formula (IV) were prepared using a solvent of any one of 1,4-dioxane, ethylene glycol, diethylene glycol, or without a solvent at a temperature of 100 to 150 ° C. By reacting for 1 to 2 hours in the range, a compound of formula (VI) which is a desired intermediate can be obtained. At this time, the amount of the aryl amine to be used is 1 to 10 equivalents.

Next, the compound of formula (VI) is synthesized by reacting the compound of formula (VI) with the compound of formula (VIII) using a palladium (Pd) catalyst. In this reaction, 1 to 10 mol% of a palladium catalyst, 1 to 5 equivalents of base, an organic or inorganic salt containing chlorine and various solvents are used to react at 80 to 150 ° C. for 3 to 4 hours. A quinoline derivative having a vinyl substituent at the position can be obtained. Preferably, palladium acetate, potassium acetate, tetrabutyl ammonium chloride, or tetrahydrofuran may be used to obtain a compound of Formula 1 having a vinyl substituent at the 3-position of quinoline.

In another aspect, the present invention provides a reversible gastric acid secretion inhibitor and a pharmaceutical composition for treating gastric ulcer as an active ingredient a quinoline derivative of Formula 1 and a pharmaceutically acceptable salt thereof.

Since the quinoline derivative having a vinyl substituent at position 3 represented by the formula (1) of the present invention and a pharmaceutically acceptable salt thereof exhibit reversibly inhibit gastric acid secretion, the pharmaceutical composition comprising these as an active ingredient is a gastric acid secretion. It is useful as an inhibitor and a therapeutic agent for gastric ulcer.

A pharmaceutical composition for treating gastric ulcers using the quinoline derivative and its salt of the present invention as an active ingredient is prepared as a preparation for oral or parenteral administration by adding a conventional non-toxic, pharmaceutically acceptable carrier adjuvant and excipient to the compound of Formula 1. can do.

Pharmaceutical compositions of the invention may be formulated for oral administration such as tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs ( elixirs). At this time, a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin to be formulated into a formulation such as tablets and capsules; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol may be included. Capsule formulations contain liquid carriers such as fatty oils in addition to the substances mentioned above.

In addition, the pharmaceutical composition comprising the compound represented by Formula 1 as an active ingredient may be parenterally administered by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. At this time, in order to formulate into a parenteral formulation, the compound of Formula 1 is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is prepared in a unit dosage form of ampoules or vials. can do.

In order to search for the pharmacological action of the quinoline derivative of the present invention, the analysis of gastric acid secretion inhibitory effect using omeprazole (European Patent Application No. 9105959.0) as a comparative material was confirmed to show an excellent gastric acid secretion inhibitory effect compared to the comparative material.

In addition, toxicity experiments were conducted on the quinoline derivatives of the present invention. The test substance was dissolved in water and administered to mice (5 mice per group) and observed for 14 days to determine mortality. As a result of administering the quinoline derivative of the present invention in five steps of 1000 mg / kg, 500 mg / kg, 250 mg / kg, 125 mg / kg and 62.5 mg / kg, the 50% lethal dose (LD ₅₀ ) was 1000 mg / kg. It was above.

The human dose of the active ingredient according to the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, the severity of the treated disease, etc. It is preferred to administer about 10 to 100 mg per day, but about 20 to 50 mg. Therefore, the unit dosage form of the present invention is prepared to have a content of 10 to 100 mg of the active substance of the present invention in consideration of the above-mentioned effective amount range. Preferably it is formulated to contain 20-50 mg. The unit dosage form thus formulated may be administered using a specialized dosage method as needed, or may be administered several times at regular time intervals, and may be preferably administered once to three times a day.

The quinoline derivative represented by Formula 1 prepared according to the present invention will be described in detail by way of examples.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention. In addition, the following examples describe a method for preparing some characteristic compounds, but other compounds may be easily prepared according to the method of the present invention.

The molecular structure of the compound of formula 1 of the present invention was confirmed by infrared spectroscopy, ultraviolet-visible light spectroscopy, nuclear magnetic resonance analysis, mass spectrometry and the like.

<Example 1> Preparation of 8-methoxy-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline

(Step 1) Preparation of 3-urido-4- (2-methylphenylamino) -8-methoxyquinoline

4-Chloro-3- iodo-8-methoxyquinoline (41.47 g, 0.13 mol) and 2-methylaniline (41 g, 0.4 mol) were refluxed at 125 ° C. for 4 hours. The reaction mixture was dissolved in methylene chloride (600 ml), washed with an aqueous solution of sodium bicarbonate, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained compound was purified by silica gel column chromatography, and the target compound (42 g, Yield 83%).

mp; 155-156 ° C.

¹ H NMR (CDCl ₃ ) δ 2.45 (s, 3H), 4.07 (s, 3H), 6.08 (brs, 1H), 6.51 (m, 1H), 6.96-7.30 (m, 6H), 9.07 (s, 1H ).

m / e; 390 (M ⁺ ).

(Step 2) Preparation of 8-methoxy-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline

In a high pressure reactor, 3-yodo-4- (2-methylphenylamino) -8-methoxyquinoline (0.78 g, 2 mmol), N -allylyaniline (0.53 g, 4 mmol) obtained in (Step 1), tetrabutyl Ammonium chloride (0.48 g, 2 mmol), potassium acetate (0.4 g, 4 mmol) and palladium acetate (20 mg) were added to tetrahydrofuran (15 ml) and stirred at 100 ° C. for 2 hours. The reaction mixture was cooled, saturated brine was added, the mixture was extracted with ethyl acetate, the separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained material was purified by silica gel chromatography to give an off-white solid (0.3 g, yield 39%). )

mp; 108-110 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.27 (s, 3H), 3.84 (d, 2H), 4.06 (s, 3H), 5.70 (brs, 1H), 6.27-7.32 (m, 14H), 8.91 (s, 1H).

m / e; 395 (M ⁺ ).

<Example 2> Preparation of 3- [3-benzylamino-1-propenyl] -8-methoxy-4- (2-methylphenylamino) quinoline

4- (2-methylphenylamino) -3-iodine-8-methoxyquinoline (0.59 g, 1.5 mmol), t -butyl N -allyl- N -benzylcarbamate (0.75 g, 3 mmol), tetra Butyl ammonium chloride (0.35 g, 1.5 mmol), potassium acetate (0.3 g, 3 mmol) and 5% palladium acetate (20 mg) were added to tetrahydrofuran (20 ml) and stirred at 100 ° C. for 2 hours. The reaction mixture was cooled, saturated brine was added, extraction was performed with ethyl acetate, the separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained material was purified by silica gel chromatography to obtain an intermediate (0.35 g, yield 46%). Trifluluic acid (2 ml) was added thereto, followed by heating and stirring for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with 5% caustic soda solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel chromatography to give the title compound (0.18 g, 64% yield) as a brown solid.

¹ H-NMR (CDCl ₃ ) δ 2.41 (s, 3H), 3.37 (dd, 2H, J = 6.0, 1.0 Hz), 3.75 (s, 2H), 4.07 (s, 3H), 5.90 (br, 1H) , 6.30-7.40 (m, 14 H), 8.93 (s, 1 H).

m / e; 409 (M ⁺ ).

<Example 3> Preparation of 8-hydroxy-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline

8-methoxy-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline (0.25 g, 0.63 mmol) is dissolved in methylene chloride (10 ml) and boron tribromide (BBr ₃ , 0.3 g, 1.2 mmol) was slowly added dropwise and stirred at room temperature for 2 hours. The reaction mixture was washed with sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a target compound (0.15 g, yield 63%) by silica gel column chromatography.

mp; 161-162 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.29 (s, 3H), 3.84 (d, 2H, J = 5.4 Hz), 5.84 (brs, 1H), 6.25-7.35 (m, 12H), 8.74 (s, 1H) .

m / e; 381 (M ⁺ ).

All compounds of the following examples were synthesized by the method of Examples 1 to 3 described above.

<Example 4> Preparation of 3- {3- (2-benzyloxyphenylamino) -1-propenyl} -8-methoxy-4- (2-methylphenylamino) quinoline

yield; 53%, paid

¹ H-NMR (CDCl ₃ ) δ 2.25 (s, 3H), 3.90-3.91 (m, 2H), 4.07 (s, 3H), 4.45 (brs, 1H), 5.02 (s, 2H), 5.64 (brs, 1H), 6.28-7.40 (m, 18H).

m / e; 501 (M ⁺ ).

<Example 5> 3- {3- ( N Preparation of -methylphenylamino) -1-propenyl} -8-methoxy-4- (2-methylphenylamino) quinoline

yield; 55%, paid

¹ H-NMR (CDCl ₃ ) δ 2.25 (s, 3H), 2.80 (s, 3H), 4.03 (m, 2H), 4.10 (s, 3H), 6.65 (brs, 1H), 6.25-7.35 (m, 14H), 8.95 (s, 1 H).

m / e; 409 (M ⁺ ).

<Example 6> Preparation of 4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) -8- (2,2,2-tripulorethoxy) quinoline.

yield; 53%, paid

¹ H-NMR (CDCl ₃ ) δ 2.30 (s, 3H), 3.90 (m, 2H), 4.75 (q, 2H), 5.75 (brs, 1H), 6.30-7.50 (m, 15H), 8.97 (s, 1H).

m / e; 463 (M ⁺ ).

<Example 7> Preparation of 3- (2-ethoxycarbonyl-1-ethenyl) -8-methoxy-4- (2-methylphenylamino) quinoline.

yield; 30%, paid

¹ H-NMR (CDCl ₃ ) δ 1.35 (t, 3H, J = 7.2 Hz), 2.38 (s, 3H), 4.05 (s, 3H), 4.20 (q, 2H, J = 7.2 Hz), 6.01 (br 1H), 6.45 (d, 1H, J = 16.4 Hz), 6.60-7.35 (m, 7H), 7.75 (d, 1H, J = 16.4 Hz).

m / e; 362 (M ⁺ ).

<Example 8> of 3- (2-ethoxy-1-ethenyl) -8-methoxy-4- (2-methylphenylamino) quinoline

Produce

yield; 35%, paid

¹ H-NMR (CDCl ₃ ) δ 1.35 (t, 3H, J = 7.2 Hz), 2.38 (s, 3H), 3.85 (q, 2H, J = 7.2 Hz), 4.04 (s, 3H), 4.45 (d , 1H, J = 2.6 Hz), 4.65 (d, 1H, J = 2.6 Hz), 6.45 (m, 1H), 6.85-6.95 (m, 3H), 7.12-7.22 (m, 4H), 8.80 (s, 1H).

m / e; 334 (M ⁺ )

<Example 9> Preparation of 8-methoxy-2-methyl-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline

yield; 55%

mp; 178-180 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.50 (s, 3H), 2.75 (s, 3H), 4.02 (s, 3H), 4.09 (d, 2H), 4.90 (br, 1H), 6.50-7.35 (m, 15H).

m / e; 409 (M ⁺ )

<Example 10> Preparation of 8-methoxy-4- (2-methylphenylamino) -3- {3- (2-pyridyl) amino-1-propenyl} quinoline

yield; 65%

mp; 115-117 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.32 (s, 3H), 4.08 (d, 2H), 4.09 (s, 3H), 4.50 (br, 1H), 5.76 (brs, 1H), 6.30-7.41 (m, 13H).

m / e; 396 (M ⁺ )

<Example 11> Preparation of 8-methoxy-methyl-4- (2-methylphenylamino) -3- {3- (2-pyridinyl) amino-1-propenyl} quinoline

yield; 58%

mp; 218 ℃ (decomposition)

¹ H-NMR (CDCl ₃ ) δ 2.48 (s, 3H), 2.75 (s, 3H), 4.04 (s, 3H), 4.10 (m, 2H), 5.90 (brs, 1H), 6.50-7.45 (m, 14H).

m / e; 410 (M ⁺ )

<Example 12> Preparation of 8-methoxy-3- {3- (2-methoxyphenyl) amino-1-propenyl} -methyl-4- (2-methylphenylamino) quinoline

yield; 47%

mp; 160-161 ℃

¹ H-NMR (CDCl ₃ ) δ 2.30 (s, 3H), 2.70 (s, 3H), 3.85 (s, 3H), 3.90 (m, 2H), 4.10 (s, 3H), 5.85 (brs, 1H) , 5.90-7.30 (m, 13H)

m / e; 439 (M ⁺ )

<Example 13> Preparation of 8-methoxy-3- {3- (2-methoxyphenyl) amino-1-propenyl} -4- (2-methylphenylamino) quinoline

yield; 20%

mp; 162-163 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.35 (s, 3H), 3.82 (s, 3H), 3.93 (m, 2H), 4.08 (s, 3H), 4.40 (br, 1H), 5.70 (brs, 1H) , 6.40-7.35 (m, 13 H), 8.95 (s, 1 H).

m / e; 425 (M ⁺ )

<Example 14> Preparation of 8-methoxy-3- {3- (2-methylphenyl) amino-1-propenyl} -4- (2-methylphenylamino) quinoline

yield; 49%

mp; 94-96 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.08 (s, 3H), 2.30 (s, 3H), 3.85 (m, 2H), 4.05 (s, 3H), 5.70 (brs, 1H), 6.35-7.35 (m, 14H).

m / e; 409 (M ⁺ ).

<Example 15> Preparation of 8-methoxy-2-methyl-3- {3- (2-methylphenyl) amino-1-propenyl} -4- (2-methylphenylamino) quinoline

yield; 37%

mp; 178-179 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.00 (s, 3H), 2.50 (s, 3H), 2.70 (s, 3H), 3.82 (m, 2H), 4.05 (s, 3H), 4.95 (brs, 1H) , 6.50-7.35 (m, 14 H).

m / e; 423 (M ⁺ ).

<Example 16> Preparation of 8- (2-hydroxyethoxy) -2-methyl-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline.

yield; 43%, mp; 173 ° C. (decomposition).

¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 2.68 (s, 3H), 3.90 (m, 2H), 4.02 (m, 2H), 4.25 (m, 2H), 4.90 (brs, 1H) , 6.50-7.35 (m, 15 H).

m / e; 439 (M ⁺ ).

<Example 17> Preparation of 8- (2-hydroxyethoxy) -2-methyl-4- (2-methylphenylamino) -3- {3- (2-pyridinyl) amino-1-propenyl} quinoline

yield; 49%, paid

¹ H-NMR (CDCl ₃ ) δ 2.23 (s, 3H), 2.60 (s, 3H), 3.98 (q, 2H), 4.25 (t, 2H), 4.35 (m, 2H), 4.70 (brs, 1H) , 5.90 (m, 1 H), 6.10 (brs, 1 H), 6.33-7.40 (m, 12 H), 8.00 (m, 1 H).

m / e; 439 (M ⁺ ).

<Example 18> Preparation of 8-methoxy-4- (2-methylphenylamino) -3- (3-phenyloxy-1-propenyl) quinoline

yield; 41%

mp; 129-132 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.35 (s, 3H), 4.05 (s, 3H), 4.62 (s, 2H), 5.74 (brs, 1H), 6.43-7.35 (m, 14H), 8.99 (s, 1H).

m / e; 396 (M ⁺ ).

<Example 19> Preparation of 8-methoxy-2-methyl-4- (2-methylphenylamino) -3- (3-phenyloxy-1-propenyl) quinoline

yield; 38%

mp; 117-120 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.34 (s, 3H), 2.70 (s, 3H), 4.06 (s, 3H), 4.84 (m, 2H), 5.92 (brs, 1H), 6.60-7.35 (m, 14H).

m / e; 410 (M ⁺ ).

<Example 20> Preparation of 8-methoxy-3- {3- (4-methoxyphenyl) oxy-1-propenyl} -2-methyl-4- (2-methylphenylamino) quinoline

yield; 35%

mp; 94-97 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.32 (s, 3H), 2.70 (s, 3H), 3.77 (s, 3H), 4.08 (s, 3H), 4.60 (m, 2H), 5.90 (brs, 1H) , 6.10 (m, 1 H), 6.42 (m, 1 H), 6.70-7.25 (m, 11 H).

m / e; 440 (M ⁺ ).

<Example 21> Preparation of 8-methoxy-3- {3- (4-methoxyphenyl) oxy-1-propenyl} -4- (2-methylphenylamino) quinoline

yield; 47%, paid

¹ H-NMR (CDCl ₃ ) δ 2.37 (s, 3H), 3.75 (s, 3H), 4.08 (s, 3H), 4.60 (m, 2H), 5.75 (brs, 1H), 6.40-7.35 (m, 13H), 8.98 (s, 1 H).

m / e; 426 (M ⁺ ).

<Example 22> Preparation of 8-methoxy-4- (2-methylphenylamino) -3- (2-phenyl-1-ethenyl) quinoline

yield; 45%

mp; 180-184 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.47 (s, 3H), 4.13 (s, 3H), 5.90 (brs, 1H), 6.58-7.40 (m, 14H), 9.13 (s, 1H).

m / e; 366 (M ⁺ ).

<Example 23> Preparation of 8-methoxy-4- (2-methylphenylamino) -3- (2-phenylsulfinyl-1-ethenyl) quinoline

yield; 49%

mp; 206-207 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 4.05 (s, 3H), 6.50 (m, 1H), 7.02-7.82 (m, 13H), 8.15 (brs, 1H), 8.96 (s, 1H).

m / e; 414 (M ⁺ ).

<Example 24> Preparation of 8-methoxy-2-methyl-4- (2-methylphenylamino) -3- (2-phenylsulfinyl-1-ethenyl) quinoline

yield; 36%

mp; 197-198 ° C.

¹ H-NMR (CDCl ₃ ) δ 2.33 (s, 3H), 2.65 (s, 3H), 4.05 (s, 3H), 6.35 (m, 1H), 6.95-7.75 (m, 14H).

m / e; 428 (M ⁺ ).

In order to confirm that the compounds represented by the general formula (1) of the present invention show excellent effects as gastric acid secretion inhibitors, biopharmacological activity was searched as follows.

Experimental Example 1 Biopharmacological Activity Search

20 mg of solution obtained by dissecting the abdominal cavity of the Sprague Dawley male rat (150-200 g) and ligation of the pyloric region, and then suspending or dissolving the test substance in 30% polyethylene glycol (PEG) 400 aqueous solution. / kg was injected into the duodenum of experimental rats. The abdominal cavity was sewn again, and left for 5 hours. The stomach was detected by cervical dislocation and the gastric juice was collected. After removing the precipitate by centrifugation, the amount and pH of gastric juice were measured, and the acidity was titrated using an Orion 960 automatic analyzer to compare and analyze the inhibitory effect of gastric juice secretion between the control, the comparative substance (omeprazole) and the test substance. The test results ( in vivo test) are shown in Table 1 below.

Example number Relative inhibition of gastric acid secretion compared to omeprazole One +++ 9 + 10 + 11 ++ 12 ++ 13 + 14 + * In vivo drug efficacy on the comparator; +++ (strong), ++ (similar), + (weak) * omeprazole; Material of European Patent Application EP 9105959.0

As a result, it was confirmed that the quinoline derivative having a vinyl substituent at position 3 of the present invention or a salt thereof showed an excellent gastric acid secretion inhibitory effect as compared to the conventional omeprazole.

The quinoline derivative having a vinyl substituent at position 3 of the present invention represented by the formula (1) and a salt thereof have excellent gastric acid secretion inhibitory effect as shown in the above experimental example, and its mechanism of action for inhibiting gastric acid secretion is reversible. It can solve the problems such as side effects caused by long-term administration of gastric acid secretion inhibitors can be very useful as a novel gastric acid secretion inhibitors and gastric ulcer therapeutic agent.

Claims (5)

Quinoline derivatives having a vinyl substituent at the 3-position represented by Formula 1 and pharmaceutically acceptable salts thereof: Formula 1 In the above formula, R ¹ is hydrogen, C _1-6 alkyl; Hydroxy; Or C _1-6 alkoxy, hydroxy or hydroxymethyl substituted or unsubstituted with fluorine; , R ² represents hydrogen or methyl, X represents phenyl, OR ³ , SR ³ , SOR ³ , NR ³ R ⁴ , OR ⁴ , CO ₂ R ⁴ , Wherein R ³ is phenyl, pyridine or benzyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl Thio, nitrile, amino, nitro, hydroxy or benzyloxy and the like, R ⁴ represents hydrogen or C _1-6 alkyl, Ar is halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylthio, nitrile, amino, nitro, hydroxy Or phenyl or pyridine substituted with benzyloxy and the like, n represents 0 or 1; The compound of claim 1, wherein R ¹ is hydrogen, hydroxy, methoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy; R ² is hydrogen or methyl; X is phenyl, OR ³ , SOR ³ , NR ³ R ⁴ , OR ⁴ or CO ₂ R ⁴ , R ³ is phenyl, pyridine or benzyl, halogen, C _1-6 alkyl, C _1-6 alkoxy, nitrile , Amino, nitro, hydroxy or benzyloxy and the like; R ⁴ is hydrogen or C _1-6 alkyl; Ar is 2-methylphenyl, 4-hydroxy-2-methylphenyl, 4-methoxy-2-methylphenyl or 4-fluoro-2-methylphenyl, n is 0 or 1, the quinoline derivative of claim 1, and Pharmaceutically acceptable salts thereof The compound of claim 1, wherein the compound is 8-methoxy-4- (2-methylphenylamino) -3- (3-phenylamino-1-propenyl) quinoline, 8-methoxy-3- {3- (2- Methoxyphenyl) amino-1-propenyl} -methyl-4- (2-methylphenylamino) quinoline or 8-methoxy-methyl-4- (2-methylphenylamino) -3- {3- (2-pyridinyl Amino-1-propenyl} quinoline, wherein the quinoline derivative of claim 1 and a pharmaceutically acceptable salt thereof 1) chlorination of a compound of formula (III) to obtain a compound of formula (IV) (first step), 2) reacting a compound of formula (IV) with an aryl amine compound of formula (V) to obtain a compound of formula (VI) (second step) and 3) reacting a compound of formula (VI) with a compound of formula (iii) to obtain a compound of formula 1 (formula (I)) having a vinyl substituent at Characterized in that the method of producing a quinoline derivative of claim 1 represented by Scheme 1 Scheme 1 In Reaction Scheme 1, R ¹ , R ² , Ar, X and n are as defined in claim 1. Pharmaceutical composition for gastric acid secretion inhibitor and gastric ulcer therapeutic agent containing the quinoline derivative of claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient