KR101621739B1

KR101621739B1 - Bicyclic lactone compound for treating gastro-intestinal disease

Info

Publication number: KR101621739B1
Application number: KR1020150047277A
Authority: KR
Inventors: 김기운; 유혜동; 김용환; 주미정
Original assignee: 초당약품공업 주식회사
Priority date: 2015-04-03
Filing date: 2015-04-03
Publication date: 2016-05-17

Abstract

The present invention relates to a bicyclic lactone compound for the treatment of gastrointestinal diseases. More particularly, the present invention relates to a synthetic bicyclic lactone compound which can be used as a therapeutic agent for gastrointestinal diseases, a derivative thereof, a pharmaceutically acceptable salt thereof and a process for producing the same.

Description

[0001] The present invention relates to a bicyclic lactone compound for treating gastro-intestinal disease,

Gastritis and gastric ulcers are caused by gastric acid damage to the gastric wall, which consists of the mucosal layer, submucosal layer, muscle layer, and serosa. Gastritis is a condition in which the mucous membrane is damaged and the gastric ulcer is damaged in the submucosal layer or muscular layer. The cause of gastritis and gastric ulcer is known to be caused by an imbalance of attack factors and defensive factors, that is, an increase of attack factors and weakening of defensive factors.

Increased factors of attack factors include acid and pepsin secretion, weakness of defensive factors such as loss of structure and morphology of gastric mucosa, decrease of mucus secretion, decrease of bicarbonate secretion, decrease of prostaglandin production , And it is known that gastric ulcers are caused by infection of Helicobacter pylori.

One of the major causes of stomach ulcers is gastric acid secretion. Gastric acid is the hydrochloric acid secreted from the gastric wall cells, which not only breaks down the protein by activating pepsin, but also acts as a fatal wound. Currently, the therapeutic agents for gastritis and gastric ulcer are classified into drugs that inhibit attack factors such as gastric acid, pepsin, smoking, oxygen free radicals and alcohol depending on their pathological physiology and agents that enhance defensive factors.

Attack factor inhibitors are representative of gastric acid secretion inhibitors such as antacids, H2 receptor antagonists (Cimetidine, Ranitidine, Famotidine, etc.) and Proton pump inhibitors (PPI: Omeprazole, Lansoprazole, etc.). In particular, the appearance of PPI makes it possible to achieve initial healing of almost 100% in the duodenum and 90% in the gastric ulcer. However, despite this initial improvement in the healing rate, the recurrence rate is still high, and the treatment of peptic ulcer remains a problem to be solved.

On the other hand, the protective factor enhancer protects the gastric mucosa by inducing ulcer lesion covering, mucus synthesis and secretion promotion, gastric mucosal blood flow increase, endogenous prostaglandine increase, and tissue regeneration increase. Depending on the type of defensive enhancer, And they are known to be particularly useful for the prevention of ulcer recurrence. Helicobacter pylori eradication therapy is also regarded as one of the antitumor drug treatment.

However, gastritis and gastric ulcer are caused by various complex causes, and the cause of the gastritis and ulcer is still unclear. Therefore, there is no absolute method of treatment.

On the other hand, Liriodendron tulipifera L. (Yellow-popular) is a deciduous broad-leaved arboreous tree belonging to the magnoliaceae of the funeral tree of Minerals. It has been mainly used as pulp solvent or wood lumber. Extracts of wood, bark and leaves of lily trees contain alkaloids, sesquiterpenes and lignan compounds.

According to a 1975 study, lanolin alkaloid fraction has been reported to have antibacterial activity. Other alkaloids, en-methyllaurotetanine, liriopherin, and lyriotripiperin, are known to have antifungal activity against fungi, and dehydroglazine and liriodenin, which are known to be cytotoxic, Are reported.

The lily extract also contains sesquiterpenolactone with antitumor action, and it has been reported that cosuronolide, turpinolide, epipurinolide, epiturate dienoride, and gamma-lyiodonolide have.

The applicant of the present invention discloses a pharmaceutical composition containing an extract of Liliaceae bark as an active ingredient in Korean Patent Registration No. 10-1346066, wherein Epitulipinolide and Costunolide extracted from bark of Liliaceae are used as active ingredients &Lt; / RTI > have been disclosed. Also disclosed is a pharmaceutical composition for treating gastrointestinal tract containing epi-tiflipinolide and cosurinolide, which are active ingredients of lily bark extract, as an effective ingredient, and its use as a therapeutic agent for gastrointestinal diseases.

Meanwhile, the present applicant has proposed a herbicidal composition comprising a sesquiterpin lactate having a chemical structure denoted by the following CD-101 derived from Parthenolide in Korean Patent Registration No. 10-1378430, 'Medicinal Composition for Treatment of Ssequiterpin Lactone Gastrointestinal Diseases' A pharmaceutical composition for the prevention or treatment of gastritis or gastric ulcer, which contains a tonic compound as an active ingredient.

The present applicant has also found that a herbicidal composition comprising a sesquiterpin lactate having the chemical structure designated by the following CD-102 derived from Parthenolide in Korean Patent Registration No. 10-1378431 " Therapeutic composition for treating gastrointestinal disorders of the sesquiterpyrrone system & A pharmaceutical composition for the prevention or treatment of gastritis or gastric ulcer, which contains a tonic compound as an active ingredient.

In addition, the present applicant has proposed a herbicidal composition comprising a sesquiterpin lactate having a chemical structure denoted by the following CD-103 derived from Parthenolide in Korean Patent Registration No. 10-1378433 " Therapeutic composition for treating a gastrointestinal disorder of the sesquiterpinactone system & Have disclosed a pharmaceutical composition for preventing or treating gastritis or gastric ulcer comprising a tonic compound as an active ingredient

However, in the case of a sesquiterpinolactone-based gastritis or medicinal composition for prevention or treatment of gastric ulcer having the chemical structure termed CD-101, CD-102, CD-103 disclosed in the above patent document, However, since the possibility of inducing a cell chromosome abnormality in a test tube increases with an increase in the dose, it has been required to develop a more safe pharmaceutical composition for preventing or treating gastric ulcer or gastric ulcer.

Therefore, the inventors of the present invention synthesized new bicyclic lactone derivatives and tested whether these compounds inhibit gastric lesions caused by gastritis or gastric ulcer, and also determine whether they induce cell chromosomal anomalies in vitro in a concentration- The present invention has been completed by developing a novel bicyclic lactone derivative which can more effectively and safely prevent or treat gastritis or gastric ulcer than a pharmaceutical composition for preventing or treating gastrointestinal gastritis or gastric ulcer.

The present invention aims to provide a novel bicyclic lactone derivative and to test whether these compounds inhibit the gastric lesion caused by gastritis or gastric ulcer and to determine whether or not they induce cell chromosomal anomalies in a concentration dependent manner will be. Further, it is intended to develop a novel bicyclic lactone derivative which can more effectively and safely prevent or treat gastritis or gastric ulcer than the pharmaceutical composition for preventing or treating stomach ulcer or gastric ulcer according to the prior art.

It is an object of the present invention to provide a method for the treatment or prophylaxis of gastritis or gastric ulcer by administering a therapeutically or prophylactically effective amount of 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan- Or a pharmaceutically acceptable salt thereof.

Equation 1

Another object of the present invention is to provide a process for the preparation of a compound of formula (I), which comprises using 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan- Methylbenzene sulfonyl chloride (III) under a nitrogen atmosphere to prepare 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate (I) .

The compound 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-2-one is brominated with cyclohept- Oxo cyclohept-2-yn-1-yl-2- (diethoxyphosphoryl) acetate (B) was obtained by reaction with potassium 2- (diethoxyphosphoryl) (C), and a ring closure reaction was carried out to obtain diethyl- (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate (D) Yl) phosphonate (E) and the leaving group was isolated to give 5-hydroxy-3-methylene-2-oxo (5-hydroxy-2-oxohexahydro- Octahydro-2H-cyclohepta [b] furan-2-one (F).

The present invention also provides a bicyclic lactone compound or a pharmaceutically acceptable salt thereof having a gastric or gastric ulcer preventive or therapeutic activity and safety represented by the following compounds.

(Compound 6) (1) N- (3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-

(2) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-ethylcarbamate (Compound 9)

(3) Synthesis of 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methanesulfonate (Compound 17)

On the other hand, the 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound of the formula 1 was tested in a direct chromosome aberration test using a Chinese hamster lung cell It is characterized by the absence of chromosomal aberrant cytotoxicity that does not cause chromosomal changes in Chinese hamster lung cells.

It is still another object of the present invention to provide a process for producing the 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound by 0.1 to 90% And a pharmaceutical composition for preventing or treating gastritis or gastric ulcer comprising a pharmaceutically acceptable carrier.

The effect of the present invention is to synthesize a novel bicyclic lactone derivative and to test the effect of these compounds to inhibit gastric lesions caused by gastritis or gastric ulcer, and to determine whether or not they induce cell chromosome abnormality in vitro in a concentration-dependent manner. It is another object of the present invention to provide a novel bicyclic lactone derivative which can more effectively and safely prevent or treat gastritis or gastric ulcer than the pharmaceutical composition for preventing or treating gastric ulcer disease or gastric ulcer.

FIG. 1 is a photograph showing the administration of Compound 3 of the present invention, the administration of 50 mg / kg of rebamipide, and the gastrointestinal condition of the control group in a hydrochloric acid-ethanol-induced gastritis model. FIG. 1A is a photograph of the gastrointestinal state of gastric lesion when Compound 3 is administered at a dose of 1 mg / kg. FIG. 1B is a photograph of the stomach of gastric lesion when Compound 3 is administered at a dose of 3 mg / kg. FIG. 1C is a photograph of the gastrointestinal state of gastric lesion when levamidic acid is administered at a dose of 50 mg / kg. FIG. 1D is a photograph of the stomach of gastric lesion of a control group to which no compound is administered.

The present invention provides a bicyclic lactone compound or a pharmaceutically acceptable salt thereof having gastric or gastric ulcer prevention or therapeutic activity and safety represented by the following formula 1:

3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate

Equation 1

The present invention also relates to a process for the preparation of 5-hydroxy-3-methylene-2-oxohexahydro-2H-cyclohepta [b] furan- B) furan-8-yl-4-methylbenzenesulfonate (I) by the addition reaction of sulfonyl chloride (III) .

The present invention also provides a bicyclic lactone compound or a pharmaceutically acceptable salt thereof having gastric or gastric ulcer prevention or therapeutic activity and safety represented by the following chemical names.

(Compound 6) (1) N- (3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-

The present invention also relates to a pharmaceutical composition comprising the 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound in an amount of 0.1 to 90% And to provide a pharmaceutical composition for preventing or treating gastritis or gastric ulcer including a carrier.

Hereinafter, the present invention will be described in more detail.

According to another embodiment of the present invention, the pharmaceutically acceptable salt is an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodide Hydrobromic acid, citric acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, And sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, naphthalenesulfonic acid and the like.

The bicyclic lactone compounds according to the invention comprising free carboxy substituents may be the above acid addition salts and salts of sodium, calcium and ammonium, and pharmaceutically acceptable base addition salts such as lithium, sodium, potassium An alkali metal or alkaline earth metal salt formed by calcium, magnesium or the like and an amino acid salt of lysine, arginine or guanidine and a salt of an amino acid such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) Ethanolamine, choline, triethylamine, and the like.

The bicyclic lactone compound of the compound 1 to 26 according to the present invention can be converted into a salt thereof by a conventional method and the preparation of the salt is easily carried out by a person skilled in the art based on the structure of the compound 1 without further explanation .

Unless otherwise stated, the bicyclic lactone compounds include pharmaceutically acceptable salts thereof, all of which should be construed as being included in the scope of the present invention. For convenience of explanation, these compounds are simply represented by compounds.

To facilitate the understanding of the present invention, the production methods of the compounds 1 to 26 will be described.

Starting from this precursor using the following cyclo-2-anion derivatives, a bromine group is introduced via bromination to the allyl position, followed by a nucleophilic substitution reaction with ethyl 2- (diethoxyphosphoryl) acetate and then 1,4 (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate is prepared via an addition reaction.

The ketone group is then selectively reduced and a double bond is introduced through a Horner-Emmons reaction with paraform-aldehyde. A protecting group is introduced into an alcohol group through reaction in an alcohol group under basic conditions.

Those skilled in the art will appreciate that compounds can be prepared by a variety of methods based on the structure of the compounds, all of which are to be construed as falling within the scope of the present invention.

That is, it is understood that compounds 1 to 26 can be prepared by any combination of the various synthesis methods described in the present specification or disclosed in the prior art, which is understood to fall within the scope of the present invention, But is not limited to what has been described.

The process for preparing 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate represented by the general formula 1 Explain. The preparation method of the compounds 1 to 26 used in the present invention will be described in detail through preparation examples.

Production Example 1 Preparation of 3-methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate (I)

(DMAP) as a starting material using 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan- Yl) -4-methylbenzenesulfonate (I) is prepared by the reaction of 3-methylene-2-oxohexahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate.

(0.207 g, 1.136 mmol) as starting materials and 0.42 g (0.42 mmol) of pyridine and dimethylaminopyridine , 0.304 mmol) was added methylbenzenesulfonyl chloride (III) in the presence of a solvent, stirred at room temperature and then purified by column chromatography to obtain 3-methylene-2-oxo-octahydro- 2H-cyclohepta [b] -4-methylbenzenesulfonate (yield: 86%).

The NMR peak of the obtained compound is as follows. ^{1 H NMR δ (400 MHz,} CDCl3): 1.49 ~ 1.56 (3H, m), 1.60 ~ 1.70 (1H, m), 1.80 ~ 1.95 (2H, m), 2.06 ~ 2.17 (2H, m), 3.44 ~ 3.50 (1H, m), 4.67 ( 1H, td, J = 12, 4 Hz), 4.77 (1H, t, J = 8 Hz), 5.42 (1H, d, J = 4 Hz), 6.23 (1H, d, J = 4 Hz), 7.34 (2H, d, J = 8 Hz), 7.77 (2H, d, J = 8 Hz).

(Preparation Example 2) Preparation of 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-

(Preparation Example 3) Preparation of 4-bromocyclohept-2-enone (B)

Benzoyl peroxide (45 mg, 0.13 mmol) and N-bromosuccinimide (3.32 g, 18.68 mmol) were added to cyclohept-2-enone (A) (1.47 g, 13.34 mmol) Acetonitrile (13 ml) was added thereto, followed by stirring at 70 ° C for 3 hours. Thereafter, 4-bromocyclohept-2-enone (B) was obtained by column chromatography (yield: 78%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.70 ~ 1.85 (3H, m), 2.30 ~ 2.35 (1H, m), 2.53 ~ 2.41 (2H, m), 4.93 (1H, q, J = 1.4 Hz), 5.82 (1H, d, J = 11 Hz), 6.44 (1H, q, J = 5.2 Hz).

(Preparation Example 4) Preparation of 4-oxocyclohept-2-yn-1-yl-2- (diethoxyphosphoryl) acetate (C)

According to the above reaction scheme, 4-bromocyclohept-2-enone (B) (1.26 g, 6.17 mmol) and potassium 2- (diethoxyphosphoryl) acetate (2.36 g, 9.3 mmol) and 18- Stir at 60 占 폚 for 3 hours. Thereafter, 4-oxocyclohept-2-yn-1-yl-2- (diethoxyphosphoryl) acetate (C) is obtained by column chromatography (Yield: 94%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.30 ~ 1.34 (6H, t, J = 12 Hz), 1.80 ~ 2.00 (3H, m), 2.16 ~ 2.27 (1H, m), 2.58 ~ 2.69 (2H, m ), 4.13 ~ 4.18 (4H, q, J = 8 Hz), 5.59 ~ 5.63 (1H, m), 6.02 (1H, dd, J = 16, 4 Hz), 6.42 (1H, dd, J = 16, 4 Hz).

Preparation Example 5 Preparation of diethyl- (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate (D)

According to the reaction formula 4-oxo-bicyclo hept-2-in-1-yl-2- (ethoxy-dideoxy phosphoryl) acetate Potassium t in (C) (0.84 g, 2.76 mmol) - butoxy site (0.285 g, 2.54 mmol) And the mixture was stirred at 0 ° C using tetrahydrofuran as a solvent. Thereafter, diethyl- (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate (D) is obtained by column chromatography (Yield: 74%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.31 ~ 1.35 (6H, m), 1.80 ~ 2.20 (4H, m), 2.47 ~ 2.52 (3H, m), 2.77 ~ 2.79 (2H, m), 3.01 ~ 3.11 (1H, m), 4.15-4.23 (4H, m), 4.89-4.94 (1H, m)

(Preparation Example 6) Preparation of diethyl- (5-hydroxy-2-oxooctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate (E)

Methanol was added to diethyl- (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate (D) (320 mg, 1.05 mmol) Sodium borohydride (199 g, 5.25 mmol) was added thereto and stirred for 10 minutes. The extracted oil was used immediately in the next reaction.

Preparation Example 7 Preparation of racemic (3aR, 5S, 8aR) -5-hydroxy-3-methyleneoctahydro-2H-cyclohepta [b] furan-

(E) (847 mg, 2.765 mmol) and potassium t (4-fluoro-2-oxoheptanoyl) -Butoxide (279 mg, 2.49 mmol) in THF (5 mL) and the mixture was stirred at -78 째 C for 30 minutes. Then paraformaldehyde (830 mg, 27.65 mmol) was added and stirred for 15 minutes, then the temperature was raised to 0 ° C and stirred for 2 hours 30 minutes. Thereafter, the diastereomer generated in the reduction process was separated by column chromatography to obtain racemic (3aR, 5S, 8aR) -5-hydroxy-3-methyleneoctahydro-2H -Cyclohepta [b] furan-2-one (F) (82%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.50 ~ 1.65 (3H, m), 1.65 ~ 1.77 (2H, m), 1.80 ~ 1.90 (1H, m), 2.04 ~ 2.08 (2H, m), 3.53 ~ 3.54 (1H, m), 4.12 ~ 4.15 (1H, m), 4.68 ~ 4.73 (1H, m), 5.56 (1H, d, J = 4 Hz), 6.25 (1H, d, J = 4 Hz)

Preparation Preparation Example 1 Preparation of diethyl- (5-morpholino-2-oxooctahydro-2H-cyclohepta [b] furan-3-yl)

[Reaction Scheme 1]

Diethyl- (5-morpholino-2-oxooctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate having the structure shown in the above Reaction Scheme 1 is prepared.

Preparation Preparation Example 2 Preparation of diethyl- (2-oxo-5- (piperidin-1-yl) octahydro-2H-cyclohepta [b] furan-3-yl)

[Reaction Scheme 2]

(2-oxo-5- (piperidin-1-yl) octahydro-2H-cyclohepta [b] furan-3-yl) phosphonate having the structure shown in Scheme 2 above.

Preparation Preparation Example 3 Preparation of diethyl- (5- (4-methylpiperazin-1-yl) -2-oxooctahydro-2H-cyclohepta [b] furan-3-yl)

[Reaction Scheme 3]

(230 mg, 0.756 mmol) and methyl piperazine (0.25 ml, 2.27 mmol) according to Reaction Scheme 3, and then reacted with diethyl- (2,5-dioxoctahydro-2H-cyclohepta [ mmol), sodium hydrogen cyanide (143 mg, 2.27 mmol) and acetic acid (0.022 ml, 0.378 mmol) were added to DCM and stirred at 0 ° C for 10 hours. Thereafter, diethyl- (5- (4-methylpiperazin-1-yl) -2-oxooctahydro-2H-cyclohepta [b] furan-3-yl) phosphonate is obtained by column chromatography (91%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.29 ~ 1.34 (6H, m), 1.40 ~ 1.45 (1H, m), 1.50 ~ 1.68 (2H, m), 1.75 ~ 1.85 (3H, m), 1.90 ~ 2.00 (2H, m), 2.01-2.10 (1H, m), 2.49-2.55 (1H, m), 2.66 (3H, s), 2.75-2.90 (5H, bs), 3.00-3.22 ~ 4.20 (4H, m), 4.70 ~ 4.82 (1H, m).

Preparation 4 Preparation of tert -butyl- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) carbamate

[Reaction Scheme 4]

Tert -butyl- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) carbamate having the structure shown in Scheme 4 is prepared.

Preparation Preparation Example 5 Preparation of N- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) acetamide

[Reaction Scheme 5]

(3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) acetamide having the structure shown in the above Reaction Scheme 5 is prepared.

Preparation Preparation Example 6 Preparation of N- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) benzamide

[Reaction Scheme 6]

(3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) benzamide having the structure shown in Scheme 6 above is prepared.

Preparation Preparation Example 7 Preparation of 3-methylenehexahydro-2H-cyclohepta [b] furan-2,5 (3H) -dion

[Reaction Scheme 7]

3-methylenehexahydro-2H-cyclohepta [b] furan-2,5 (3H) -dione with the structure shown in Scheme 7 above is prepared.

Preparation Preparation Example 8 Preparation of racemic (3aR, 5S, 8aR) -3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-4-methylbenzenesulfonate

[Reaction Scheme 8]

Cyclohepta [b] furan-2-one (0.207 g, 1.136 mmol) was reacted with racemic (3aR, 5S, 8aR) -5-hydroxy-3- methylene-2- oxoctahydro- Dimethylaminopyridine (0.42 g, 0.304 mmol) was added thereto and stirred at room temperature using pyridine as a solvent. Thereafter, racemic (3aR, 5S, 8aR) -3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-4-methylbenzenesulfonate is obtained Yield: 86%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.49 ~ 1.56 (3H, m), 1.60 ~ 1.70 (1H, m), 1.80 ~ 1.95 (2H, m), 2.06 ~ 2.17 (2H, m), 3.44 ~ 3.50 (1H, m), 4.67 ( 1H, td, J = 12, 4 Hz), 4.77 (1H, t, J = 8 Hz), 5.42 (1H, d, J = 4 Hz), 6.23 (1H, d, J = 4 Hz), 7.34 (2H, d, J = 8 Hz), 7.77 (2H, d, J = 8 Hz).

Preparation Preparation Example 9 Preparation of 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methanesulfonate

[Reaction Scheme 9]

3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methanesulfonate having the structure shown in Scheme 9 is prepared.

Preparation Preparation Example 10 Preparation of 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-phenylcarbonate

[Reaction Scheme 10]

Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-phenyl carbonate having the structure shown in Scheme 10 is prepared.

Preparation Preparation Example 11 Preparation of 3-methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-ethylcarbamate

[Reaction Scheme 11]

Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-ethylcarbamate having the structure shown in Scheme 11 is prepared.

(Preparation Preparation Example 12) Preparation of 5- (methoxymethoxy) -3-methyleneoctahydro-2H-cyclohepta [b] furan-

[Reaction Scheme 12]

5- (Methoxymethoxy) -3-methyleneoctahydro-2H-cyclohepta [b] furan-2-one having the structure shown in Scheme 12 is prepared.

Preparation Preparation Example 13 Preparation of 3-methylene-2-octahydro-2H-cyclohepta [b] furan-5-yl-acetate

[Reaction Scheme 13]

3-methylene-2-octahydro-2H-cyclohepta [b] furan-5-yl-acetate having the structure shown in Scheme 13 is prepared.

Preparation Preparation Example 14 Preparation of 3-methylene-5-morpholinooctahydro-2H-cyclohepta [b] furan-2-one

[Reaction Scheme 14]

3-methylene-5-morpholinooctahydro-2H-cyclohepta [b] furan-2-one having the structure shown in Scheme 14 above is prepared.

Preparation 15) Preparation of 3-methylene-5- (piperidin-1-yl) octahydro-2H-cyclohepta [b] furan-

[Reaction Scheme 15]

3-methylene-5- (piperidin-1-yl) octahydro-2H-cyclohepta [b] furan-2-one having the structure shown in Scheme 15 above is prepared.

Preparation 16 Preparation of 5- (4-methylpiperazin-1-yl) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b] furan-

[Reaction Scheme 16]

(106 mg, 0.273 mmol) was reacted with diethyl (5- (4-methylpiperazin-1-yl) -2-octahydro-2H-cyclohepta [ And potassium t -butoxide (24.5 mg, 0.218 mmol), and the mixture was stirred at -78 ° C for 30 minutes. 4-Nitrobenzaldehyde (82 mg, 0.546 mmol) was added thereto, and the mixture was stirred for 10 minutes. The mixture was stirred at room temperature for 2 hours. After that, potassium t -butoxide (24.5 mg, 0.218 mmol) was added, and the reaction was terminated after 6 hours. Thereafter, 5- (4-methylpiperazin-1-yl) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b] furan-2-one is obtained by column chromatography 80%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.48 ~ 2.08 (6H, m), 2.1 ~ 2.25 (8H, m), 2.40 ~ 2.60 (2H, m), 2.85 ~ 3.00 (1H, bs), 3.89 ~ 3.93 (1H, m), 4.85 ~ 4.89 (1H, m), 5.26 (3H, s), 7.60 (1H, s), 7.61 (2H, d, J = 12 Hz), 8.23 (2H, d, J = 12 Hz).

Preparation Preparation 17 Preparation of 5- (methoxymethoxy) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b] furan-

[Reaction Scheme 17]

(Methoxymethoxy) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b] furan-2-one having the structure shown in Scheme 17 above.

(Preparation 18) Preparation of 3- (4-nitrobenzylidene) -2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-

[Reaction Scheme 18]

To give 3- (4-nitrobenzylidene) -2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-acetate having the structure shown in Scheme 18 above.

Preparation Preparation Example 19 Preparation of racemic (3aR, 5S, 8aR) -3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-3- (trifluoromethyl) benzenesulfonate Manufacturing

[Reaction Scheme 19]

Cyclohepta [b] furan-2-one (0.10 g, 0.548 mmol) was reacted with racemic (3aR, 5S, 8aR) -5-hydroxy-3- methylene-2- oxoctahydro- Dimethylaminopyridine (0.025 g, 0.219 mmol) was added, and the mixture was stirred at room temperature using pyridine as a solvent. After column chromatography, the racemic (3aR, 5S, 8aR) -3-methylene-2-oxoctahydro-2H-cyclohepta [b] furan-5-yl-3- (trifluoromethyl) (Yield: 71%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.48 ~ 1.75 (4H, m), 1.80 ~ 1.92 (1H, m), 1.92 ~ 2.05 (1H, m), 2.05 ~ 2.15 (1H, m), 2.15 ~ 2.25 (1H, m), 3.42 ~ 3.55 (1H, m), 4.65 ~ 4.78 (1H, td, J = 12, 4 Hz), 4.85 ~ 4.95 (1H, m), 5.49 (2H, d, J = 4 Hz ), 6.28 (1H, d, J = 4 Hz), 7.73 (1H, t, J = 8 Hz), 7.92 (1H, d, J = 8 Hz), 8.10 (1H, d, J = 8 Hz), 8.16 (1 H, s).

Preparation Preparation Example 20 Preparation of racemic (3aR, 5S, 8aR) -3-methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-4-fluorobenzenesulfonate

[Reaction Scheme 20]

Cyclohepta [b] furan-2-one (0.93 g, 0.510 mmol) was reacted with racemic (3aR, 5S, 8aR) -5-hydroxy-3- methylene-2- oxoctahydro- Dimethylaminopyridine (0.019 g, 0.153 mmol) was added thereto, and the mixture was stirred at room temperature using pyridine as a solvent. Thereafter, racemic (3aR, 5S, 8aR) -3-methylene-2-oxoctahydro-2H-cyclohepta [b] furan-5-yl-4-fluorobenzenesulfonate is obtained by column chromatography (Yield: 91%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.45 ~ 1.62 (3H, m), 1.63 ~ 1.75 (1H, m), 1.80 ~ 1.87 (1H, m), 1.92 ~ 2.02 (1H, m)), 2.03 ~ 2.12 (1H, m), 2.15 ~ 2.25 (1H, m), 3.49 ~ 3.53 (1H, m), 4.68 ~ 4.72 (1H, td, J = 12, 4 Hz), 4.79 ~ 4.84 (1H, m), (2H, t, J = 8 Hz), 7.94 (2H, m), 5.50 (1H, d, J = 4 Hz), 6.27 (1H, d, J = 4 Hz).

Preparation Preparation Example 21 Preparation of racemic (3aR, 5S, 8aR) -3 - ((dimethylamino) methyl) -2-oxohexahydro-2H-cyclohepta [b] furan- Manufacture of Nate

[Reaction Scheme 21]

Dichloromethane was added as a solvent to dimethylamine hydrochloride (0.437 g, 5.34 mmol) and potassium carbonate (1.48 g, 10.68 mmol) according to Reaction Scheme 21 and stirred. When the salt disappeared, the solution was treated with racemic (3aR, 5S, 8aR) -3-methylene-2-oxohexahydro-2H- cyclohepta [b] furan- 5-yl-4-methylbenzenesulfonate (0.120 g, 0.356 mmol) and stirred at room temperature. After column chromatography, the racemic (3aR, 5S, 8aR) -3 - ((dimethylamino) methyl) -2-oxohexahydro-2H-cyclohepta [b] furan- Sulfonate (yield: 61%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.53 ~ 1.75 (6H, m), 2.05 ~ 2.15 (1H, m), 2.26 (6H, s), 2.30 ~ 2.40 (1H, m), 2.47 (3H, s ), 2.48 ~ 2.65 (3H, m), 2.85 ~ 2.95 (1H, m), 4.62 ~ 4.65 (1H, td, J = 12, 4 Hz), 4.82 ~ 4.90 (1H, t, J = 8 Hz), 7.37 (2H, d, J = 8 Hz), 7.82 (2H, d, J = 8 Hz).

Preparation Preparation Example 22 Preparation of racemic (3aR, 5S, 8aR) -3 - ((Dimethylamino) methyl) -2-oxooctahydro-2H-cyclohepta [b] furan- Manufacture of Nate

[Reaction Scheme 22]

Dichloromethane was added as a solvent to dimethylamine hydrochloride (0.536 g, 6.57 mmol) and potassium carbonate (1.816 g, 13.14 mmol) according to the above scheme 22 and stirred. When the salt disappeared, the solution was treated with racemic (3aR, 5S, 8aR) -3-methylene-2-oxohexahydro-2H-cyclohepta [b] furan- mmol) and stirred at room temperature. This was purified by column chromatography to give racemic (3aR, 5S, 8aR) -3 - ((Dimethylamino) methyl) -2-oxooctahydro-2H-cyclohepta [b] furan- Benzenesulfonate (yield: 68%).

^{1 H NMR δ (400 MHz,} CDCl3): 1.51 ~ 1.85 (5H, m), 2.08 ~ 2.17 (2H, m), 2.19 (6H, s), 2.35 ~ 2.45 (2H, m), 2.50 ~ 2.60 (2H m), 2.90-2.98 (1H, m), 3.03 (3H, s), 4.60-4.65 (1H, m), 5.05-5.08 (1H, m).

The specific compounds of the present invention prepared according to Preparation Preparation Examples 1 to 22, the structural formulas and the compound names are shown as follows.

(Compound 1) tert-Butyl- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) carbamate.

(Compound 2) 3-Methylenehexahydro-2H-cyclohepta [b] furan-2,5 (3H) -dione.

(Compound 3) 3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate.

(Compound 4) 3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-benzoate.

(Compound 5) 3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-phenyl carbonate.

(Compound 6) N- (3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl) acetamide.

(Compound 7) N- (3-methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-8-yl) benzamide.

(Compound 8) 5-Hydroxy-3-methyleneoctahydro-2H-cyclohepta [b] furan-2-one.

(Compound 9) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-ethylcarbamate.

(Compound 10) 5- (Methoxymethoxy) -3-methyleneoctahydro-2H-cyclohepta [b] furan-2-one.

(Compound 11) 3-Methylene-2-octahydro-2H-cyclohepta [b] furan-5-yl-acetate.

(Compound 12) 3-Methylene-5-morpholinooctahydro-2H-cyclohepta [b] furan-2-one.

(Compound 13) 3-Methylene-5- (piperidin-1-yl) octahydro-2H-cyclohepta [b] furan-2-one.

(Compound 14) 5- (4-Methylpiperazin-1-yl) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b] furan-2-one.

(Compound 15) 3- (4-Nitrobenzylidine) hexahydro-2H-cyclohepta [b] furan-2,5 (3H)

(Compound 16) A mixture of 5- (methoxymethoxy) -3- (4-nitrobenzylidene) octahydro-2H-cyclohepta [b]

(Compound 17) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-8-yl-4-methanesulfonate.

(Compound 18) 3- (4-Nitrobenzylidene) -2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-acetate.

(Compound 19) 5 - ((2-Hydroxylethyl) amino) -3-methyleneoctahydro-2H-cyclohepta [b] furan-

(Compound 20) Methyl- (3-methylene-2-oxohexahydro-2H-cyclohepta [b] furan-8-yl) carbamate

(Compound 21) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-dimethylsulfonate.

(Compound 22) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-3- (trifluoromethyl) benzenesulfonate.

(Compound 23) 3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-3-2,3,4,5,6-pentafluorobenzenesulfonate.

(Compound 24) 3 - ((Dimethylamino) methyl) -2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-methanesulfonate.

(Compound 25) 3 - ((Dimethylamino) methyl) -2-oxooctahydro-2H-cyclohepta [b] furan-5-yl-4-methylbenzenesulfonate.

(Compound 26) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-4-fluorobenzenesulfonate.

(Example 1) Anti-gastritis in the hydrochloric acid-ethanol-induced gastritis model of the compound of the present invention

Effect test

Rats were fasted for 24 hours and then Compound 1 to Compound 26 prepared as described above were orally administered according to the method of Mizui et al. (J. J. Pharmacol. 33: 939-945, 1983), and after 1 hour, 150 mM HCl-60 % Ethanol was orally administered in 1.5 ml per animal. After 1 hour, cervical dislocations were performed and the animals were sacrificed. The stomachs were immediately removed and 13 ml of 2% formalin was injected into the stomach for more than 1 hour. The lesion area (gastric lesion, mm ² ) was measured using a computer program image J 1.38 (NIH, Bethesda, Md.) After taking a photograph with a digital camera. 1 was used to calculate the gastric lesion inhibition rate. The 50% effective dose (ED ₅₀ ) was calculated by regression analysis. Rebamipide was used as a comparative substance.

Equation 1

Table 1 is a chart showing the gastric lesion inhibitory effect when Compound 1 to Compound 26 were administered at a dose of 1 mg / kg in a hydrochloric acid-ethanol-induced gastritis model. As shown in Table 1, Compounds 1, 2, 3, 6, 9, 11, and 17, when compared with the group administered with 50 mg / kg of rebamipide, showed that the gastric lesion inhibitory effect was significantly higher Compound.

Table 2 is a chart showing the gastric lesion inhibitory effect when Compound 1 to Compound 26 were administered at a dose of 3 mg / kg in a hydrochloric acid-ethanol-induced gastritis model. As shown in Table 2, compounds 3, 6, 9, 11, 15, 17, and 24 were found to be effective compounds having a gastric lesion inhibitory effect significantly higher than that of rebamipide in the 3 mg / kg administration group.

Table 3 shows the gastric lesion inhibitory effect when Compound 24 to Compound 26 were administered at a dose of 10 mg / kg in a hydrochloric acid-ethanol-induced gastritis model. As shown in Table 3, compound 24 was found to be an effective compound having a gastric lesion inhibitory effect significantly higher than rebamipide in the 10 mg / kg administration group.

In conclusion, compounds 3, 6, 9, 11, and 17 are effective compounds for inhibiting gastric lesion in both the 1 mg / kg dose group and the 3 mg / kg dose group, kg-treated group, respectively.

Thus, compounds 3, 6, 9, 11, 17, and 24 were selected as novel bicyclic lactone compounds exhibiting an effective gastric lesion inhibitory effect in the hydrochloric acid-ethanol-induced gastritis model through this Example.

Compound 1 to Compound 26 in a hydrochloric acid-ethanol-induced gastritis model were administered at a dose of 1 mg / kg, compound Capacity (mg / kg) Number of animals Gastric lesion area (mm ² ) Lesion inhibition rate (%) Compound 1 One 6 86.6 ± 16.4 62.2 Compound 2 One 6 93.7 ± 14.6 59.2 Compound 3 One 6 87.4 ± 10.8 61.8 Compound 4 One 6 182.3 ± 24.2 20.1 Compound 5 One 6 201.7 ± 27.9 11.8 Compound 6 One 6 131.3 ± 29.1 42.5 Compound 7 One 6 209.2 + 34.3 8.3 Compound 8 One 6 184.1 ± 28.5 19.3 Compound 9 One 6 121.4 ± 37.1 46.9 Compound 10 One 6 152.6 ± 18.3 33.0 Compound 11 One 6 86.1 ± 15.6 62.2 Compound 12 One 6 246.3 ± 38.5 0 Compound 13 One 6 189.3 ± 27.3 17.1 Compound 14 One 6 191.0 + - 34.3 16.2 Compound 15 One 6 186.4 ± 36.5 18.3 Compound 16 One 6 224.7 ± 38.9 1.7 Compound 17 One 6 124.6 ± 21.7 45.6 Compound 18 One 6 231.3 ± 20.9 0 Compound 19 One 6 218.3 ± 21.5 4.3 Compound 20 One 6 214.1 ± 17.9 6.1 Compound 21 One 6 226.6 ± 32.1 0.1 Compound 22 One 6 231.2 + - 26.0 0 Compound 23 One 6 229.0 ± 23.1 0 Control group - 6 228.0 ± 30.4 - Rebamipide 50 6 168.4 ± 25.8 26.3

Compounds 1 to 26 in the hydrochloric acid-ethanol-induced gastritis model were administered at a dose of 3 mg / kg, compound Capacity (mg / kg) Number of animals Gastric lesion area (mm ² ) Lesion inhibition rate (%) Compound 1 3 6 149.2 ± 12.9 29.1 Compound 2 3 6 149.3 ± 14.5 29.2 Compound 3 3 6 79.1 ± 4.0 62.5 Compound 4 3 6 213.6 ± 39.8 0 Compound 5 3 6 188.7 ± 50.8 10.5 Compound 6 3 6 82.4 ± 54.2 60.9 Compound 7 3 6 154.2 ± 46.5 26.9 Compound 8 3 6 181.4 ± 18.4 14.0 Compound 9 3 6 67.4 ± 19.1 68.0 Compound 10 3 6 129.1 ± 23.7 38.5 Compound 11 3 6 59.1 ± 31.9 72.0 Compound 12 3 6 143.5 ± 47.5 31.9 Compound 13 3 6 121.6 ± 14.2 42.3 Compound 14 3 6 220.4 ± 47.4 0 Compound 15 3 6 84.1 ± 26.6 60.1 Compound 16 3 6 229.3 ± 51.8 0 Compound 17 3 6 90.5 ± 46.2 57.1 Compound 18 3 6 243.2 ± 16.1 0 Compound 19 3 6 189.8 ± 7.7 10.0 Compound 20 3 6 188.4 ± 36.6 10.7 Compound 21 3 6 214.9 ± 58.8 0 Compound 22 3 6 169.4 ± 61.8 19.7 Compound 23 3 6 235.7 ± 40.6 0 Compound 24 3 6 72.7 ± 23.5 65.5 Compound 25 3 6 119.8 ± 16.5 43.2 Compound 26 3 6 137.2 ± 36.4 34.9 Control group - 6 210.9 ± 23.1 - Rebamipide 50 6 149.4 ± 25.8 29.1

Compounds 24 to 26 in a hydrochloric acid-ethanol-induced gastritis model were administered at a dose of 10 mg / kg, compound Capacity (mg / kg) Number of animals Gastric lesion area (mm ² ) Lesion inhibition rate (%) Compound 24 10 6 40.1 ± 2.4 31.4 Compound 25 10 6 14.3 ± 3.0 75.5 Compound 26 10 6 17.2 ± 16.1 70.6 Control group - 6 58.5 ± 4.7 - Rebamipide 50 6 28.4 ± 3.2 51.4

(Example 2) Anti-ulcer effect in the indomethacin-induced gastric ulcer model of the compound of the present invention

Rats were fasted for 24 hours and then tested by the method of Yamasaki et al. (Jap. J. Pharmacol. 49, 441-448, 1989). Each of the bicyclic lactone compounds produced by the method of the present invention was orally administered and oral administration of indomethacin (50 mg / kg) was effected orally in 0.5 ml per one hour after 1 hour. After 5 hours of fasting, cervical dislocations were performed and animals were sacrificed. Immediately, stomachs were removed and 13 ml of 2% formalin was injected into the stomach and fixed for 1 hour or more. The lesion area (mm ² ) was measured using a computer program image J 1.38 (NIH, Bethesda, Md.) After the incision was made along the fixed upper part of Taiwan and the photograph was taken with a digital camera. And the rate of gastric lesion inhibition was calculated.

The bicyclic lactone compounds that measured the anti-ulcer activity in this Example were compounds 3, 6, 9, 11, 17, and 24, which were partially approved in Example 1 and were administered at a dose of 10 mg / kg and 20 mg / kg .

The effect of the bicyclic lactone compound of the present invention obtained in the above method on the indomethacin-induced gastric ulcer model is shown in Table 4. [ As shown in Table 4, Compound 3, Compound 11 and Compound 24 showed the best anti-ulcer effect in both 10 mg / kg and 20 mg / kg administration groups.

Inhibitory effect of the compounds of the present invention on gastric lesions in an indomethacin-induced gastric ulcer model compound Capacity (mg / kg) Number of animals Gastric lesion area (mm ² ) Lesion inhibition rate (%) Compound 3 10 6 32.9 ± 8.7 62.5 20 6 18.4 ± 7.8 79.0 Compound 6 10 6 50.5 ± 6.9 42.4 20 6 45.3 ± 7.2 48.3 Compound 9 10 6 58.4 ± 6.5 33.4 20 6 47.6 ± 8.5 45.7 Compound 11 10 6 27.8 ± 5.9 68.3 20 6 22.5 ± 7.2 74.3 Compound 17 10 6 62.4 8.3 28.8 20 6 44.6 ± 6.9 49.1 Compound 24 10 6 31.7 ± 7.4 63.9 20 6 26.5 ± 9.1 69.8 Control group - 6 87.7 ± 7.2 - Rebamipide 50 6 68.9 ± 4.5 21.4

(Example 3) Acute toxicity test of the compound of the present invention for oral administration to rats

Acute toxicity tests for Compounds 3, 6, 9, 11, 17, and 24 were performed using specific pathogen member (SPF) SD male and female rats at 7 weeks of age. The animals were groomed for more than 7 days after the gross examination of the appearance of the animals, and the animals were selected for the experiment. The animals were kept at a temperature of 22 ± 2 ℃, a relative humidity of 50 ± 5% , And 12 hours of illumination (07:00 lit - 19:00 off). Diets were fed free of solid feed for laboratory animals and free water was used for negative water. Feed composition was provided by the supplier and no factors influencing the test were observed in feed and water.

Compounds 3, 6, 9, 11, 17, and 24 were administered at a dose of 100 mg / kg to 5 animals of each male and female in each group. The test materials were dissolved in 30% Cremophor EL and dissolved in physiological saline Once orally. After the administration of the test substance, the mortality and clinical symptoms of the animals were observed at a frequency of once / day for 14 days. After the end of the experiment, the abdominal organs and thoracic organs were visually observed under ether anesthesia.

Experimental results showed that all the animals treated with Compounds 3, 6, 9, 11, 17, and 24 did not exhibit any significant clinical symptoms during the experiment, but died in animals treated with Compounds 9 and 17 . The results are shown in Table 5.

The mortality of rats upon administration of the compounds of the present invention Dose
(mg / kg) Mortality rate Number of our rats Elapsed days after administration One 2 3 4 5 6 7 8 9 10 11 12 13 14 Control group - 0/10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Compound 3 100 0/10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Compound 6 100 0/10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Compound 9 100 1/10 0 0 0 0 0 0 One One One One One One One One Compound 11 100 0/10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Compound 17 100 1/10 0 0 0 0 0 0 0 One One One One One One One Compound 24 100 0/10 0 0 0 0 0 0 0 0 0 0 0 0 0 0

(Example 4) Chromosome aberration test using culture Chinese Hamster Lung (CHL) cells

The test compounds used in this Example were Compound 3, Compound 6, Compound 11 and Compound 24 selected in Examples 1 to 3. In addition, dimethylsulfoxide (DMSO) was used as a negative control, and benzopyran was used as a positive control agent and mitomycin was used as a positive control agent.

The metabolically active system consisted of S9 and Cofactor, S9 was a liver of male Sprague Dawley (SD) rats induced with Aroclor-1254, and Cofactor-1 was a coenzyme manufactured by Wako Pure Chemical Industries, Japan. The composition of the S9 mix used in this experiment was 5000 g of S9, centrifuged for 5 minutes, and then the supernatant was collected and mixed with Cofactor-1 and S9 in a ratio of 7: 3.

Cell culture was performed using a CHL cell line derived from lung fibroblasts of Chinese hamster. The culture medium was prepared by adding 10% fetal bovine serum (Gibco) and 1% penicillin / streptomycin (Gibco) to the minimum essential medium (Gibco). Cells were cultured using a cell culture flask in a 37 ° C incubator containing 5% carbon dioxide and saturated water vapor, and cells were separated with 0.1% trypsin solution every 2-3 days and subcultured.

The cytotoxicity test was carried out to determine the treatment concentration of this test. The cells were cultured in 96-well plates at a density of 1 × 10 ⁴ cells / 200 μl / well and incubated for 24 hours. The cells were cultured for 24 hours, and the test substances were treated with and without metabolic activation system. The test substances were in the range of 1 to 5,000 μg / ml 8 steps. After incubation for 4 hours after the treatment with MTT reagent, the absorbance was measured at 595 nm, and the IC50 was deduced. The precipitated wells were excluded from the evaluation. The concentrations showing a decrease in cell number of 50% or more as compared with the control group were set at the highest concentrations, and a total of three doses were determined as the present test doses.

In this test, 5 ml of 1 × 10 ⁴ cells / ml was dispensed into a 25 cm ² culture flask, and after 3 days of culture, all the culture medium of each flask was removed before treatment of the test material, After 6 hours, the cells were further incubated for 18 hours after replacing with fresh medium.

Colcemid was treated with 0.2 μg / ml of Colcemid in all the flasks cultured for 24 hours after the test substance and metabolic activation system treatment, and the medium cells were collected by shaking method after 2 hours. The medium containing the medium cells was centrifuged, and treated with 0.075 M KCl solution and fixed (methanol: acetic acid = 3: 1, v / v) to prepare chromosome samples and stained with 3% Giemsa solution. Three specimens were prepared for each flask. One type of specimen was selected and counted at a magnification of 1,000 times.

Structural anomalies were observed for the number of mobilization bodies and chromosomal anomalies in the medium phase of 23-27 nucleotides, and the number and types of chromosomal abnormalities were recorded. Numerical averages were categorized according to the number of entities while counting 100 middle phases, and the results were expressed as averages of two repetitions. Chromosomal anomalies were evaluated as negative, negative (5% ~ 10%) and positive (10% or more) when the frequency of middle phase with chromosomal abnormality was less than 5% in the test substance treatment group.

As a result of the test, chromosome aberration test of CHL cells was carried out after administration of Compound 3, Compound 6, Compound 11 and Compound 24. As a result of counting the chromosomal abnormalities, the frequency of the abnormal middle phase in the concentration group of Compound 3, Compound 11 and Compound 24 did not increase in a dose-dependent manner, and was within the range of 5%.

However, in the case of Compound 6, the frequency of chromosomal abnormalities was increased in a dose - dependent manner, and the result was within the range of 5% to 41%.

Through this test, Compound 3, Compound 11 and Compound 24 proved to be safe compounds without chromosomal abnormality in CHL cells.

Table 6 shows the results of chromosome aberration test using Chinese Hamster Lung (CHL) cells cultured with the compound of the present invention.

CHL cell chromosome aberration test of the compound of the present invention Test substance Concentration (μg / ml) Chromosomal abnormality
Results compared to negative controls Evaluation of results Control
(1% DMSO) + S9 4% -S9 4% Compound 3 + S9 19.5 0% voice 9.75 0% 4.88 One% -S9 4.88 One% 2.44 3% 1.22 0% Compound 6 + S9 39.1 37% positivity 19.5 7% 9.75 4% -S9 4.88 13% 2.44 4% 1.22 0% Compound 11 + S9 19.5 5% voice 9.75 3% 4.88 0% -S9 2.44 4% 1.22 3% 0.61 2% Compound 24 + S9 78.2 5% voice 39.1 4% 19.5 One% -S9 9.75 5% 4.88 One% 2.44 0%

Compounds 3, 6, 9, 11, 17, and 24 showed high gastric lesion inhibitory effects through Examples 1 and 2 and Compound 3, 6, 11, and 24 were found to be safe Compound. Finally, Chromosomal aberration test of Chinese Hamster Lung (CHL) cells revealed that Compound 3, Compound 11, and Compound 24 are the safest compounds that do not cause acute toxicity and chromosome abnormality together with high anti-gastritis and anti-gastric effect .

In addition, the inventors of the present invention judged compound 3 as the most safe drug candidate having excellent anti-gastritis and anti-gastric activity and toxicity, by judging both the gastric lesion suppression effect, acute toxicity and chromosome aberration in a comprehensive manner, 0.0 > 1 < / RTI >

(Example 5) A photograph of gastric lesion in which Compound 3 of the present invention was administered

In Example 1, the anti-gastritis effect was measured in a hydrochloric acid-ethanol-induced gastritis model of the compound of the present invention. The gastric lesion state in which the compound 3 selected as the bicyclic lactone compound for treating gastrointestinal disease of the present invention was administered was photographed.

FIG. 1 is a photograph showing the administration of Compound 3 of the present invention, the administration of 50 mg / kg of rebamipide, and the gastrointestinal condition of the control group in a hydrochloric acid-ethanol-induced gastritis model.

FIG. 1A is a photograph of the gastrointestinal state of gastric lesion when Compound 3 is administered at a dose of 1 mg / kg. FIG. 1B is a photograph of the stomach of gastric lesion when Compound 3 is administered at a dose of 3 mg / kg. FIG. 1C is a photograph of the gastrointestinal state of gastric lesion when levamidic acid is administered at a dose of 50 mg / kg. FIG. 1D is a photograph of the stomach of gastric lesion of a control group to which no compound is administered.

As shown in Table 1 and Table 2 of Example 1, when Compound 3 was administered at a dose of 1 mg / kg, the rate of gastric lesion inhibition was 61.8%. When Compound 3 was administered at a dose of 3 mg / kg, 62.5% Respectively. On the other hand, when 50 mg / kg of rebamipide was administered, the rate of gastric lesion inhibition was 26.3%.

Claims

3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound represented by the following formula 1 having therapeutic or prophylactic activity against gastritis or gastric ulcer, Acceptable salt.

Equation 1

(DMAP) as a starting material using 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan- Yl) -4-methylbenzenesulfonate (I) is prepared by reacting 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate.

The process according to claim 2, wherein the 5-hydroxy-3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan- (4-bromocyclohept-2-enone (B) and reacting with potassium 2- (diethoxyphosphoryl) acetate to obtain 4-oxocyclohept- Diethoxyphosphoryl) acetate (C) was obtained and a ring closure reaction was carried out to obtain diethyl- (2,5-dioxoctahydro-2H-cyclohepta [b] furan-3-yl) , Followed by reduction with diethyl- (5-hydroxy-2-oxooctahydro-2H-cyclohepta [b] furan-3- yl) phosphonate Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-2-one (F).

A bicyclic lactone compound or a pharmaceutically acceptable salt thereof, having the gastric or gastric ulcer prevention or therapeutic activity and safety represented by the following chemical names.
(Compound 6) (1) N- (3-Methylene-2-oxooctahydro-2H-cyclohepta [b] furan-
(2) 3-Methylene-2-oxo-octahydro-2H-cyclohepta [b] furan-5-yl-ethylcarbamate (Compound 9)
(3) Synthesis of 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methanesulfonate (Compound 17)

The method according to claim 1, wherein the 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound of Formula 1 is a metabolic active system using Chinese hamster lung cells A compound or a pharmaceutically acceptable salt thereof, which is free of chromosomal aberration cytotoxicity which does not cause chromosomal changes of Chinese hamster lung cells in a direct chromosomal aberration test.

A pharmaceutical composition comprising 0.1 to 90% by weight of the 3-methylene-2-oxooctahydro-2H-cyclohepta [b] furan-8-yl-4-methylbenzenesulfonate compound of claim 1, A pharmaceutical composition for preventing or treating gastritis or gastric ulcer.