JPS5910582A - Novel imidazole derivative having gastric juice secretion suppressing effect - Google Patents

Abstract

NEW MATERIAL:4- Methyl-5- [2-( N-2- thiazolylamino )ethylthiomethyl]imidazole of formula I . USE:A gastric juice secretion suppressing agent having excellent histamine H2 receptor antagonistic activity. PROCESS:The compound of formula I can be prepared either by reacting 4-methyl- 5-(2-aminoethylthiomethyl)-imidazole of formula II with 2-thiomethylthiazoline hydrogen iodide in an organic solvent such as methanol, ethanol, etc. under heat refluxing, or by reacting the compound of formula II with beta-chloroethyl isothiocyanate in an organic solvent such as THF, acetonitrile, etc. under cooling, and completing the reaction at room temperature (10-25 deg.C).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel thiazoline derivatives represented by formula [l],
It relates to 4-methyl-5-(2-(N-2-thiazolinylamino)ethylthiomethylcoimidazole and its tautomer.

The compound of formula [1] was synthesized for the first time by the present inventors and was found to have excellent histamine H2 receptor antagonism. It is a new substance that is expected to be a long-lasting gastric acid secretion inhibitor.

Furthermore, since the compound of formula 2 [1] has the following tautomerism at the thiazoline moiety and imidazole moiety in its structural formula, these tautomers are naturally included in the present invention.

Conventionally, compounds with histamine H2 receptor antagonism are:
Many drugs are known, including cimetidine and ranitidine, but they generally have many side effects and their effect on suppressing gastric acid secretion is temporary.

It is not always satisfactory due to problems such as the large dose and frequency of administration.

The present inventors synthesized a large number of compounds and conducted intensive research to solve these problems.

We succeeded in creating a gastric acid secretion suppressant with extremely long-lasting effects.

Compound [13 of the present invention] can be produced, for example, by the following method.

(1) The compound of formula [1] is obtained by reacting the compound of formula Elf) with 2-thiomethylthiazoline hydroiodide in an organic solvent such as methanol, ethanol, or isopropyl alcohol under heating under reflux.

(11) Formula (1
) is obtained.

QiD After reacting the compound of formula [■] with trinoenylphosphine and diethyl azodicarboxylate in an organic solvent such as tetrahydrofuran or acetonitrile,
By reacting with 2-aminothiazole, the formula [■]
The compound is obtained.

In the methods (1) and (11) above, 2 formulas [11]
1 mole of 2-thiomethylthiazoline hydroiodide or β-chloroethyl isothiocyanate per mole of the compound
It is suitable to use ˜3 mol.

The reaction temperature and time in method (1) vary depending on the type of solvent used, but 2 it is usually appropriate to carry out the reaction under reflux for 2 to 6 hours.

In method (it), in order to prevent side reactions of β-chloroethyl isothiocyanate itself, it is preferable to first react under cooling and then complete the reaction at room temperature (10 to 25°C).

In the method of 0++), 1 mol of the compound of formula 2 [1[1] is reacted with 1 mol of triphenylphosphine and 1 mol of diethyl azodicarboxylate.

Then 1 to 3 moles of 2-aminothiazoline are used.

It is preferable to react at a reaction temperature of 10 to 25°C for 20 to 40 hours.

The gastric acid secretion inhibitor of the present invention can use the compound of the above formula El) in the form of a pharmaceutically acceptable acid addition salt. Suitable acids in this case include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid,
Examples include tartaric acid, citric acid, gluconic acid 9, and the like.

Examples and Test Examples will be shown below to explain in detail the manufacturing method and gastric acid secretion suppressing effect of the nine compounds of the present invention.

Example 1 513 μl of 4-methyl-5-(2-aminoethiomethyl)-imidazole and 1.05 μl of 2-thiomethylthiazoline hydroiodide were heated under reflux for 4 hours in 8 μg of ethanol. After cooling with ice water, the precipitated crystals were collected by filtration, and the crystals were dissolved in water.

After adding anhydrous potassium carbonate to adjust the pH to 9-10, it was dried under reduced pressure, the residue was extracted with n-propyl alcohol, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-methyl-5-[2-( 7251v of N-2-% azolinylamino)ethylthiomethylcoimidazole was obtained.

Melting point 179-180.5℃ Elemental analysis value CIOHle N482.

6% N% N% Calculated value 46.85 6.29 21.85 Actual value
46.98 6.47 21.7ONMR: δ,
DMSO-d.

2.40 S (3H) 2.28 t (2H, J = 6Hz) 3.45
~4.40 m (8H) 8.63 s (I
H) 9.63 8 (2H) Example 2゜4-Methyl-5-(2-aminoethylthiomethyl)-imidazole 513μ was dried in tetrahydrofuran 10
After cooling with water and stirring, 390 μl of β-chloroethyl isothiocyanate was added dropwise and stirred for 1 hour, then the temperature was raised to room temperature and further stirred for 2 hours.

The reaction solution was dried under reduced pressure, and the residue was treated in the same manner as in Example 1 to obtain 480 μ of 4-methyl-5-(2-(N-2-thiazolinylamino)ethylthiomethylquimidazole. Ta.

When compared with the standard sample obtained in Example 1, the properties were consistent.

Example 3 2. triphenylphosphine in 25 acetonitrile.
6Sl + 1.8 t of dietherazodicarboxylene (dietherazodicarboxylate) was added while cooling under a N2 stream,
4-Methyl-5-(2-hydroxyethylthiomethyl)
- Added 2.52 imidazole.

Then, 1.1 t of 2-aminothiazole was immediately added, and the mixture was stirred at room temperature for 36 hours.

Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to leave 0.0%. I
The solution was dissolved in N-hydrochloric acid, extracted with methylene chloride, the extract was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 4-methyl-5-(2-(N-2-thiazolinylamino)ethylthio). 2.22 ml of methyltuimidazole was obtained.

Compared with those obtained in Example 1, various properties were consistent.

Test example 1. Histamine H2 Receptor Antagonism Test After the head of a Hartley guinea pig (male: 300-350 f) was bruised and blood was exsanguinated, the heart was removed.

The atrium is dissected in oxygen-saturated Lock-Ringer solution,
Attach a thread to both ends. Contains Lock-Ringer liquid maintained at 37°C, mixed gas (0295%, COx 5
The atrium was suspended at a tension of 500 WIg using threads attached to both ends in a Magnus tube (3 Qm/) through which air was ventilated. The contraction movement of the atrium was measured using a strain gauge (Nihon Kohden, T
B-612T).

Also, measure the output using a tachometer (Nihon Kohden AT-600).
The heart rate was measured via G) respectively.

Histamine (used in the form of dihydrochloride; the same applies hereinafter) was administered at doses such that the logarithm of the added amount was at equal intervals of H, until the maximum response of increasing heart rate was obtained, from 1x10-'M to lXl0-
'Mitt' was added cumulatively into the Magnus tube to obtain a histamine dose-response curve. After washing the inside of the Magnus tube several times and stabilizing the atrium for 30 minutes, the above procedure was repeated again to obtain a histamine dose-response curve.

After washing the inside of the Magnus tube several times and stabilizing the atrium for 30 minutes, a test compound (3XIF'M) was added into the Magnus tube and 10 minutes later, a dose-response curve of histamine in the presence of the test compound was obtained.

From the second histamine dose-response curve and the third histamine dose-response curve in the presence of the test compound, J.
M. Van Rossum's method (Arch, in
k, Ph-armacodyn, 143.29
9.1963), the PA value of the test compound (the negative number of the logarithm of the molar concentration of the test compound required to double the histamine concentration in the Magnus tube required to cause a certain reaction) was calculated.

The results are shown below.

1y) tQV 6.10° (Brimblec
ombe, R, W, eL alBr, J, Ph
armac, 53.1975435-436) Test Example 2 Gastric juice secretion suppressive effect test SD rats (male: 200-220 F) were fasted for 24 hours (but allowed free access to water), then the abdomen was opened under ether anesthesia, and the pylorus was opened. Ligated. A small hole is made in the proventriculus.

Insert a polyethylene tube (inner diameter 7 + mn).

It was fixed on the front back.

After rinsing the stomach several times with warm saline (37° C., approximately 5 rnt), the tip of the tube was pulled out of the abdominal cavity and the abdominal incision was closed.

A 23G needle was inserted into the tail vein, and after fixing with tape, it was connected to a mini pump (Perista 8J-1220 model, manufactured by Atto Corporation). After awakening, the rats were placed in a KNN Ballman type cage (two people attached a test tube to the end of the tube to collect gastric fluid).

As a gastric juice secretion stimulant, histamine (used in the dihydrochloride form) was dissolved in saline and infused continuously for 5 hours at a rate of 8~/~/hr. The test compound (60 μ/Kf) was administered once into the tail vein at a volume of 0.5 d/10 (l) 30 minutes after administration of the stimulating drug.

Gastric juice was collected every hour, and the gastric juice volume, acidity, and PEP gastric acidity were measured at 0.0 with a pH meter. using IN NaOH.

Titrate to pH 7.0 and calculate acid output (/Z Eq/hr
) was calculated. In addition, pepsin activity was measured using Anson's method (
J, gen.

PhysioL, 21.79.1938) was modified and measured, and the amount of pepsin excreted (Li/hr) was calculated.

The test results of the compounds of the present invention using physiological saline as a control and cimetidine as a comparative drug are shown in Table 1.

Table 1 (The values in the table are the average values of 21 cases.) As is clear from the results in Table 1, it has a significantly better residual effect than cimetidine, a known drug in the same family, although it is slightly less fast-acting. It was shown to be effective.

[Brief explanation of drawings]

FIGS. 1, 2, and 3 are graphs of Table 1 of Test Example 2. In each drawing, 10- is the compound of the present invention, △... is the comparative drug cimetidine, and - is the control (
(Physiological saline) results are shown below. Patent Applicant Wakamoto Pharmaceutical Co., Ltd. No. 1 Figure 012 345 Hours (hr-) Figure 2 0:1234 5 Figure 3 12345 Hours (hr) Procedure Amendment Letter March 1982 Kazuo Sugi 1, Incident Display 1981 Patent Application TS11781
No. 8 No. 2, Title of the invention: New imidazole derivative with gastric acid secretion suppressing action 3, Relationship with the case of the person making the amendment Patent applicant 5, Number of inventions increased by the amendment 06, Subject of the amendment Description 7, Amendment Contents ■ Correct the statement on page 3, line 1. ■ In the last line of page 3, line 2 of page 5, and lines 10 to 11 of page 6, the text [2-thiomethylthiazoline] is corrected to "2-methylthiothiazoline." ■ On page 7, line 1, replace “179-180.5℃” with “
144-145℃'' 〇■ Add the following between lines 5 and 6 on page 7. rHigh-resolution mass spectrometry C1゜H111N4 St (M+) Calculated value 2
56.0794 Actual value 256.0815 Mass spectrometry 5 256 (M+), l 61 (S-CH2CH
INH-(fi Miko (Nao, quality mackerel analyzer equipment is Jl; OL
TM8 D-300 type was used. )
”■ On page 7, lines 7-11, r2.40 s (3H) 2.28 1 (2H, J=6Hz) 3.45-4.
40 m (8H) 8.63 s (IH) 9.63 8 (2H) J and r2.
23 8 (3H) 2.73 1 (2H, J-J exit) 3.37-4.23 m (8H) 7.93 8
(IH) 7.67 s (21-1) Corrected to J.

Claims (2)

[Claims] (1) An imidazole derivative represented by formula [l] and its tautomer. (2) A gastric acid secretion inhibitor characterized by containing an imidazole derivative represented by formula (1) or a tautomer thereof as an active ingredient