JPH01160972A - 1,2,4-triazole derivative and antiulcer agent containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The 1,2,4-triazole derivative of formula I [R1 is H or acyl; R2 and R'2 are H or acyl; R3 is phenyl, pyridyl or quinolyl which may be substituted with-NR4R'4(R4 and R'4 are H or acyl); excluding the case that R1, R2 and R'2 are H and R3 is 2-pyridyl]. EXAMPLE:3-Amino-5-(2-pyridylmethylthio)-1,2,4-triazole. USE:An antiulcer agent. PREPARATION:The objective compound of formula I can be produced e.g., by reacting 3-amino-5-mercapto-1,2,4-triazole of formula II with an (acylated) benzyl halide of formula IV (X is halogen; Ac is acyl) and hydrolyzing the resultant compound of formula III with an acid or an alkali.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a hetero compound, particularly a 12,4-)lyazole derivative, and an antiulcer agent containing the derivative as an active ingredient.

The 1,2,4-1-lyazole derivative according to the present invention is a new substance that has not been described in any literature, and is useful as a medicine.

[Conventional technology and problems]

In recent years, the number of patients with peptic ulcers due to stress, drug stimulation, excessive secretion of gastric acid, etc. has been increasing, and to treat this, we are developing antacids, anticholinergic agents, histamine H2 receptor antagonists, etc. is in progress. However, these drugs have not reached the level of ideal and excellent drugs from the point of view of completely curing ulcers.

Therefore, there has been a need for substances with better anti-ulcer effects.

[Means for Solving the Problems] The present inventors synthesized and screened various new compounds in order to find substances with better anti-ulcer effects, and found that 1.2.4-triazole derivatives Based on this new knowledge, they conducted extensive research, leading to the completion of the present invention.

That is, the present invention is based on the general formula (wherein R represents a hydrogen atom or an acyl group;
Rt+ Rx may be the same or different and represent a hydrogen atom or an acyl group; R3 may be substituted with -NRJj (R4, R: may be the same or different and represent a hydrogen atom or an acyl group) Represents a phenyl, pyridyl or quinolyl group. However, the case where R+, Rz, and R2' are all hydrogen atoms and R1 is a 2-pyridyl group is excluded. ) and an antiulcer agent containing the derivative as an active ingredient.

In the compound of general formula (1), the acyl group refers to multiple groups such as formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, toluoyl, naphthoyl, and furoyl.

To obtain the compound of the present invention, commercially available 3
-Amino-5-mercapto-1,2,4-triazole (II) is used as a raw material, for example, by the following method (A
).

That is, a benzyl halide having an acylated/unacylated amino group may be allowed to act on the triazole, or (Il) (I[[) (wherein, X represents a halogen and Ac represents an acyl group) ) When the compound of formula (III) is hydrolyzed using an acid or an alkali, it is deacylated and 3-amino-
5-(aminobenzylthio)-L2°4-triazole is obtained.

The compound of the present invention can also be obtained by the following method.

That is, as shown in the following reaction formula (B), first, starting material triazole (II) is mixed with compound XCIIz Y (IV) represented by formula (IV) (wherein X
represents a halogen, and Y represents a pyridyl or quinolyl group.

) to introduce a pyridyl or quinolylmethyl group to produce a compound of formula (V).

Reaction B is particularly preferably carried out using a phase transfer catalyst in the presence of a base. Specific examples of phase transfer catalysts include:
Examples include quaternary ammonium salts such as tetra-n-butylammonium bromide, triethylbenzylammonium chloride, and tetra-n-butylammonium hydrogen sulfate. Examples of bases include sodium hydroxide, sodium carbonate, potassium carbonate, and water. Examples of the solvent include potassium oxide, and a mixed solvent of water and a water-insoluble organic solvent such as benzene, chloroform, methylene chloride, and toluene is preferable. Specific examples of pyridyl groups include 2
-pyridyl group, 3-pyridyl group, and 4-pyridyl group, and a specific example of quinolyl group is 2-quinolyl group. The reaction time is appropriate for about 1 hour to 30 hours, and the reaction is sufficient at room temperature, but heating may be used depending on the case. After the reaction is completed, the product can be purified by a general purification method, for example, by recrystallization using a commonly used appropriate solvent (methanol, ethanol, acetonitrile, etc.).

Subsequently, by acylating the compound of formula (V) as shown in reaction formula (C), the desired compounds (Vl) and (■) are obtained.
is obtained.

(V) (Vl) C (■) Acylation is carried out by a conventional method, and the corresponding acid, acid anhydride,
The acid halide or ketene may be reacted with the compound (V). Examples of the acid anhydride include acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, phthalic anhydride, succinic anhydride, benzoic anhydride, and the like. In addition, acid halides include acetyl chloride, formyl chloride, propionyl chloride, butyryl bromide, valeryl bromide, acryloyl chloride, benzoyl chloride, oxalyl chloride, succinyl chloride, and other commonly used acid chlorides, acid bromides, acid iodides, etc. All acid halides included are included. Compound (Vl) precipitates as a solvent-insoluble substance, and compound (■) can often be extracted from the soluble portion, so if these are separated, each compound can be obtained separately. These are purified according to conventional methods. These compounds not only exhibit excellent anti-ulcer properties when separated individually in this way, but also a mixture of these compounds without separation is sufficiently effective.

By the method described above, the compound of the present invention represented by formula (1) is produced, which will be specifically shown in the examples below, but the following compounds can also be produced in the same manner. , these are also included in the present invention.

(1) 2-acetyl-3-amino-5-(2-quinolylmethylthio)-2H-1,2,4-)riazole (2) 2-propionyl-3-amino-5-(2-pyridylmethylthio) -2H-1,2,4-triazole (3) 2-butyryl-3-amino-5-(2-pyridylmethylthio)-2H-1,2,4-) riazole (4) 3-amino-5-( 2-benzoylaminobenzylthio)-1,2,4-triazole (5) 2- (2
-naphthoyl)-3-amino-5-(2-pyridylmethylthio)-20-1,2゜4-triazole(6)2-formyl-3-amino-5-(3-pyridylmethylthio)-2H-1, 2,4-1-Riazole (7) 3-acetylamino-5-(2-propionylaminobenzylthio)-1,2,4-triazole (8) 3-amino-5-(3-aminobenzylthio)-
L2,4-triazole(9)3-amino-5-(4-aminohensylthio)-
1,2,4-1-Riazole=i All the compounds represented by the formula (1) are useful as medicines or pharmaceutical intermediates, have particularly strong anti-ulcer effects, and can be used alone as anti-ulcer agents. Used or used together. Furthermore, if necessary, it can also be used in combination with various medicines including other anti-ulcer agents.

The anti-ulcer effect of the compound of general formula (1) will be explained below using experimental examples.

Experimental Example 1 Weight: 180-2 after fasting for 24 hours and water for 16 hours
00g Wistar male runt (
The test compound was administered intraperitoneally in a 0.5% CMC (carboxymethyl cellulose) solution to 5 or 7 animals per group, and 30 minutes later, 1 rnl of a 150 mM hydrochloric acid-60% ethanol mixture was orally administered. One hour after administration of the 150mM hydrochloric acid-60% ethanol mixture, laparotomy was performed, and the length of the damaged area on the gastric mucosa was defined as the mucosal damage coefficient, and compared with the control group. The control group contains no test compound.
% CMC solution was administered intraperitoneally.

The table below shows the suppression rate calculated using the following formula.

-B Suppression rate (%) = - x i o.

A: Value of control group B: Value of test compound administration group From these results, the therapeutic effect of the compound of general formula (I) on ulcers was recognized.

Next, the compounds obtained in Examples 1 to 5 below, which are the active ingredients of the anti-ulcer agent of the present invention, were orally administered to ddY mice (10 mice per group at each dose). However, no fatalities were observed, and it was confirmed that the acute toxicity was low and that it was extremely safe.

As described above, since the anti-ulcer agent according to the present invention can be administered in large quantities, even if the anti-ulcer effect is somewhat low, it is sufficient to administer a large amount, and the intended purpose can be sufficiently achieved. Ru.

Next, the dosage and formulation of the compound of the present invention will be explained.

Compounds of formula -I'G can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to achieve the desired effect as an oral agent, an adult dose of 100 to 900 mg of the compound of the general formula should be administered in divided doses several times a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take it.

Oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, white Ti, mannitol, carboxymethyl cellulose, cornstarch, 11dI-free, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

Compounds of the general formula can also be administered as suspensions, emulsions, syrups, elixirs,
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary to administer 0.1 to 30 mg of the compound of the general formula per day intravenously for adults, although this will vary depending on the age, weight, and severity of the disease of the patient. , intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

The present invention will be explained specifically and in detail by Examples regarding the synthesis of compounds according to the present invention, and Preparation Examples regarding the preparation of drugs, but the present invention is not limited thereto.

Example 1 3-Amino-5-(2-pyridylmethylthio)-1,2
, 4-) Production of lyazole Sodium hydroxide (95%) 4.5 under argon atmosphere
Dissolve 6g in water 20-3-amino-5-mercap)
-1,2,4-) Rear sole (95%) 6.14g
, 1.61 g of tetra-n-butylammonium bromide
.

60 mf of benzene and 8.40 g of 2-picolyl chloride hydrochloride were added, and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with water and benzene, treated with activated carbon, and then recrystallized with methanol to obtain 7.41 g of 3-amino-5-(2-pyridylmethylthio")-1,2,4-)riazole ( 7
1.3%).

Molecular formula: C, l19NSS [207,25) Melting point:
175-177°C Infrared absorption spectrum J/IIaxcm-' (KBr)
: 3264°314B, 1648, 1574.14
9B, 1474.1432°1304, 1292.6
94 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-db): 4.32 (S, 2H), 6.05
(brS, 2) 1).

7.26 (m, LH), 7.44 (d, J = 8.1
Hz, IH).

7.73 (m, 1) 1), 8.49 (brd, J=4
．． 9Hz, 1) 1) Mass spectrum m/z (χ) (El
): 207 (M”, 22%), 174 (10χ)
, 93(60χ), 92(IO ri, 65(152).

40(tooχ) Examples 2, 3 2-acetyl-3-amino-5-(2-pyridylmethylthio)-2H-1,2,4-1-riazole and 3-acetylamino-5-(2-pyridylmethylthio) )-1,
Production of 2,4-1-riazole Under argon atmosphere, 3-
Amino-5-(2-pyridylmethylthio)-1,2,4
- To 2.07 g of triazole, acetic anhydride (
96%) 2.35- was added and stirred at room temperature for 3.5 days. Toluene was added to the reaction mixture to separate the insoluble crystal part and the soluble part, and the insoluble crystal part was washed with a mixed solvent of toluene and hexane and dried under reduced pressure to give 2-acetyl-3-amino-5-(2-pyridyl). methylthio)-2H-1,2,4
- 976 mg (39.2%) of triazole were obtained. Further, the toluene-soluble portion was concentrated under reduced pressure, methanol was added, and after stirring at room temperature for 2 to 3 days, the precipitated crystals were collected by filtration.

This was washed with methanol, dried under reduced pressure, and 3-acetylamino-5-(2-pyridylmethylthio)-1,2,
4-) 391 mg (15.7%) of lyazole was obtained.

2-acetyl-3-amino-5-(2-pyridylmethylthio)-2H-1,2,4-)riazole molecular formula:
Cl0HIINSOS (249,29) Melting point: 151
~152°C Infrared absorption spectrum νm5xcrn-'CKBr)
: 3400+3052.2988,1704,164
2.1496.1478°1376, 1324.126
6, 1146,654,586,556 proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d,):
2.48 (S, 311), 4.42 (S, 211)
, 7.28 (m, IH), 7.50 (d, J=7.
811z, 18), 7.62 (brS, 211),
7.76 (m, IH), 8.51 (m, LH) 7ss hector m/z ($) (EI): 249 (M”, 2
8%), 207 (78χ), 93 (100χ), 92
(21χ) + 65(25χ).

43 (51%) 3-acetylamino-5-(2-pyridylmethylthio)
-1,2,4-1-Riazole Molecular formula: 01°11. ,
NSO3 (249,29) Melting point: 236-239°C Infrared absorption spectrum v @@Xcm-' (KBr)
: 3212+3080.3012,2940.17
02.1608.1386゜1300, 1270.12
44.1062,750,724 proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-db): 2.
08(S, 31(), 4.40(S, 2+1), 7.
26 (m, LH), 7.45 (d, J=7.811z
, III), 7.74 (m, LH), 8.49 (d
, J=5.4Hz, III), 11.54(brS, L
H), 13.34 (brS, IH) mass spectrum m/
z(X) (EI): 249(M”, 69X), 2
07 (17χ), 123 (32χ), 93 (100χ)
, 92 (33χ).

85 (18ri, 65 (37%), 43 (81χ) Example 4 3-Amino-5-(2-acetylaminobenzylthio)
-1,2,4-1 riazole Sodium hydroxide (95%) 0.6 under argon atmosphere
Dissolve 9 g in 8- of water, 3-amino-5-mercapto-
L2,4-1-Riazole (95% N, 53 g, Hensen 30-, tetra-n-butylammonium bromide 3
86 mg and 2'-chloromethylacetanilide 2.3
1 g was added and stirred at room temperature for 19 hours. An oily substance insoluble in water and benzene was separated, dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a7tonitrile to give 3-amino-
5-(2-acetylaminobenzylthio)-1,2,4
-475 mg (14,5x) of triazole was obtained.

Molecular formula: CIIH13NSOS (263,32) Melting point: 142-147°C Infrared absorption spectrum ν,, cm-' (KBr):
3448°3316.3116,2952,1676
, 1654. 1642°1588.1554.15
02.1284 Proton nuclear magnetic resonance spectrum (200
MZ) δ(DMSO-d6): 2.09(S, 3+1
), 4.24 (S, 2+1), 6.11 (brS, 2
H), 7.05-7.51 (m, 411), 9.7
6(brS, 18), 12.08(brS, L
H) Mass spectrum m/z (χ) (El): 263
(M”, 14χ), 220 (13%), 148
(70%), 106 (100%), 77 (1
3ri.

43(31χ) Example 5 3-amino-5-(2-aminobenzylthio)-1,2
,4-1-riazole3-amino-5-(2-acetylaminobenzylthio)
-L2.4-1 riazoyl 260mg, ethanol i
ml and 1 ml of concentrated hydrochloric acid was stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. 3-amino-5-(2-aminobenzylthio) from the ethyl acetate elution fraction
-L2,4-triazole1I Omg (64,8%)
I got it.

Molecular formula: C9HIINSS (221,28) Melting point:
108.5-110.0°C Infrared absorption spectrum, Xcm-' (KBr):
3384°3352.3176.1648,1634
．． 1606.1584°1494, 1268.746 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-dh): 4.13 (S, 21 (), 5.12 (
brS, 2H).

6, 10 (brs, 211), 6.45 Cd
d, J=1.3.7.3Hz.

III), 6.62 (d, J=7.8Hz, l1l)
, 6.94 (dd.

J = 7.8, 7.311z, IH), 7.05 (d, J
=1.3Hz.

Mass spectrum m/z (χ) (EI): 22BM
”, 11χ), 18B (1χ), 106 (100χ)
, 79 (8χ), 77 (10χ) (blank below next summer) Preparation example 1 Preparation of tablets (2) Milk 11 90g (3) Cornstarch 29g (
4) Magnesium stearate 1g10
00 tablets 130g (1), (2) and 17g of cornstarch were mixed together and granulated with a paste made from 7g of cornstarch, 5g of cornstarch and (4) were added to the granules, and the mixture was compressed using a compression tablet machine. per tablet (1
) 1000 tablets containing 10 mg are manufactured.

(Leaving space below next summer) Preparation example 2 Preparation of capsules (2) Milk #U 150g (3) Cornstarch 100g
(4) Crystalline cellulose 40g (5)
Light anhydrous silicic acid 5g 1000 pieces
500 g According to a conventional method, the above ingredients are mixed and granulated and filled into 1000 capsules, each weighing 500 mg.

Preparation Example 3 Preparation of injection (2) Sodium chloride 9g (3)
Chlorobutanol 5g (4) Sodium bicarbonate Ig all ingredients in distilled water 100%
Dissolve in 0a/, dispense into 1000 brown ampoules, replace with nitrogen gas, and seal. The entire process is carried out under aseptic conditions.

[Effect of the invention] As described above, according to the present invention, a novel 1°2.4-
Provided are 1-IJ azole derivatives and highly effective anti-ulcer agents containing the derivatives as active ingredients.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 represents a hydrogen atom or an acyl group; R
_2, R_2' may be the same or different and represent a hydrogen atom or an acyl group; R_3 is -NR_4R_4' (R
_4 and R_4' may be the same or different and represent a phenyl, pyridyl or quinolyl group which may be substituted with a hydrogen atom or an acyl group. However, R_1, R_2, R
Excluding the case where all _2' are hydrogen atoms and R_3 is a 2-pyridyl group. ] A 1,2,4-triazole derivative represented by: (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 represents a hydrogen atom or an acyl group; R
_2, R_2' may be the same or different and represent a hydrogen atom or an acyl group; R_3 is -NR_4R_4' (R
_4 and R_4' may be the same or different and represent a phenyl, pyridyl or quinolyl group which may be substituted with a hydrogen atom or an acyl group. However, R_1, R_2, R
Excluding the case where all _2' are hydrogen atoms and R_3 is a 2-pyridyl group. ] An anti-ulcer agent containing a 1,2,4-triazole derivative represented by the following as an active ingredient.