JPH07113030B2 - Thiazole derivative and antiulcer agent containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel thiazole derivative and an antiulcer agent containing the same.

[Conventional technology]

Although the development of histamine H ₂ antagonists has facilitated the treatment of ulcers, the current high recurrence rate after discontinuation of administration is a major problem. Since recurrence is considered to be caused by a decrease in defense factors, it is desired to develop a drug having both gastric acid secretion inhibitory action and defense factor enhancing action.

[Problems to be Solved by the Invention]

The present inventors have variously synthesized thiazole derivatives, and as a result of diligent research on their physiological actions, they found that the thiazole derivatives according to the present invention have a strong gastric acid secretion inhibitory action and defense factor enhancing action, and thus the present invention is completed. I arrived. The thiazole derivatives of the present invention are useful in treating ulcers.

Therefore, an object of the present invention is to provide a thiazole derivative having such useful properties and an antiulcer drug containing the same.

[Means for Solving the Problems]

The present invention in accordance with the above object is represented by the general formula (I) (Wherein R ₁ and R ₂ represent a lower alkyl group or R ₁ and R ₂ together represent a group having the formula CH _{2 m} , wherein m is 4 or 5; n is 1 To an integer of 5) or a physiologically acceptable salt thereof. The present invention also provides an antiulcer agent containing the thiazole derivative represented by the above formula (I) or a salt thereof. The thiazole derivative represented by the above formula (I) of the present invention is an amine derivative represented by the following formula (II) (Wherein R ₁ , R ₂ and n have the same meanings as described above) and 3- (2-chloropyridyl) isothiocyanate. Airnol, methanol and the like can be used as the solvent. The reaction temperature is preferably 0 ° to the reflux temperature.

In the general formula (I), R ₁ and R ₂ are linear or branched lower alkyl groups each having 1 to 4 carbon atoms, examples of which include methyl, ethyl, n-propyl and iso-. Propyl, n-butyl, iso-butyl, tert
-Butyl is mentioned.

[Action]

The thiazole derivative of the present invention is used as an anti-ulcer agent,
The daily dose for adults varies depending on the symptoms, but is generally 10 to 2000
The dose is preferably 20 to 60 mg, and may be administered in 1 to 3 divided doses depending on the symptoms. The administration method can be any form suitable for administration, and oral administration is particularly preferable, but intravenous injection is possible.

The compound of the present invention is used as an active ingredient or one of the active ingredients, alone or mixed with a pharmaceutical carrier or excipient by a usual method, and then tablets, dragees, powders, capsules, granules, suspensions, emulsions, It can be applied in various forms formulated into injection solutions and the like. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

Next, the present invention will be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these.

Example 1 N- [3- [3- (Piperidinomethyl) phenoxy] propyl] phthalimide (5 g) was dissolved in ethanol (60 ml), hydrazine hydrate (80%) (1.20 ml) was added, and the mixture was refluxed for 2 hours. did. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was stirred for a while and then allowed to pass. The liquid is concentrated under reduced pressure,
3- [3- (piperidinomethyl) phenoxy] propylamine (3.28 g) was obtained.

Next, under an argon atmosphere, 4- (phthaloylamino) butyric acid (3.01 g) and 4-dimethylaminopyridine (0.16 g) were dissolved in methylene chloride (40 ml), and N, N′-dicyclohexylcarbodiimide (3.06 g) was dissolved. Was added and the mixture was stirred at room temperature for 15 minutes. Furthermore, 3- [3- (piperidinomethyl) phenoxy] propylamine (3.28 g) in methylene chloride (20 m
l) The solution was added and stirred for 16 hours. Benzene was added to the reaction mixture and the mixture was filtered, and the solution was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with a chloroform-methanol (30: 1 to 20: 1 v / v) elution fraction to obtain N- [3-
[3- (piperidinomethyl) phenoxy] propyl]-
4- (phthaloylamino) butyramide (3.48 g) was obtained.

Furthermore, N- [3- [3- (hyperidinomethyl) phenoxy] propyl] -4- (phthaloylamino) butyramide (3.48 g) was dissolved in ethanol (35 ml), and hydrazine hydrate [80%] (0.91 ml) was added. Was added and refluxed for 1.5 hours. The reaction solution was concentrated under reduced pressure, chloroform was added and the mixture was stirred for a while and then allowed to pass, and the solution was contracted under reduced pressure. Then, the residue was dissolved in ethanol (20 ml), 3- (2-chloropyridyl) isothiocyanate (1.28 g) was added, and the mixture was stirred at room temperature for 64 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous potassium hydroxide solution and saturated brine were added to the residue, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [3- [3- (3- (piperidinomethyl) phenoxy] propyl] -4- [2-] was extracted from the fraction eluted with chloroform-methanol (20: 1 to 10: 1 v / v). Pyrido [2,3-d] thiazoloamino] butyramide (2.17 g) was obtained. Its spectroscopic data supports the structure of formula (III) below.

NMR (CDCl ₃ ) δ: 1.49 (6H, m), 3.44 (2H, s), 4.00 (2
H, t, J = 5.8Hz), 6.48 (1H, m), 6.69 ~ 7.31 (5H, m),
8.13 to 8.46 (3H, m).

Example 2 N-phthaloylglycine (1.5 g) and 4-dimethylaminopyridine (0.09 g) methylene chloride (2
4 ml) -N, N-dimethylformamide (3 ml),
N, N'-Dicyclohexylcarbodiimide (1.73 g) was added, and the mixture was stirred at room temperature for 15 minutes. Furthermore, 3- [3- (piperidinomethyl) phenoxy] propylamine (1.82 g)
Methylene chloride (12 ml) solution was added and stirred for 17 hours.
Benzene was added to the reaction mixture and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [3- [3- (piperidinomethyl) phenoxy] propyl] -2- (phthaloyl) was eluted with a fraction eluted with chloroform-methanol (30: 1 to 20: 1 v / v). Amino) acetamide (2.22g) was obtained.

Furthermore, N- [3- [3- (piperidinomethyl) phenoxy] propyl] -2- (phthaloylamino) acetamide (2.16 g) was dissolved in ethanol (25 ml), and hydrazine hydrate [80%] (0.60 ml). Was added and refluxed for 1.5 hours. The reaction solution was concentrated under reduced pressure, chlorohomul was added and the mixture was stirred for a while and then allowed to pass, and the solution was concentrated under reduced pressure. The residue was then dissolved in ethanol (15 ml) and 3- (2-chloropyridyl) isothiocyanate (0.85 g) was added to give 64.
Stir at room temperature for hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous potassium hydroxide solution and saturated brine were added to the residue,
It was extracted twice with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [3- [3- (3- (piperidinomethyl) phenoxy] propyl] -2- [2-] was extracted from the chloroform-methanol (20: 1-10: 1 v / v) elution fraction. Pyrido [2,3-d] thiazoloamino] acetamida (1.79 g) was obtained. Its spectroscopic data supports the structure of formula (IV):

NMR (CDCl ₃ ) δ: 1.51 (6H, m), 3.57 (2H, s), 4.02 (2
H, t, J = 5.8Hz), 4.38 (2H, s), 6.72 ~ 7.30 (6H, m),
8.11 to 8.39 (3H, m).

Example 3 N-carbobenzyloxy-β-alanine (1.77 g) and 4-dimethylaminopyridine (0.10) under an argon atmosphere.
g) was dissolved in methylene chloride (25 ml) -N, N-dimethylformamide (2 ml), N, N'-dicyclohexylcarbodiimide (1.88 g) was added, and the mixture was stirred at room temperature for 15 minutes. Further, a solution of 3- [3- (piperidinomethyl) phenoxy] propylamine (1.97 g) in methylene chloride (10 ml) was added, and the mixture was stirred for 15 hours. Benzene was added to the reaction solution and the mixture was filtered, and the solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (30: 1 to 20: 1 v / v) fraction to obtain N- [3- [3-
(Piperidinomethyl) phenoxy] propyl] -3-
(Carbobenzyloxyamino) propionamide (2.
02g) was obtained.

Next, N- [3- [3- (piperidinomethyl) phenoxy] propyl] -3- (carbobenzyloxyamino)
Propionamide (2.02 g) was dissolved in methanol (15 ml), 5% palladium carbon (0.5 g) was added under argon substitution, the atmosphere was further replaced with hydrogen, and then catalytic hydrogenation was carried out for 22 hours. After the reaction solution was passed, it was concentrated under reduced pressure. Ethanol (20 ml) was added to the residue to dissolve it, 3- (2-chloropyridyl) isothiocyanate (0.76 g) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, 1N aqueous potassium hydroxide solution and saturated brine were added to the residue, and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the chloroform-methanol (20: 1-10: 1 v / v) elution fraction,
N- [3- [3- (piperidinomethyl) phenoxy] propyl] -3- [2-pyrido [2.3-d] thiazoloamino] propionamide (1.09 g) was obtained. Its spectroscopic data supports the structure of formula (V):

NMR (CDCl ₃ ) δ: 1.53 (6H, m), 3.56 (2H, s), 3.99 (2
H, t, J = 6Hz), 6.60 ~ 7.30 (6H, m), 8.02 ~ 8.38 (3H,
m).

Example 4 2.00 g of N- [3- [3-piperidinomethyl) phenoxy] propyl] phthalimide was dissolved in 40 ml of ethanol, 0.45 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. After adding chloroform and stirring,
I had The liquid was concentrated under reduced pressure to obtain 3- [3- (piperidinomethyl) phenoxy] propylamine. This is dissolved in 30 ml of methylene chloride to prepare 5-phthaloylaminovaleric acid 1.31.
g and 1-ethyl-3- (3-dimethylaminopropyl)
Carbodiimide hydrochloride (1.02 g) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.29 g of N- [3- [3- (piperidinomethyl) phenoxy] propyl] -5- (phthaloylamino) pentylamide from the fraction eluted with 2% methanol-chloroform. This is ethanol 2
It was dissolved in 0 ml, 0.22 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was stirred and passed. The solution was concentrated under reduced pressure and N- [3- [3-
(Piperidinomethyl) phenoxy] propyl] -5-aminopentylamide was obtained. This was dissolved in 20 ml of ethanol and 3- (2-chloropyridyl) isothiocyanate was added.
46 g was added, and the mixture was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with 5% methanol-chloroform, N- [3- [3- (piperidinomethyl) phenoxy] propyl] -5- [2-pyrido [2,3-d] thiazoloamino] pentyl was obtained. 0.56 g of amide was obtained.

Its spectroscopic data supports the structure of formula (VI) below.

_{NMR (CDCl 3) δ: 1.5~2.7} (18H, m), 3.2~3.9 (4H,
m), 3.65 (2H, s), 4.00 (2H, t, J = 6Hz), 6.6 to 7.4
(6H, m), 8.0 to 8.4 (3H, m).

Example 5 1.50 g of N- [3- [3- (piperidinomethyl) phenoxy] propyl] phthalimide was dissolved in 30 ml of ethanol, 0.45 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. After adding chloroform and stirring,
I had The liquid was concentrated under reduced pressure to obtain 3- [3- (piperidinomethyl) phenoxy] propylamine. This was dissolved in 30 ml of methylene chloride, 1.03 g of 6-phthaloylaminohexanoylamide and 0.76 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [3- [3- [3- [3-
(Piperidinomethyl) phenoxy] propyl] -6-
1.50 g of (phthaloylamino) hexylamide was obtained. This was dissolved in 30 ml of ethanol, 0.24 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was stirred and passed. The liquid was concentrated under reduced pressure to give N- [3- [3- (piperidinomethyl) phenoxy] propyl] -6-aminohexylamide. This was dissolved in 20 ml of ethanol, 0.52 g of 3- (2-chloropyridyl) isothiocyanate was added, and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N was extracted from the fraction eluted with 5% methanol-chloroform.
0.60 g of-[3- [3- (piperidinomethyl) phenoxy] propyl] -6- [2-pyrido [2,3-d] thiazoloamino] hexylamide was obtained.

The spectroscopic data of this support the structure of formula (VII) below.

NMR (CDCl ₃ ) δ: 1.5 to 2.7 (20H, m), 3.2 to 3.9 (4H,
m), 3.66 (2H, s), 4.00 (2H, t, J = 6Hz), 6.6 to 7.5,
8.0 to 8.4 (3H, m).

[Example 6] 2.00 g of N- [3- [3- (pyrrolidinomethyl) phenoxy] propyl] phthalimide was dissolved in 40 ml of ethanol, 0.44 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. After adding chloroform and stirring, it was passed. The liquid was concentrated under reduced pressure to obtain 3- [3- (pyrrolidinomethyl) phenoxy] propylamine.
This was dissolved in 30 ml of methylene chloride, 1.28 g of 4- (phthaloylamino) butyric acid and 1.06 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1.10 g of N- [3- [3- (pyrrolidinomethyl) phenoxy] propyl] -4- (phthaloylamino) butyramide was obtained from the fraction eluted with 2% methanol-chloroform. This was dissolved in 20 ml of ethanol, 0.20 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was stirred and passed. The liquid was concentrated under reduced pressure and N- [3-
[3- (pyrrolidinomethyl) phenoxy] propyl]-
4-aminobutyramide was obtained. 20 ml of ethanol
Was dissolved in the above solution, 0.42 g of 3- (2-chloropyridyl) isothiocyanate was added and the mixture was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and N- [3- [3- (pyrrolidinomethyl) phenoxy] propyl] -5- [2-pyrido [2,3] was obtained from the fraction eluted with 6% methanol-chloroform.
0.41 g of -d] thiazoloamino] butyramide was obtained.

Its spectroscopic data supports the structure of formula (VIII):

NMR (CDCl ₃ ) δ: 1.5-2.7 (14H, m), 3.2-3.8 (4H,
m), 3.66 (2H, s), 4.00 (2H, t, J = 6Hz), 6.6 to 7.4
(6H, m), 8.0 to 8.4 (3H, m) Example 7 N- [3- [3- (diethylaminomethyl) phenoxy] propyl] phthalimide (1.7) g was added to ethanol (3
0 ml), hydrazine hydrate [80%] (0.56 ml) was added, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added, and the mixture was stirred for a while and then allowed to pass. The liquid was concentrated under reduced pressure to obtain 3- [3- (diethylaminomethyl) phenoxy] propylamine (1.1 g).

Next, a solution of 3- [3- (diethylaminomethyl) phenoxy] propylamine (1.1 g) in methylene chloride (30 ml) was added to 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide-hydrochloride (0.98g) was added. 5- (phthaloylamino)
After adding valeric acid (1.26g), it stirred at room temperature for 16 hours.
Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the liquid was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-2 to 4% (v / v) methanol eluate fraction was treated with N
-[3- [3- (diethylaminomethyl) phenoxy]
Propyl] -5- (phthaloylamino) pentylamide (1.84g) was obtained.

Furthermore, N- [3- [3- (dimethylaminomethyl) phenoxy] propyl] -5- (phthaloylamino) pentylamide (1.12 g) was dissolved in ethanol (20 ml),
Hydrazine hydrate [80%] (0.29 ml) was added, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added and the mixture was stirred for a while and then allowed to pass. The liquid is concentrated under reduced pressure, and N-
[3- [3- (diethylaminomethyl) phenoxy]-
Propyl] -5-aminopentylamide (0.70 g) was obtained.

Then N- [3- [3- (diethylaminomethyl) phenoxy] propyl] -5-aminopentylamide (0.
70 g) was dissolved in ethanol (20 ml), 3- (2-chloropyridyl) isothiocyanate (0.41 g) was added under an argon atmosphere, and the mixture was stirred at room temperature for 40 hours. After heating under reflux for a further 7 hours, the reaction solution was concentrated under reduced pressure. 1 for residue
A normal aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-2.
From the 10% (v / v) methanol elution fraction, N- [3-
[3- (Diethylaminomethyl) phenoxy] -propyl] -5- [2-pyrido [2,3-d] thiazoloamino]
Pentylamide (0.58g) was obtained.

Its spectroscopic data supports the structure of formula (IX) below.

NMR (CDCl ₃ ) δ: 1.03 (6H, t, J = 6Hz), 1.5 to 2.4 (8H,
m), 2.55 (4H, q, 7.5Hz), 3.2 to 3.8 (6H, m), 4.00 (2
H, t, J = 6Hz), 6.4 (1H, m), 6.6 to 7.4 (5H, m), 7.7 to
8.6 (3H, m).

[Test Example] (1) Inhibitory effect on water immersion restraint stress ulcer After fasting SD male rats (body weight 200 to 300 g) for 24 hours, the thiazole derivative according to the present invention is orally administered at a dose of 32 mg / kg body weight, It was put in a stress gauge and subjected to immersion restraint stress in a water bath at 23 ° C. Seven hours after the stress was applied, the rat was killed with ether, the stomach was removed, and after formalin treatment, the area of damage (mm ² ) generated in the glandular stomach was measured, and the total damage per animal was calculated as the ulcer index (Ulcer). Index).

As shown in the test result table, a remarkable antiulcer action was found. It was also confirmed that the thiazole derivative according to the present invention, which is not shown in the table, has a similar antiulcer action.

The ulceration inhibition rate (%) in the table means the value obtained by dividing the value obtained by dividing the ulcer index of the rat to which the thiazole derivative according to the present invention was orally administered by the ulcer index of the rat not to be orally administered, from 1.
It is 100 times.

(2) Inhibitory effect on ethanol ulcer After fasting SD male rats (body weight 200 to 300 g) for 24 hours, the thiazole derivative according to the present invention is orally administered at a dose of 32 mg / kg body weight, and 1 hour later ethanol 0.5 ml / It was orally administered at a dose of 100 g body weight. One hour after ethanol administration, the rats were killed with ether, the stomach was removed, and after formalin treatment, the area of damage (mm ² ) generated in the glandular stomach was measured, and the total damage per animal was calculated as the ulcer index (Ulcer). Index).

As shown in the test result table, a remarkable antiulcer action was found. It was also confirmed that the thiazole derivative according to the present invention, which is not shown in the display, has a similar antiulcer action.

The ulceration inhibition rate (%) in the table means the value obtained by dividing the value obtained by dividing the ulcer index of the rat to which the thiazole derivative according to the present invention was orally administered by the ulcer index of the rat not to be orally administered, from 1.
It is 100 times.

[Acute toxicity] An acute toxicity test by oral administration was performed using ICR male mice (5-week-old).

The LD ₅₀ value of each of the compounds of the present invention was 1000 mg / kg or more, confirming higher safety than the effective dose.

〔The invention's effect〕

According to the present invention, a novel thiazole derivative and an antiulcer drug containing the same are provided. The above compounds of the present invention have been shown to have excellent anti-ulcer activity. In other words, by suppressing acid secretion, healing of ulcer can be promoted and recurrence after discontinuation of administration can be prevented by a strong potentiating effect of protective factor, so that it can be effectively used as a therapeutic drug for gastric ulcer and the like.

Claims (2)

[Claims] 1. A general formula (I) (Wherein R ₁ and R ₂ represent a lower alkyl group or R ₁ and R ₂ together represent a group having the formula CH _{2 m} , wherein m is 4 or 5; n is 1 To an integer of 5) or a physiologically acceptable salt thereof. 2. An anti-ulcer agent containing the thiazole derivative according to claim 1 or a physiologically acceptable salt thereof.