JPH01160976A - 1,3,4-thiadiazole derivative and antiulcer agent containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound formula I[R1 is alkyl, amino, alkylamino, phenyl, pyridyl, quinolyl or R-CONH (R is alkyl, phenyl, pyridyl, cyclohexyl or quinolyl; R and CONH may be bonded together through a saturated or unsaturated carbon chain); R2 is phenyl, pyridyl, quinolyl or 5-membered heterocyclic group having hetero-atom selected from N and S]. EXAMPLE:2-Ethyl-5-(2-pyridylmethylthio)-1,3,4-thiadiazole. USE:An antiulcer agent. PREPARATION:For example, 2-amino-5-mercapto-1,3,4-thiazole of formula II or 2-pyridyl-1,3,4-thiadiazoline-5-thione of formula III is made to react with 3-chloromethylpyridine of formula IV or 2-chloromethylquinoline of formula V to obtain the corresponding compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a hetero compound, particularly an L3.4-thiadiazole derivative, and an antiulcer agent containing the same as an active ingredient.

The 1,3,4-thiadiazole derivative according to the present invention is a novel compound that has not been described in any literature, and is very promising as a pharmaceutical agent such as an anti-ulcer agent or as an intermediate thereof.

[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 a number of new compounds in order to find a substance with a more effective anti-ulcer effect, and found that 13.4-thiadiazole derivatives They discovered that there are effective compounds among them, and as a result of extensive research based on this new knowledge, they have completed the present invention.

That is, the present invention provides a compound of the general formula [wherein R represents an alkylamino, phenyl, pyridyl, quinolyl, or R-CONH- group which may be substituted with an alkyl, amino, or methoxy group: [wherein, ~
means that R and the -CON8 group are bonded directly or via a saturated or unsaturated carbon chain; R represents an alkyl, phenyl, pyridyl, cyclohexyl, or quinolyl group (provided that , these may be substituted by the following; an alkyl group that may be substituted with an amino or alkoxy group, an alkoxy group, a hydroxyl group, a carboxyl group, an amino group, an acyloxy group, or a halogen)] R2 is phenyl , pyridyl, quinolyl, or a 5-membered heterocyclic group having a heteroatom selected from the group consisting of nitrogen and sulfur (which may be fused with a carbocyclic ring or (Optionally substituted; alkyl group, alkoxy group, amino group optionally substituted with alkyl group, acylamino group, or halogen) (provided that R is an amino group and R2 is 2-pyridyl, 4- Compounds where R+ is 4-pyridyl and R2 is 2-
Excludes compounds when they are pyridyl. )] 1
, a 3,4-thiadiazole derivative and an antiulcer agent containing it as an active ingredient.

In the compound of general formula (1), among P and R2, the alkyl group includes methyl, ethyl, propyl, butyl, pentyl, hexyl group, etc., and the alkylamino group includes these alkyl groups. or refers to a di-substituted amino group.

Examples of the 5-membered heterocyclic group containing nitrogen and/or sulfur for R2 include imidazolyl and thiazolyl groups, as well as partially saturated groups such as imidazolinyl, Thiazolinyl group, etc.

Examples of condensed systems with carbon rings include benzimidazolyl and benzothiazolyl groups.

The carbon ring is not particularly limited, but a 6-membered ring is preferred.

The acyl group refers to multiple groups such as formyl, acetyl, propionyl, butyryl, valeryl, benzoyl, toluoyl, naphthoyl, and furoyl.

It goes without saying that the present invention includes not only the above-mentioned free 1,3,4-thiadiazole derivatives but also their salts, S-oxides, and the like.

Compound (1) according to the present invention is, for example, represented by the following formula (, II)
2-amino-5-mercapto-1,3゜4-
Thiadiazole can be produced by the following method using 2-pyridyl-1,3,4-thiadiazolin-5-thione represented by the following formula (■') as a raw material.

For example, these mercapto forms (II) or thione forms (
■') is reacted with a halogen such as 3-chloromethylpyridine (1) or 2-chloromethylquinoline (IV) to thioetherify it to form compounds (V) and (Vl) into which a pyridyl group and a quinolyl group are introduced, respectively. Just manufacture:
Reaction Formulas (A), (B) (■') The above reaction is particularly preferably carried out using a phase transfer catalyst in the presence of a base. Specific examples of phase transfer catalysts include, for example, tetra-n-butylammonium bromide,
Triethylbenzylammonium chloride, tetra-n
-4 such as butylammonium hydrogen sulfate
Examples of bases include sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, etc., and mixtures of water and water-insoluble organic solvents such as benzene, chloroform, methylene chloride, and toluene as solvents. Solvents are preferred. 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 conventional purification method, for example, by recrystallization using a commonly used appropriate solvent (methanol, ethanol, acetonitrile, etc.).

In this way, the above reactions all involve the starting material mercaptothiadiazole (n) or thiadiazolinthione (■').
A thioether is obtained by reacting a halogen represented by
Various cyclic groups represented by R2 in 1) can also be used freely, and the desired compounds can be obtained respectively. Furthermore, in addition to the case where X is a chlorine atom in XCHz-Y, it goes without saying that other halogen atoms can also be used freely.

Further, the compound obtained as described above can be made into an S-oxide by reacting with a peroxide.

Specific examples of peroxides include metachloroperbenzoic acid, hydrogen peroxide, sodium periodate, etc. In halogenated hydrocarbon organic solvents such as chloroform and methylene chloride (
If the raw material is not soluble, alcohols such as methanol and ethanol or water may be used as appropriate. ), 0~40°
The reaction is completed in 115 minutes to 6 hours. After the reaction is complete,
It can be purified in the same manner as described above.

Mercapto compound, which is a raw material compound in these reactions,
Both the thione compound and the halogen compound are available or manufacturable compounds, and there is no problem in supplying the raw materials, so there is no problem in the industrial implementation of the present invention.

In other words, some of the mercapto forms are already commercially available, and for the thione forms, for example, nitrile is used as a raw material, and hydrazine is reacted on this to form the amithracine form, which is then converted into carbon disulfide. It is also possible to produce it by a method such as cyclization with (Ch
em, Pharm, Bull, 1B(8), 169
6 (1970)).

There are commercially available compounds as A rogens to be reacted with mercapto or thione bodies, and they can also be produced, for example, by the following method. Taking 2-chloromethylpyridine as an example of a halogen, it can be synthesized by the following route: Route 1: 2- and choline-N-oxide are synthesized by p-1-luenesulfonyl chloride, methanesulfonyl chloride, thionyl A method of rearrangement using chloride, etc.

Route 2: A method in which 2-picoline-N-oxide is rearranged with acetic anhydride or the like, and then hydrolyzed and halogenated using hydrochloric acid, thionyl chloride, or the like.

By using a compound in which various substituents such as amino, alkyl, halogen, nitro, and alkoxy are introduced into the pyridine ring of the raw material N-oxide, a halogen compound having a pyridine ring substituted with these groups can be obtained. The following method can be used: A method in which 2-picoline is chlorinated and then oxidized, and the obtained 5-chloro-2-picoline-N-oxide is subjected to a rearrangement reaction: 2-picoline A method in which -N-oxide is nitrated, chlorinated, and then subjected to the above rearrangement reaction; or a method in which the nitro group of the above nitrated product is replaced with a methoxy group by a nucleophilic substitution reaction, and this is subjected to the above rearrangement reaction. ;This methoxy form is obtained by, for example, methylating hydroxy-substituted 2-picoline,
In addition to the method described above, halogen compounds can also be produced by halogenating available alcohol compounds: For example, in the case of aromatic ring compounds, (substituted ) When benzyl alcohol is chlorinated with thionyl chloride or the like, (substituted) benzyl chloride, which is a halogen compound, is obtained.

Oo Also, in the case of heterocyclic compounds, for example, 4-hydroxymethyl-imidazole is treated with thionyl chloride, or thioacetamide is reacted with dichloroacetone to form 4-hydroxythiazoline, and then thionyl chloride is converted into 4-hydroxythiazoline. etc., to obtain chloromethyl derivatives of imidazole and thiazole, respectively: In this way, among the compounds of the present invention represented by formula (I), compounds in which R1 is other than the R-CONH- group are produced. Ru.

Next, the compound (1
) production will be described.

In this case, a compound in which R1 is an amino group is used as a raw material, and the amino group is acylated (reaction formula C).

]1 The above reaction C may be carried out by a conventional acylation method, and the amino compound may be reacted with, for example, an acid halide, M anhydride, or ester. The acid halogens include benzoyl chloride, nicotinic acid chloride, tranexamic acid chloride, acetyl chloride, propionyl bromide, valeryl chloride,
Examples include butyryl chloride, acryloyl chloride, oxalyl chloride, succinyl chloride, and the like. Examples of the acid anhydride include acetic anhydride, phthalic anhydride, propionic anhydride, acetic anhydride, valeric anhydride, succinic anhydride, benzoic anhydride, and the like.

If a compound in which a substituent is introduced into these acylating agents is used, an amide compound having a corresponding substituent can be obtained. For example, using a ring carboxylic acid having a substituent as a raw material,
After protecting the substituents by acetylation if necessary, the ring carboxylic acid chloride having the desired substituent may be produced by chlorination using thionyl chloride or the like.

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-ethyl-5-(2-pyridylmethylthio)-
1,3,4-thiadiazole (2) 2-propyl-5-(2-pyridylmethylthio)
-1,3,4-thiadiazole (3) 2-hexyl-5
-(2-pyridylmethylthio)-1,3,4-thiadiazole (4) 2-dipropylamino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole (5) 2
- (2-quinolyl)-5-(2-pyridylmethylthio)-13,4-thiadiazole (6) 2-propionylamino-5-(2-pyridylmethylthio)-1,3,4
-thiadiazole (7) 2-(3-quinolylcarbonylamino)-5-(2-pyridylmethylthio)-1,3,
4-thiadiazole (8) 2- (2-pyridylmethylthio)-5-(3,
4,5-triethylbenzoylamino)-1゜3.4-
Thiadiazole (9) 2-methoxyacetylamino-5-(2-pyridylmethylthio)-L3,4-thiadiazole (10) 2-(2-pyridylmethylthio)-5-(
3,4,5-1-ethoxybenzoylamino)-1,
3,4-thiadiazole (11) 2-amino-5-((3-methylpyridine-
2-yl)methylthio-13.4-thiadiazole (12) 2-amino-5-((4-aminopyridine-
2-yl)methylthio)-1,3,4-thiadiazole (13) 2-amino-5-(2-methylaminobenzylthyl)-1,3,4-thiadiazole (14) 2-
Amino-5-(2-dimethylaminohensylthio)-1
, 3,4-thiadiazole tree The compounds according to the invention are all new and, as is clear from the experimental examples described below, exhibit excellent anti-ulcer effects, and are particularly advantageously used as anti-ulcer agents. . At that time, other anti-ulcer drugs and/or
It goes without saying that it can also be used in combination with other medicines.

Experimental examples of the present invention will be described below.

Experimental Examples 1-3 Weight 180-2 after 24 hours of fasting and 16 hours of water deprivation
00g Wistar store rat (
A test compound was suspended in a 0.5% CMC (carboxymethylcellulose) solution and administered intraperitoneally or orally to 1 group of 10 mice, and 30 minutes later, a mixture of 150 mM hydrochloric acid and 60% ethanol 1- 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.
5% CM CQ9 solution was administered intraperitoneally or orally. Three types of tests were conducted, and the results are shown in Tables 1 to 3 as inhibition rates calculated using the following formulas.

A: Value of control group B: Value of test compound administration group (margin below next summer) Table 1 Test compound Inhibition rate (%) Compound obtained in Example 1 82.8 Compound obtained in Example 2 50.0 Compound obtained in Example 3
75.5 Compound obtained in Example 4 76.3 Compound obtained in Example 5 19.7 Compound obtained in Example 6 52.8 (Left below next summer) Table 2 Compound obtained in Example 9 78 .1 Compound obtained in Example 10 60.7 Compound obtained in Example 11
61.9 Compound obtained in Example 12 57.0
Compound obtained in Example 13 80.7 Compound obtained in Example 15 48.3 Compound obtained in Example 16
19.8 Compound obtained in Example 18 32.
4 Compound obtained in Example 20 17.0 (white space below) Table 3 Compound obtained in Example 25 28.3 Compound obtained in Example 26 77.4 Compound obtained in Example 27
12.2 From these results, it was confirmed that the compound of form (1) had a therapeutic effect on ulcers.

Next, the compound obtained in the example below, which is the active ingredient of the anti-ulcer agent of the present invention, was orally administered to ddY mice (
No deaths were observed even when administered up to 1000 mg/kg (10 animals per group), confirming that acute toxicity was low and safe.

The compounds according to the invention are particularly useful as anti-ulcer agents, as described above.

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

Compounds of formula -FIQ 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, sucrose, mannite, carboxymethyl cellulose, corn starch, W, machine salts, 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.

[Binding agent] Starch, dextrin, gum arabic powder, gelaten,
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 colauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant 1 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.

The -form compounds 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 kg of the general formula compound per day for adults, although this will vary depending on the age, weight, and severity of the disease of the patient. Injection, 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 more specifically and in detail using Examples for the synthesis of the compounds according to the present invention, and Preparation Examples for the preparation of the drugs according to the present invention, but the present invention is not limited thereto. .

Example 1 2-methyl-5-(2-pyridylmethylthio)-L3,
4-thiadiazole Sodium hydroxide (95%) under argon atmosphere 1.7
Dissolve 7g in 1 orri of water, 1.32g of 2-mercapto-5-methyl-1,3,4-thiadiazole, 30ml of benzene, 322mg of tetra-n-butylammonium bromide and 1 ml of 2-picolyl chloride hydrochloride.
64 g was added and stirred at room temperature for 13.5 hours. After separating the benzene layer and the aqueous layer, the benzene layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. From the ethyl acetate elution fraction, 2.109 g of 2-methyl-5-(2-pyridylmethylthio)-1,3,4-thiadiazole (
94.6%) was obtained.

Molecular formula: C9H9N3S2 (223,31) Properties Two-oil infrared absorption spectrum νmaxcm-' (N
aC1): 1592°1472, 1436.138
2.1068.1048° Proton nuclear magnetic resonance spectrum (200MZ) δ (CDCl2): 2.70 (S,
311), 4.66 (S, 2H), 7.19 (ddd
, J = 7.4.4.9.1.2Hz, IH), 7.4
9 (d, J=7.8Hz, IH), 7.64 (ddd
, J=7.8.7.4,1.7)12. III),
8.56 (brd, J=4.911z, III) Mass spectrum m/z (X) (EII: 223 (M”)
, 53χ') , 190 (74X) , 137
(33ri, 124 (39ri, 123 (34
χ).

92 (97χ), 78 (37χ), 65 (10
0χ), 59(44χ) Example 2 2-acetylamino-5-(2-pyridylmethylthio)
-1,3,4-thiadiazole under argon atmosphere, 2-
Amino-5-(2-pyridylmethylthio')-L3,4
-0.58mf of acetic anhydride in 1.009g of thiadiazole
f was added, and the mixture was allowed to stand at room temperature for 4 days. The reaction mixture was washed with toluene and recrystallized with methanol to give 2-acetylamino-
1.103 g (84.7%) of 5-(2-pyridylmethylthio)-1,3,4-thiadiazole was obtained.

Molecular formula: Cl0HION40SZ (266,34)
Melting point: 225-227"C (dec,) Infrared absorption spectrum νl, 1..cm-' (KBr): 290
8゜2784.1702, 1556, 1434.141
0.1396°137B, 1314.1252.12
36.1046.742 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d, ): 2.17 (S
, 3H), 4.59 (S, 2H), 7.30 (ddd
, J=7.6, 4.9, 1.0Hz, LH), 7.48
(d.

J=7.8Hz, 1tl), 7.78(ddd, J=
7.8, 7.6°2.0Hz, IH), 8.51
(brd, J=4.9Hz, III).

12.58 (brS, 1ll) Mass spectrum m/z (χ) (El): 266 (
M”, 61X), 233 (30χ), 224 (26χ
), 124 (20χ), 93 (83χ).

92 (712), 78 (23χ), 65 (50
χ), 43 (100χ) Example 3 2-methylamino-5-(2-pyridylmethylthio)-
1,3,4-thiadiazole (I) 2-mercapto-5-methylamino-1,3゜4
-Thiadiazole under argon atmosphere, potassium hydroxide (85%) 3.18
A mixture of 5.0 g of 1.4-methylthiosemicarbazide and carbon disulfide (99%) was stirred under reflux for 30 hours. The reaction mixture was concentrated, the residue was dissolved in water, the pH of the aqueous layer was adjusted to 2 to 3 with hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water, it was dried under reduced pressure to obtain 5.525 g (79.0%) of 2-mercapto-5-methylamino-1,3,4-thiadiazole.

Molecular formula: C3H3NISZ (147) Melting point: 18
1~185°C Infrared absorption spectrum ν,, cm-' (KBr):
3264°3132.2916,1584,1480
．． 1316. 1056° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-db): 2.75
(d, J=4.4Hz, 31(), 7.46(brs.

LH), 13.29 (brS, IH) Mass spectrum m/z (X) (EI): 147 (M”, 1
00χ), 74(36χ), 71(45χ), 59(3
7χ) (2) 2-Methylamino-5-(2-pyridylmethylthio")-1,3,4-thiadiazole Under an argon atmosphere, 3.41 g of sodium hydroxide (95%) was dissolved in 20% of water, 2-Mercapto-5- obtained in (1)
Methylamino-1,3,4-thiadiazole 2.94g
, benzene 60m1. 644 mg of tetra-n-butylammonium bromide and 3.28 g of 2-picolyl chloride hydrochloride were added, and the mixture was stirred at room temperature for 7 hours. Ethyl acetate was added to the reaction mixture, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetonitrile to give 2-methylamino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 1,1
39 g (23.9%) were obtained.

Molecular formula: C9H. Na5z [:238.323 Melting point 774.5~75.0''C Infrared absorption spectrum v mmxcm-' (KBr)
: 3224°3024.2984,1594.15
60.1398.1156° Proton nuclear magnetic resonance spectrum (200MZ) δ (CDCI j): 3.01 (
S, 3H), 4.45 (S, 2H), 6.01 (brS
, IH), 7.18 (dd, J=7.6, 4.9H
z, III), 7.41 (d, J = 7.81 (z, IH
), 7.64 (ddd, J=7.8°7.6,1.
711z, IH), 8.55 (brd, J=4.911
z.

Mass spectrum m/z (X) (El): 238 (M
”, 93χ”), 205(81χ), 93(
85χ), 92 (100″1.), 79 (46%
).

74 (95χ), 65 (61%) Example 4 2-dimethylamino-5-(2-pyridylmethylthio"
)-1,3,4-thiadiazole (CH3), NCN
HNH□ Dimethylthiocarbamoyl chloride (97%) 763m
2 ml of benzene was added to the mixture of g and hydrazine-hydrate, and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction mixture;
The residue was recrystallized from a mixed solvent of methanol and water, and 4,4
-dimethylthiosemicarbazide 566 mg (79,5%
) was obtained.

Molecular formula: C, H, N, S (119) Melting point = 154
~156°C Infrared absorption spectrum ν,, cm-' (XBr):
3292°3236.1530.1384,1356
, 1266.980,668 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-cL): 3.1
0 (S, 6H), 4.64 (brS, 2H).

8.71 (brS, 1tl) Mass spectrum m/z (X) (El): 119 (M
”, 62Z), 88(100χ'), 44(
47%) (2) 2-dimethylamino-5-mercapto-
1゜3.4-Thiadiazole Under argon atmosphere, potassium hydroxide (85%) 290m
g1 0.25 m of water & 6 mf of ethanol, 524 mg of 4,4-dimethylthiosemicarbazide obtained in (1)
17. and 0.4 rd of carbon disulfide under reflux.
Stirred for 5 hours. The reaction mixture was concentrated, the residue was dissolved in water, the pH of the aqueous layer was adjusted to 4 to 6 with hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water, drying under reduced pressure, 2-dimethylamino-5-mercapto-1,3,4-thiadiazole 506
mg (71.5%) was obtained.

Molecular formula: C411JzSz (161) Melting point: 169
~175°C Infrared absorption spectrum v m@gCm-' (KBr)
: 2904°1590.1494.1376.12
90. 1272.1050° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d6): 2.9
2 (S, 6H) Mass spectrum m/z (El): 16HM”
, 100%), 85 (27χ), 56 (31%) (3) 2-dimethylamino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole Potassium hydroxide (95%) under argon atmosphere 254mg to 2.5mg of water
- dissolved in 5 ml of ethanol, 483 mg of 2-dimethylamino-5-mercapto-1°3.4-thiadiazole obtained in (2) and 49 mg of 2-picolyl chloride hydrochloride.
2 mg was added and stirred under reflux for 17.5 hours. The reaction solution was concentrated, and the residue was dissolved in chloroform, washed with 1% sodium hydroxide and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. From the ethyl acetate elution fraction, 581 mg of 2-dimethylamino-5-(2-pyridylmethylthio)-L3,4-thiadiazole (76.9%
) was obtained.

Molecular formula: C1°H, □N<Sz (252,35)
Properties: Oily infrared absorption spectrum v,,Xcm-'
(NaC1): 1590+1554, 1434.
1410 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
Ch): 3.10 (s, 6) 1), 4.46 (s, 2H
), 7.18 (aa, r=7.6.4.9Hz, IH
), 7.44 (d, J=7.8Hz, 1ll
).

7.63 (ddd, J=7.8.7.6.1.711z
, 1ll).

8.55 (brd, J=4.9Hz, LH) Mass spectrum m/z (χ) (EI): 252 (M”, 100
X), 219 (86%), 92 (65X),
8B (95χL79(23χ), 65(50χ”)
, 56 (52χ) Example 5 2-((5-amino-1,3,4-thiadiazole-2
-ylthio)methyl]benzimidazole II Under argon atmosphere, 2-amino-5-mercap 1--1
．． 3.4-thiadiazole 1.357g, 2-chloromethylbenzimidazole 1.700g, ethanol 60
A mixture of rnl and 1.385 g of potassium carbonate was added to 60
2-((5-amino-1,3 ,4-thiadiazol-2-ylthio)methyl]henshiimidazole (461 mg (17,5χ)) was obtained.

Molecular formula: C1゜HqNsSz (263,33) Melting point:
210°C (dec,) Infrared absorption spectrum v mixcm-' (KBr)
: 3300°1630, 1504.1454.14
38.1274.748 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-db): 4.49 (S
, 2H), 7.14 (m, 2) 1), 7.36 (br
S, 211), 7.50 (m, 2H) mass spectrum m/z (χ”) (El): 263 (M”, 3
8X), 230 (4Z), 131 (100χ),
77(17Z), 60(IIX) Example 6 2-amino-5-(2-acetylaminobenzylthio)
-1,3,4-thiadiazole (1) 2'-hydroxymethylacetanilide 2-aminobenzyl alcohol 7
．． 38g and triethylamine (99%) 18.1
n& was dissolved in dichloromethane (70°C), 12.07 g of acetic anhydride (96%) was added to the solution under stirring under water cooling, and the mixture was stirred at room temperature all day and night. The reaction solution was concentrated under reduced pressure, and to the residue were added 25 g of potassium carbonate, 7 k of methanol, and 70 m7 of water, and the mixture was stirred at room temperature overnight.

Brine was added to the reaction mixture, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was recrystallized from ethyl acetate to obtain 7.372 g (74.5%) of 2'-hydroxymethylacetanilide.

Molecular formula: C9HIINO□f:165] Melting point: 11
7.5-118.5°C Infrared absorption spectrum ν,, cm-' (KBr):
3276°3192.1654.1588,1536
．． 1454.1368°1296, 1280.1038
．． 758 proton nuclear magnetic resonance spectrum (200MZ)
δ (DMSO-di): 2.05 (S, 3H), 4.
48(d, J=5.4Hz.

2H), 5.26 (t, J=5.4Hz, LH),
7.10-7.25 (m, 2H), 7.38-7.50
(m, 21(), 9.29(brS, IH) Mass spectrum m/z (%) (EI): 165(
M”), 147 (88χ).

104 (52χ), 93 (42%), 78
(53χ), 43(100χ) (2) 2'-chloromethylacetanilide Under argon atmosphere, 6.0 g of 2'-hydroxymethylacetanilide and 3.52 g of pyridine.
rnl was dissolved in 120 rBl of dichloromethane, 3.18-thionyl chloride was added dropwise with stirring under water cooling, and the mixture was stirred at the same temperature for 1.25 hours.

The reaction mixture was concentrated, and the residue was dissolved in dichloromethane, washed with water, and then dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 4.23 g (63 g) of 2'-chloromethylacetanilide.
, 5%).

Molecular formula: Cqll+. ClN0 (183,5) Melting point: 100.5-102.5"C Infrared absorption and absorption spectrum v 1naXC"-' (KB
r): 3256+2848.1656,1588,
1532.1496. 1460°1368, 1300
．． 1264.672 proton nuclear magnetic resonance spectrum (2
00MZ) δ(DMSO-db): 2.08(S,
3H), 4.81 (S, 2H), 7.14-7.4
7 (m, 4H), 9.59 (brS, IH) mass spectrum m/z (χ) [El): 185.183 (
M”, 10χ).

147 (100χ), 106 (87χ), 7B (53χ
), 43(94χ)(3) 2-amino-5-(2-acetylaminobenzylthio)-1,3,4-thiadiazole Sodium hydroxide (95%) 1.72g was dissolved in water 10rn
2-amino-5-mercapto-1,3,4
-Thiadiazole (98% 0.36g, benzene 40m
1. Tetra-n-butylammonium bromide 322m
g and 1.134 g of 2'-chloromethylacetanilide
was added and stirred at room temperature for 6 hours. The precipitated crystals were collected by filtration, washed with water and benzene, and recrystallized with methanol to give 2-amino-5-(2-acetylaminobenzylthio)-1,3
, 1.359 g (48.5%) of 4-thiadiazole was obtained.

Molecular formula: C++)It□Nn03z (280,3B
) Melting point: 203-207°C (dec,) Infrared absorption spectrum ν,, cm-' (KBr): 3348
゜3164.3000, 1688, 1644.1592
．． 1550°1530, 1454.1370 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-db): 2.07 (S, 3H), 4.36 (S
, 2H), 7.11-7.52 (m, 4m), 7.
30 (brs, 2H), 9.60 (brs, 1) 1) Mass spectrum m/z (X) (El]: 280 (M”
, 6χ), 148 (68%), 147 (46%), 1
06(1002), 43(86Z) Example 7 2-amino-5-(2-aminobenzylthio)-1,3
,4-thiadiazole 2-amino-5-(2-acetylaminobenzylthio)
-1,3,4-thiadiazole 1.178g, concentrated hydrochloric acid 8
．． 76- and ethanol 9rrl! The mixture was stirred under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydroxide solution was added to the residue to adjust the pH of the aqueous layer to 8 to 9, and the precipitated crystals were collected by filtration. Wash with water and benzene,
After drying under reduced pressure, 797 mg of 2-amino-5-(2-aminobenzylthio)-1,3,4-thiadiazole (79,
8%).

Molecular formula: CeH+. Na5t (238,32) Melting point: 149°C (decomposition) Infrared absorption spectrum v (n@Xcm-' (KBr
): 3444+3360.3316,3140,1
636.1502.1054° Proton nuclear magnetic resonance spectrum (200 membered 2) δ (DMSO-db): 4.
20 (S, 2B), 5.17 (brS, 28).

6.45 (dd, J=7.6, 7.3tlz, 111)
, 6.63 (d.

J=8.3Hz, IH), 6.93-7. OO(m,
2H).

7.25 (brS, 2H) Mass spectrum m/z (χ) (EI:l: 23
8 (M”, 4%), 205 (2χ), 135 (16
χ'), 106 (100χ), 78 (18χ).

76 (30″g), 64 (28%) Example 8 2-(N,N-bis(methoxymethyl)amino]5-
(2-pyridylmethylthio) -1,3,4-thiadiazole 2-amino-5-(2-pyridylmethylthio) -1,3,4-thiadiazole 224m
A suspension of 608 mg of sodium borohydride (90%) in methanol (lk) was added dropwise thereto, and the mixture was stirred at room temperature all day and night. While cooling, the reaction mixture was made alkaline by adding an aqueous sodium hydroxide solution, extracted with benzene, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. 2-[N,N-bis(
methoxymethyl)amino)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 123 mg (3
9.4%).

Molecular formula e CIZII16N40! S2 (312,4
0) Properties: Oily infrared absorption spectrum v m*xc
m-' (NaC1): 2932+1592.15
16,1470,1438.1396.1276゜11
30, 1076 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
Cl2): 3.39 (S, 6H), 4.56 (S, 2
H), 4.91 (S, 4H).

7.19 (dd, J = 7.6.4.9H, z, IH),
7.46 (d.

7.8Hz, 18), 7.64(dd, J=7.8.
7.6Hz.

LH), 8.56 (brd, J=4.9Hz, 1) 1)
Mass spectrum m/z (X) (El): 312 (
M”, 6%), 297 (3χ), 281 (7%)
, 267(8χ)+251(3χ).

237 (2%), 220 (19%), 15
1 (16χ), 92 (33χ).

65 (18χ), 45 (100%) Example 9 2-amino-5-((4-chloropyridin-2-yl)
Methylthio)-1,3,4-thiadiazole I (1) 4-nitro-2-picoline-N-oxide ↓ 50.0 g of 2-picoline-N-oxide was placed in a 12 eggplant-shaped flask equipped with a reflux condenser. Ice-cooled concentrated sulfuric acid 175
- was added little by little, 150 ml of fuming nitric acid was added little by little, and the mixture was stirred for 30 minutes while cooling with water.Then, the temperature was gradually raised and the mixture was heated on an oil bath (external temperature 80 to 90°C) for 3 hours. This reaction solution was returned to room temperature, poured into ice water (11), and cooled with water for 3 minutes.
After making it weakly acidic (pH 5 to 6) with a 0% aqueous sodium hydroxide solution and making it weakly alkaline (pH 10) with potassium carbonate, it was extracted twice with chloroform (2fX2) and dried (
K2CO,) and the solvent was distilled off under reduced pressure to obtain a yellow solid. This was recrystallized from methanol to obtain 62.50 g (yield 88.5%) of 5-nitro-2-picoline-N-oxide as pale yellow needles (melting point 152-154°C).

Molecular formula: CJiOJz (154,12) Melting point: 15
2~154°C Properties: Pale yellow needle crystals Infrared absorption spectrum ν, xcm-' (KBr): 3116°308
0.3048.1612, 1516, 1462.134
4゜1338.12B6,1270.1234.120
0.1214°1092.932,844,786,7
50,660 proton nuclear magnetic resonance spectrum (200M
Z) δ (CDC13): 2.57 (3H, S), 8.
00(11(,dd,J・7.1,3.2H2),8
．． 14 (IH, d, J = 3.211z), 8.31 (
LH, d.

J・7.111z) Mass spectrum m/z (%) (El): 154 (1
00χ, M”), 137 (477;), 108 (
33%>, 91 (34%), 64 (60χ
) (2) 4-chloro-2-picoline-N-oxide (4
-Chloro-2-methylpyridine-N-oxide) I Put 10.0 g of 4-nitro-2-picoline-N-oxide into a 200rnl three-necked flask, and after purging with nitrogen gas, acetyl chloride 30- was added under water cooling. The mixture was stirred for 2 hours under water cooling. The reaction solution was poured into ice and made weakly acidic (pH 5-6) with a 5% aqueous sodium hydroxide solution, then made weakly alkaline (pH 10) with potassium carbonate, extracted twice with chloroform (200x2), and the chloroform layer was extracted with saturated sodium chloride. The residue was washed once with water, dried (K, CO,), and the solvent was distilled off under reduced pressure to obtain a yellow oil.

Add 30rnl of 10% hydrochloric acid/methanol solution to this,
After dissolving, the solvent was distilled off under reduced pressure, and then methanol-
Recrystallized from ethyl acetate to give 5-chloro-2-picoline-
5.5 g (yield 47%) of N-oxide/llCl salt was obtained as a pale yellow prism product (melting point 133-135°C).

Molecular formula: CaHJOCl (143,57) Melting point:
133-135°C Properties: Pale yellow prism product Infrared absorption spectrum v maxcm-' (KBr) (HCl
salt)=3080.3036.2372,1618.15
66, 1462°1454, 13B2.1260.11
88.1126,838,674゜552.448 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
C13): 2.51 (311,S), 7.16
(IH, dd, J=6.8.2.9tlz).

7.30 (IH, d, J=2.911z), 8
．． 20 (LH, d, J=6.8Hz) Mass spectrum m/z (χ) (El]: 145 (25χ
, M''), 143 (74%, M''), 128
(34ri, 126 (100X), 101(1
5ri, 99(43χ), 92(19χ), 90(5
0%).

73 (15%), 65 (21χ), 63 (22
%) 51 (41%) (3) 4-Chloro-2-picolyl chloride
Add 3.50 g of -chloro-2-picoline-N-oxide and 9.26 g of P-1-luenesulfonyl chloride, and after purging with nitrogen gas, add and dissolve 10 mt' of anhydrous dioxane, and place on an oil bath (external temperature). 130°C) for 6 hours.
It flowed. The reaction solution was returned to room temperature, water was added thereto, insoluble matter was filtered through Celite, the filtrate was made weakly alkaline (pH 10) with potassium carbonate, and extracted twice with chloroform (1
50X2), wash the chloroform layer once with saturated saline,
Drying (NazSO4) and removal of the solvent under reduced pressure gave a brown oil. Flash column chromatography 1 (silica gel; 230-400 mesh, φ4.5X
10. Approximately 80 g, elution solvent: ethyl acetate: n-hexane = 1:2, pressure = 0.2 kg / c + fl) was used to separate and purify (separate 70 mf each), and the 2nd to 4th fractions were combined to obtain the desired 4 2.89 g (yield 73%) of -chloro-2-picolyl chloride was obtained as a colorless oil. (The desired colorless oil could be obtained by purification by main distillation.) Molecular formula: C6H, NCI!
[162,016] Properties Di-oil proton nuclear magnetic resonance spectrum (200MZ) δ (CDCh): 4.65 (
2H, S), 7.26 (LH, dd, J=5.1,2
．． 0Hz), 7.52 (Ill, d, J=2.0Il
z), 8.47 (18°d, J・5.IH2) (4) 2-Amino-5-[(4-chloropyridine-2-
yl) methylthio]-13,4-thiadiazole 200 mj Sodium hydroxide 1.5 in an eggplant flask
After adding 15 mm of water and dissolving it, 2-amino-5-mercapto-1,3,4-thiadiazole 2.3
7 g was added and dissolved by stirring at room temperature for 10 minutes, then a solution of 0.57 g of tetra-n-butylammonium bromide and 2.89 g of 4-chloro-2-picolyl chloride dissolved in 45 ml of benzene was added, and the mixture was heated to room temperature. The mixture was stirred vigorously overnight. Insoluble matter in the reaction solution was filtered out (washed well with water and then washed with benzene 2 to 3 times), and then dried to obtain a yellow powder (3.21 g). This was recrystallized from methanol to obtain 3.08 g of a yellow prism product (yield: 67%). Further, this was dissolved in hot methanol, decolorized with activated carbon, and then recrystallized from methanol again to obtain the desired 2-amino-
5-C(4-chloropyridin-2-yl)methylthio]
-1,3,4-thiadiazole 2.86 g (yield 6
2%) was obtained as a colorless prismatic product (melting point 133-135°C).

Molecular formula: csllJ4s2cl (258,748)
Melting point: 133-135°C Properties: Colorless prism product Infrared absorption spectrum v,,Xcm-' (KBr): 3
272.3076°2972, 1640,1574,
1556, 1504. 1470°1416.1388
, 1330, 1214, 1136. 1102°107
2.1038,878,836,712. 640,6
08 proton nuclear magnetic resonance spectrum (20(llIZ)
δ(DMSO-d6): 4.40(2H,S"),
7.32 (2+1.S, disappeared by adding DzO), 7.4
5 (LH, dd, J=5.6, 2.01lz).

7.58 (if, d, J=2.0Hz), 8.49
(ill, d, J=5.611z) Mass spectrum m/z (χ) (El): 260 (3
42, M'), 258 (79χ, M''), 243 (1
0%), 241 (20χ), 227 (38X)
, 225 (tooχ), 185 (15χ), 18
3 (32z).

171 (16χ), 158 (39χ) + 126(
80χ), 113 (39χ), 90 (32χ),
60(74Z) Example 10 2-Amino-5-((5-chloropyridin-2-yl)
Methylthio)-1,3,4-thiadiazole (1) 5-chloro-2-picoline and 3-chloro-2-
35.8 g of anhydrous aluminum chloride was placed in a 500 m1 three-necked flask equipped with a Picoline dry ice condenser, an inlet tube (for CI! gas), and a dropping funnel, and the mixture was stirred at room temperature.
Picolin 10. After adding Og dropwise and stirring at room temperature for 2 hours, chlorine gas was introduced by bubbling, and then heated and stirred on an oil bath (external temperature 80-90"C) for 5 hours. The reaction solution was heated at room temperature Reconstitute it, carefully pour it into ice water (500X), make it alkaline (pH>12) with a 30% aqueous sodium hydroxide solution, and extract with ether twice (400X).
2) Wash the ether layer once with saturated saline and dry (K2
CO3) and the solvent was distilled off under reduced pressure to obtain a brown oil. This was subjected to flash column chromatography 1 (silica gel;
230-400 mesh, φ6.5 x 20, approx. 300
g, eluent; ethyl acetate: n-hexane = l: 3, pressure = 0.2 kg/cfflS1 fraction = approximately 80-)
5 from the first elution fraction (10th to 12th)
-Chloro-2-picoline 1, 96 g (yield 14%) was obtained as a colorless oil. In addition, the second elution fraction (13 to 18
2.87 g (yield 21%) of 3-chloro-2-picoline was obtained as a colorless oil.

(*The desired oil could also be obtained by purification by distillation) 5-chloro-2-picoline: Molecular formula: C6H6NCl (127,57) Properties: Oily proton nuclear magnetic resonance spectrum (200MZ) δ
(CDCh): 2.53 (3H, S), 7.10 (I
H, d, J 8.3).

7.54 (IH, dd, J=8.3, 2.411z)
, 8.45 (IH.

d, J・2.4Hz) 3-chloro-2-picoline: Molecular formula: C60,NC1 (127,571 Properties: Oily proton nuclear magnetic resonance spectrum (200MZ) δ (CD
CI: 2.63 (38, S), 7.09 (IH, d
d, J=8.1, 4.6Hz), 7.63(LH, dd
, J=8.1,1.511z), 8.39(1)1. d
d, J=4.6, 1.5Hz) (2) 5-chloro-2
-Picoline-N-oxide (5-chloro-2-methylpyridine-N-oxide) Φ Put 1.96 g of 5-chloro-2-picoline in a 100 mf eggplant flask, add 40-chloroform and dissolve,
After stirring at room temperature, 3.64 g of m-chloroperbenzoic acid was added little by little, and the mixture was stirred at room temperature for 3 hours. The white insoluble matter in this reaction solution was removed by filtration, water was added to the filtrate, the pH was made weakly alkaline (pH 10) with potassium carbonate, and then extracted with chloroform twice (100 x 2), and the chloroform layer was diluted with saturated saline once. Washing twice, drying (K, C03), removing the solvent under reduced pressure,
1.95 g (yield: 88%) of 5-chloro-2-picoline-N-oxide was obtained as a white solid.

Molecular formula: C6H60NCI (143,57:1 Melting point: 60-65°C Properties: White amorphous Infrared absorption spectrum v, mXcm-' (KBr): 30
36°1610.1492.1448,1364.12
58.1216°1096.990,916,892,
798,662,582 proton nuclear magnetic resonance spectrum (200MZ) δ (CDCh): 2.49 (3H,S)
, 7.20 (2H, m) , 8.32 (IH, m)
.

Mass spectrum m/z (X) (ET): 145 (2
3χ, M”), 143 (75χ, M”), 128 (
35χ), 126(100χ), 101(11χ),
99 (33%), 90 (44χ), 73 (1
3%), 63 (15χ), 51 (25χ) (3) 2-acetoxymethyl-5-chloro-pyridine 5-chloro-2-picoline-N-oxide 1. 80 g and 10 ml of acetic anhydride were added, and the mixture was heated and stirred on an oil bath (external temperature 90 to 100°C) for 1.5 hours. Pour this reaction solution into ice water (30)
and make it weakly alkaline with potassium carbonate (p I-I 1
0), then extracted with chloroform twice (150X2)
, the chloroform layer was washed once with saturated saline and dried (K2
CO3) and the solvent was distilled off under reduced pressure to obtain a brown oil. Flash column chromatography 1 silica gel; 2
30-400 mesh, φ4.5 x 20. Approximately 160g
, eluent; ethyl acetate: n-hexane = 1:5, pressure =
0.2kg/c111. 1 fraction = approx. 70rd
) to obtain 1.31 g (yield 56%) of 2-acetoxymethyl-5-chloropyridine as a colorless oil from the eluted fractions (7th to 10th). (*The desired oil could also be obtained by purification by distillation) Molecular formula: C, ++, 0□NCI (185,60) Properties: Oil Proton nuclear magnetic resonance spectrum (200MZ)
δ (CDC13): 2.16 (3H, S), 5.20
(211, S), 7.32 (IH.

d, J=8.1)1z), 7.69(IH, dd, J
=8.1,2.411z), 8.56 (LH,d,
J=2.4Hz) (4) 5-chloro-2-picolyl chloride (2-chloromethyl-5-chloropyridine) Hydrochloride HCl salt 2-acetoxymethyl-5- Chloropyridine 1.30g and 35
Add 7% hydrochloric acid and place on oil bath (external temperature 100-105"C)
The mixture was heated and stirred for 1.5 hours. The reaction solution was returned to room temperature, and hydrochloric acid was completely removed by distillation under reduced pressure. After that, 3.5 ml of thionyl chloride was added and stirred at room temperature for 1 hour.

This reaction solution was distilled off under reduced pressure to remove excess thionyl chloride,
H of 5-chloro-2-picolyl chloride as a white solid
1.16 g (yield 84%) of CI salt was obtained.

Molecular formula: C, H6NCl3 (198,476) Properties: White amorphous proton nuclear magnetic resonance spectrum (200MZ) δ (CD
, OD): 4.81 (2) 1. S), 7.80 (I
H, d, J = 8.5Hz).

8.21 (LH, dd, J=8.5.2.4Hz)
, 8.75 (LH.

d, J=2.4Hz) (5) 2-amino-5-((5-chloropyridine-2-
yl)methylthio)-13,4-thiadiazole 1.16 g of 5-chloro-2-picolyl chloride HCI salt, 5 ml of water, and 1 benzene in a 100- eggplant flask.
Then, 0.98 g of sodium hydroxide was added, and after stirring for 10 minutes, 0.79 g of 2-amino-5-mercapto-1,3,4-thiadiazole and tetra-
188 mg of n-butylammonium bromide was added, and the mixture was vigorously stirred at room temperature overnight. Insoluble matters in the reaction solution were collected by filtration (washed well with water and then washed with benzene 2 to 3 times), and then dried to obtain light brown powder crystals (1.28 g). This was recrystallized from methanol to produce light brown needle-like products 1, 19g.
(yield 79%). Further, this was dissolved in hot methanol, decolorized with activated carbon, and then recrystallized from methanol again to obtain the desired 2-amino-5-((5-chloropyridin-2-yl)methylthio)-1,3,4 - Thiadiazole 1.09g (yield 72%) was synthesized into colorless needle crystals (melting point 15).
5-157°C).

Molecular formula: C, H, N4S, CI (25B, 748)
Melting point: 155-157°C Properties: Colorless needle crystals Infrared absorption spectrum ν, Xcm-' (KBr): 3296.3
116°1644, 1498.1468, 1404.1
106,1030°842.674.636,570,
506 proton nuclear magnetic resonance spectrum (200MZ) δ
(DMSO-d6): 4.39 (2H,S), 7.
31 (disappeared by addition of 2H, S, DzO), 7.48 (l
tl, d, J=8.511z).

7.91 (LH, dd, J=8.5.2.7[1z
), 8.56 (ltl.

d, J=2.7Hz).

Mass spectrum m/z (X) (EI): 260 (
31χ, M”), 258 (76LM”), 22
7 (30χ), 225 (79%), 185 (13χ)
, 183 (33X) , 157 (18%)
, 126 (100χ).

113 (32χ), 99 (30χ'), 90
(32χ), 60(45χ) Example 11 2-Amino-5-((4-methoxypyridin-2-yl)methylthio)-1,3,4-thiadiazole Me Dew(1) 4-methoxy-2-picoline -N-oxide (4
-methoxy-2-methylpyridine-N-oxide) Me ↓ 4-nitro-2-picoline- in a 300 m1 three-necked flask
After adding 10.0 g of N-oxide and purging with nitrogen gas, it was dissolved in 100 ml of anhydrous methanol, then 26 ml of 28% sodium methoxide was added, and the mixture was stirred at room temperature for 2 hours. This reaction solution was distilled off under reduced pressure, and water (100%
), then extracted twice with chloroform (300X2)
, the chloroform layer was washed once with saturated saline and dried (K,
C03), the solvent was distilled off under reduced pressure to obtain 8.28 g (yield: 92%) of 4-methoxy-2-picoline-N-oxide as a colorless oil. This was also recrystallized from ethyl acetate-n-hexane to produce a colorless prism product (melting point 81-83°C).
I got it.

Molecular formula; C? H90□N (139,15) Melting point: 8
1~83°C Properties: Colorless prism crystal Infrared absorption spectrum ν,,Xcm-' (KBr): 1632+156
2.1496. 1318, 1210, 1180, 10
52°926, 894, 838, 788.742
, 648.568 proton nuclear magnetic resonance spectrum (2
00MZ) δ(CDCI 3) :2.53(3H,S
), 3.85 (3H, S), 6.72 (IH, dd.

J=7.1, 3.411z), 6.79(III, d
, J=3.4Hz).

8.17 (IH, dd, J = 7.111z) Mass spectrum m/z (%) (El): 139 (100χ,
M”), 122 (85%), 92 (36%),
80 (15X), 65 (50Z), 53
(24%) (2) 4-methoxy-2-picolyl chloride (2-chloromethyl-4-methoxypyridine) Me 8.28 g of 4-methoxy-2-picolin-N-oxide was placed in a 2O0rIi eggplant flask, After purging with nitrogen gas, 40 ml of anhydrous benzene was added and dissolved, and then p
- Add 12.48 g of 1-luenesulfonyl chloride,
Stirred at room temperature for 2 hours. This reaction solution was distilled off under reduced pressure to remove benzene, and then heated on an oil bath (external temperature 80-100'C) for 3 hours. Next, water (200) was added to this reaction solution, and after washing once with chloroform, the aqueous layer was made weakly alkaline (pH 10) with potassium carbonate, extracted twice with chloroform (150×2), and the chloroform layer was extracted once with saturated saline. Washing twice, drying (NazSO4), and removing the solvent under reduced pressure.
A brown oil was obtained. Flash column chromatography - 1 silica gel, 230-400 mesh; diameter 4
．． 5 cm x length 10 cm; about 80 g; elution solvent; ethyl acetate: n-hexafka-: l; pressure car. 2kg/
c + d) to separate and purify (separate 70 ml each) and combine the 3rd to 7th fractions to obtain the desired 4-methoxy-
2.40 g (yield 26%) of 2-picolyl chloride was obtained as a colorless oil. (*The target oil could also be obtained by purification by distillation) Molecular formula: C7HaONCI (157,59) Properties: Oil proton nuclear magnetic resonance spectrum (200MZ)
δ(CDCh)': 3.87(3H,S), 4.63
(2B, S), 6.76 (ill, dd.

J=5.9, 2.7Hz), 7.00(LH, d, J=
2.711z).

8.39 (Ill, d, J=5.9Hz) (3)2
-amino-5-((4-methoxypyridin-2-yl)
Methylthio)-1,3,4-thiadiazole 200 rnl Sodium hydroxide 1.
After adding 22 g of water and dissolving it, add 2.0 g of 2-amino-5-mercapto-13,4-thiadiazole.
7 g was added and dissolved by stirring at room temperature for 10 minutes, and then a solution of 0.49 g of tetra-n-butylammonium bromide and 2.40 g of 4-methoxy-2-picolyl chloride dissolved in benzene 45- was added and the mixture was heated at room temperature. The mixture was stirred vigorously overnight. The insoluble matter in this reaction solution was filtered out (washed thoroughly with water and then with benzene 2 to 3 times), and then dried to produce a yellow powder (
3.31 g) was obtained. This was recrystallized from methanol,
3.15 g (yield: 81%) of a yellow prism product was obtained. Furthermore, this was dissolved in hot methanol, decolorized with activated carbon, and then recrystallized from methanol again to obtain the desired 2-amino-
5-((4-medoxypyridin-2-yl)methylthio]-1.3.4-thiadiazole 2.62 g (yield 68
%) as a colorless prism product (melting point 141-143°C).

Molecular formula: C, HION, O52 (254,328) Melting point: 141-143°C Properties: Colorless prism infrared absorption spectrum v maxCm-' (XBr):
3260.3076°1650.1602,1562,
1504.14B6.1426°1306.1290.
1124.1034,828,762,672,576 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-d, ): 3.81 (3H, S), 4.33 (
2+1. S), 6.88(l)1. dd, J=5.6,
2.411z), 7.00(1)1. d, J=2.4H
z), 7.30 (2t(, S, disappeared by addition of DzO).

8.32 (IH, d, J = 5.6 tlz) Mass spectrum m/z (χ) (El) 254 (100χ, M”)
, 237 (12X) , 221 (48X) ,
212 (11%), 19B (14χ).

179 (36X), 166, (18χ”), 154 (
47χ), 148 (18χ), 122 (89'A
), 109 (42χ), 92 (24χ).

65 (42χ) Example 12 2-Amino-5-((5-methoxypyridin-2-yl)methylthio)-1,3,4-thiadiazole (1) 5-methoxy-2-picoline-N-oxide (5
-Methoxy-2-methylpyridine-N-oxide) Φ Put 15.0 g of 5-hydroxy-2-picoline into a 200 m1 three-necked flask equipped with a reflux condenser and replace the atmosphere with nitrogen gas, then add 60 mf of anhydrous dimethyl sulfoxide and dissolve. Then, 31 mL of a 28% methanol solution of sodium methoxide was added, stirred at room temperature for 10 minutes, and further heated on an oil bath (external temperature 80 to 90°C) for 30 minutes. After the reaction solution was returned to room temperature, 9.4-methyl iodide was added and stirred for 1 hour. After adding water to this reaction solution, extraction was carried out twice with chloroform (200x2), the chloroform layer was washed twice with water, dried (KzCO3), the solvent was distilled off under reduced pressure, concentrated to about 300 rnl, and then stirred. 15.0 g of perbenzoic acid was added little by little, and the mixture was stirred at room temperature overnight. Water was added to this reaction solution, and potassium carbonate was added to make it weakly alkaline (pH
10) and then extracted with chloroform twice (200X2)
, the chloroform layer was washed once with saturated saline and dried (Kz
CO3) and the solvent were distilled off under reduced pressure to obtain 6.65 g (yield 35%) of 5-methoxy-2-picoline-N-oxide as a white solid. This was also recrystallized from ethyl acetate-n-hexane to produce colorless prismatic crystals (melting point 88-90°C).
I got it.

Molecular formula: C7H302N (139,15) Melting point = 8
8-90'C Properties: Colorless prismatic crystal infrared absorption spectrum v @@xcm-' (KBr): 1632+1
562.1502,1472.1370.1290,1
228°119B, 1120,1024,826,
806,728,580° Proton nuclear magnetic resonance spectrum (200) IZ) δ (CDC13): 2.49 (3H
, S), 3.82 (3H, S), 6.83 (III, d
d.

J=8.8.2.411z), 7.13(LH,d,J
=8.811z).

8.03 (111, d, J・2.4H2) Mass spectrum m/z ($) (El): 139 (52LM”)
, 122 (100%) , 10B (23%) ,
80 (29ri), 53 (34ri (2) 5-methoxy-2-picoline chloride (2-chloromethyl-5-methoxypyridine) and 4-chloro-5-methoxy-2-
Picoline (4-chloro-5-methoxy-2-methylpyridine) I A) 5-
Add 0.89 g of methoxy-2-picoline-N-oxide and 2.46 g of P-toluenesulfonyl chloride, replace with nitrogen gas, add 5 ml of anhydrous dioxane, dissolve, and place on an oil bath (external temperature 130°C). The mixture was heated under reflux for 14 hours. After returning the reaction solution to room temperature and adding water, it was washed once with chloroform, the aqueous layer was made weakly alkaline (pH 10) with potassium carbonate, and extracted with chloroform twice (pH 10).
X2), the chloroform layer was washed once with saturated brine, dried (K2CO2), and the solvent was distilled off under reduced pressure to obtain a brown oil. This was subjected to flash column chromatography (silica gel; 230-400 mesh, φ4.5 Xl01
Approximately 80 g, elution solvent; tyl acetate: n-hexane = 1:1
, pressure 0.2 kg/cffl.

1 fraction = approximately 50 rnl), and 18 mg (1.8%) of the desired 5-methoxy-2-picolyl chloride was obtained as a colorless oil from the first elution fraction (third). In addition, 450 mg of 4-chloro-5-methoxy-2-picoline (yield 44
%) was obtained.

B) In a 50 roll eggplant flask equipped with a reflux condenser, add 5
-Methoxy-2-picoline-N-oxide (3.80 g) and methanesulfonyl chloride (4.23 m) were added, the atmosphere was replaced with nitrogen gas, and the mixture was stirred at room temperature for 1 hour.
0°C) for 3 hours. The reaction solution was brought to room temperature, water was added, and then washed once with chloroform. The aqueous layer was made weakly alkaline (pH 10) with potassium carbonate and extracted with chloroform twice (150x2). The chloroform layer was extracted once with saturated saline. The residue was washed, dried (K, C03), and the solvent was distilled off under reduced pressure to obtain a brown oil.

This was subjected to flash column chromatography (silica gel: 230-400 mesh, φ4.5 Xl01 approx. 8
0g, eluent; ethyl acetate: n-hexane = 1:l, pressure 0.2 kg/c+fl, 1 fraction = approx. 6
0-), and 137 mg of the target 5-methoxy-2-picolyl chloride was obtained from the first elution fraction (third).
(yield 3.1%) was obtained as a colorless oil. Also the second
2.3 g (yield: 53%) of 4-chloro-5-methoxy-2-picoline was obtained from the elution fractions (4th to 5th).

5-Methoxy-2-picolyl chloride: Molecular formula: C?
) IIIONCI (157,59) Properties: Oily proton nuclear magnetic resonance spectrum (200MZ) δ (CD
C1+)+3.85(3+1.S), 4.64(H
, S), 7.20 (ill, dd.

J=8.6, 2.9Hz), 7.37(IH, dd,
J=8.6°0.7Hz), 8.26(ltl, dd,
J=2.9,0.7Hz) 4-chloro-5-methoxy-
2-Picoline: Molecular formula: CJeONCI C157
, 59) Properties: Oily proton nuclear magnetic resonance spectrum (200MZ) δ (CDCI+): 2.48 (3B, S
), 3.96 (311, S), 7.17 (l) 1. S)
.

8.15 (IH, 5) (3) 2-acetoxymethyl-5-methoxypyridine in a 100 rnl eggplant flask equipped with a reflux condenser.
3.30 g of -methoxy-2-picoline-N-oxide and 23 ntt' of acetic anhydride were added, and the mixture was purged with nitrogen gas, and then heated and stirred on an oil bath (external temperature: 100°C) for 3 hours.

The reaction solution was returned to room temperature, evaporated under reduced pressure to remove acetic anhydride, water was added, and potassium carbonate was added to make it weakly alkaline (pH 1).
0), extracted with chloroform twice (200X2), washed the chloroform layer once with saturated saline, and dried (K2CO2).
The solvent was distilled off under reduced pressure to obtain a brown oil.

This was subjected to Franche column chromatography (silica gel; 230-400 mesh, φ4.5 x 20, about 1
60 g, pressure 0.2 kg/cut, 1 fraction = approximately 80 m, separated and purified, and 3.15 g of 2-acetoxy-methyl-5-methoxypyridine (yield 73%) was obtained from the eluted fractions (6th to 12th). was obtained as a colorless oil. (
Purification by main distillation also yielded the desired oil: 148-150°C/12mmHg) Molecular formula: C
9HII03N (tat, +9) Properties: Oily proton nuclear magnetic resonance spectrum (200MZ) δ (CDCl
2).

2.13 (38, S), 3.86 (3H, S), 5
．． 16 (2+1.S).

7.20(1)1. dd, J=8.5.2.9tl
z), 7.31 (IH.

d, J=8.5Hz), 8.30(LH, d, J=2
．． 911z) (4) 5-Methoxy-2-picolyl chloride (2-chloromethyl-5-methoxypyridine) hydrochloride In a too mZ eggplant flask equipped with a reflux condenser, 2-
Add 3.70 g of acetoxymethyl-5-methoxypyridine and 20 ml of 35% hydrochloric acid, and place on an oil bath (external temperature 100°C).
) for 4 hours with stirring. The reaction solution was returned to room temperature, evaporated under reduced pressure to completely remove hydrochloric acid, and 1
0ml was added and stirred at room temperature for 1 hour. The reaction solution was distilled off under reduced pressure to remove excess thionyl chloride, and a brown solid was obtained as a brown solid.3.
94 g (yield 99.5%) was obtained.

Molecular formula: Cqtl, 0NC1z (194,05) Proton nuclear magnetic resonance spectrum (200MZ) δ (CIh
OD) :4.0B(31(,S), 4.99(2H
, S), 8.10(1)1; d.

J=9.011z), 8.23(IH, dd, J=9.
0.2.7Hz).

8.62 (IH, d, J = 2.7 Hz) (5) 2-Amino-5-(5-methoxypyridin-2-yl-methylthio)-1,3,4-thiadiazole 5- in a 200d eggplant flask Add 3.94 g of methoxy-2-picolyl chloride HCI salt, 15-g of water and 45+n/ of benzene, and then add 3.42 g of sodium hydroxide.
After stirring for 10 minutes, 2.71 g of 2-amino-5-mercapto-C3,4-thiadiazole and tetra-
0.65 g of n-butylammonium bromide was added, and the mixture was vigorously stirred at room temperature overnight. Insoluble matter in this reaction solution was filtered out (washed well with water and then washed with benzene 2 to 3 times) and then dried to obtain a brown powder (5.07 g). This was recrystallized from methanol, and 4.01 g of yellow needle crystals (yield: 7
8%). Furthermore, dissolve this in hot methanol,
After decolorizing with activated carbon, it is recrystallized again from methanol to obtain the desired 2-amino-5-((5-methoxypyridine-
3.10 g (yield 60%) of 2-yl)methylthio)-1,3,4-thiadiazole was converted into colorless needle crystals (melting point 139~
141°C).

Molecular formula: C9HI. N, OS2 (254,328)
Melting point: 139-141°C Properties: Colorless acicular crystals Infrared absorption spectrum ν11. , cm-(KBr): 3276
゜3088, 164B, 1572.1492,145
4,1400°12B8.1230.1118.103
0,842,662 proton nuclear magnetic resonance spectrum (2
00MZ) δ(DMSO-d6): 3.81(3H,
S), 4.33 (28, S), 7.29 (21L S)
, disappeared by addition of DzO), 7.36 (21 Lm).

8.2HILra) 7ss hector m/z<”A”) (EI): 254
(16LM”), 221 (9χ), 212 (8%L
179 (17X), 122 (1002).

80(14X) Example 13 2-amino-5-((3-chloropyridin-2-yl)
Methylthio)-1,3,4-thiadiazole (1) 3-chloro-2-picoline-N-oxide (3-
(Chloro-2-methylpyridine-N-oxide) ↓ Put 2.87 g of 3-chloro-2-picoline in a 100 ml eggplant-shaped flask, add 50 m/ml of chloroform and dissolve, then add 5 m-chloroperbenzoic acid while stirring at room temperature. .34 g was added little by little and stirred at room temperature for 3 hours. Insoluble materials in this reaction solution were removed by filtration, water was added to the filtrate, and the mixture was made weakly alkaline (pH 10) with potassium carbonate, followed by extraction with chloroform twice (150x2), and the chloroform layer was washed once with saturated saline. Drying (KzCOi), removing the solvent under reduced pressure,
3.12 g (yield 97%) of 3-chloro-2-picoline-N-oxide was obtained as a white solid.

This was further recrystallized from ethyl acetate-n-hexane,
2.30g (as colorless needle crystals (melting point 90-92°C)
Yield: 71%).

Molecular formula: C686NOCI (143,57) Melting point:
90-92°C Properties: Colorless needle crystals Infrared absorption spectrum ν,,Xcm-' (KBr): 1688°1600
．． 1546,1476.1438.1384.1244
゜1216.1158,1018,882,810.6
9(i, 648°560, 500 proton nuclear magnetic resonance spectrum (200MZ) δ(CD
C13): 2.64 (3H,S), 7.07 (
LH, dd, J=7.8.6.611z).

7.29 (III, d, J=7.8. fiz)
, 8.20 (IH, d, J = 6.611z) (2) 2-acetoxymethyl-3-chloropyridine In a 50 rnl eggplant flask equipped with a reflux condenser, 3-chloro-2-picoline-N-oxide 1 .90 g and 10 In of acetic anhydride! After replacing the water with nitrogen gas, place it on an oil bath (
The mixture was heated and stirred at an external temperature of 100°C for 3 hours. The reaction solution was returned to room temperature and evaporated under reduced pressure to remove acetic anhydride, then water was added and made weakly alkaline (pH 10) with potassium carbonate, extracted with chloroform twice (150x2), and the chloroform layer was washed once with saturated saline. , dried (K2CO3) and evaporated the solvent under reduced pressure to obtain a brown oil.

This was subjected to fludge column chromatography 1 (silica gel; 230-400 mesh, φ4.5 x 20, about 16
0 g, eluent; ethyl acetate: n-hexane = l: 3, pressure - 0.2 kg/crA, 1 fraction approximately 70 r
Separation and purification by n-times, 1.54 2-acetoxymethyl-3-chloropyridine was obtained from the eluted fraction (10th to 15th).
g (yield 63%) was obtained as a colorless oil. (*The desired oil could also be obtained by purification by distillation) Molecular formula: CIHaO! NCI (185,60)
Properties: Oily proton nuclear magnetic resonance spectrum (200MZ
) δ (CDC13): 2.1B (3H, S), 5.35
(2H,S), 7.24 (LH,dd.

J = 8.1, 4.6Hz), 7.71 (IH, dd, J
=8.1, 1.2Hz), 8.52(LH, dd, J
= 4.6.1.2tlz) (3) 3-Chloro-2-picolyl chloride (2-10 methyl-3-chloropyridine) hydrochloride HCl salt In a 50-shaped eggplant flask equipped with a reflux condenser. 1.54 g of 2-acetoxymethyl-3-chloropyridine and 3
1. Add 8 d of 5% hydrochloric acid and place on an oil bath (external temperature 100''C).
The mixture was heated and stirred for 5 hours. The reaction solution was returned to room temperature and evaporated under reduced pressure to completely remove the hydrochloric acid, and thionyl chloride 4. O
rnl was added and stirred at room temperature for 1 hour.

This reaction solution was distilled off under reduced pressure to remove excess thionyl chloride,
1.38 g (yield: 84%) of the hydrochloride of 3-chloro-2-picolyl chloride was obtained as a pale brown homologue.

Molecular formula: C,)i&Nch (198,476) Properties: Light brown amorphous (4)2-amino-5-((3-chloropyridine-2-
yl) methylthio)-1,3,4-thiadiazole 1.38 g of 3-chloro-2-picolyl chloride HCI salt and 5 ml of water in a 50 ml eggplant-shaped flask! and benzene 1
5-, then 1.17 g of sodium hydroxide was added and stirred for 10 minutes, and then 2-amino-5-mercapto-1
0.95 g of 3,4-thiadiazole and 224 mg of tetra-n-butylammonium bromide were added, and the mixture was vigorously stirred at room temperature overnight. Insoluble matters in the reaction solution were collected by filtration (washed well with water and then washed with benzene 2 to 3 times), and then dried to obtain a light brown powder (1.43 g). This was recrystallized from methanol, and 1.20 g of light brown needle crystals (yield 67
%) was obtained. Further, this was dissolved in hot methanol, decolorized with activated carbon, and then recrystallized from methanol again to obtain the desired 2-amino-5-((3-chloropyridin-2-yl)methylthio)-1,3,4 -thiadiazole 1.1
0 g (yield 61%) was converted into colorless needle crystals (melting point 162-164
°C).

Molecular formula: Cs)17N4sgc1 (2ss, 74B
) Melting point: 162-164°C Properties: Colorless acicular crystals Infrared absorption spectrum v, cm-' (KBr): 32
84.3100°2968, 1640.1574,15
02.1430.1330°1222, 1134.10
70.1032,812,684,624° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d6
): 4.50 (2H, S), 7.34 (21 (, s,
Disappeared with nzoi membership), 7.39 (1) 1. dd, J=
8.1, 4.911z).

7.96 (ill, dd, J=8.1.1.511z)
, 8.47 (III.

dd, J=4.9.1.5Hz) Mass spectrum m/z (X) (El): 260 (
7LM, 258 (17χ, M+), 243 (5χ),
24H11χ), 225 (26χ), 223
(100ri, 183 (81), 158 (9
%), 126 (39χ), 113 (10χ), 99
(17ri, 90 (23%).

60(33χ) Example 14 2-(2-pyridylmethylthio)-5-(3°4.5-
2-amino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 1.042 g under argon atmosphere
1.658 g of 3.4°5-trimethoxybenzoyl chloride was added to a mixture of 10- and pyridine at room temperature.
Stir for hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with an aqueous potassium carbonate solution and water.1.
655 g of crude crystals were obtained. This product was recrystallized from methanol and 2-(2-pyridylmethylthio)-5-(3,4
,5-)rimethoxyhenzoylamino)-1,3,4-
1.458 g (75.0%) of thiadiazole was obtained.

Molecular formula: C+5LsLOaSz (418,48)
Melting point: 185-188°C Infrared absorption spectrum v m@Xcm-' (KBr)
: 1648+ 1582°1544, 1504.1
464.1444.1428, 1412°1330, 1
296.1254.1226.112B, 996,75
0 proton nuclear magnetic resonance spectrum (200MZ) δ(D
MSO-d6): 3.75 (S, 3H), 3.88
(S, 6H), 4.63 (S.

2) 1) , 7.31 (ddd, J=7.8.4
．． 9.1.5Hz, IB).

7.49 (S, 211),? , 51 (d, J=7.8
)1z, l1l).

7,80 (d t, J=7.8.2.0Hz, L
H), 8.54 (brd.

J=4.9Hz, IH), 13.08 (brS, IH)
Mass spectrum m/z (χ) (El): 418 (
M”, 26?(Li2S(100χ) Example 15 2-isonicotinoylamino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole Under argon atmosphere, methylthio)-1
, 3,4-thiadiazole 1.286g, pyridine 10
2.03 g of isonicotinoyl chloride hydrochloride was added to a mixture of m1 and 20 m of methylene chloride at room temperature, and the mixture was stirred for 20 hours. The precipitated crystals in the reaction mixture were collected by filtration and recrystallized with methanol to give 2-isonicotinoylamino-5-(2-
Pyridylmethylthio)-1,3,4-thiadiazole 0
．． 883 g (46.8%) was obtained.

Molecular formula: C,,H,,N,052 (329,39)
Melting point: 221-223°C (dec,) Infrared absorption spectrum ν,, Xcm-' (KBr): 1666.15
32°1476.1398,1304.1050,74
4,678 proton nuclear magnetic resonance spectrum (200MZ
) δ (DMSO-d6): 4.65 (S, 211)
, 7.32 (dd, J・7.8°4.9Hz, IH
), 7.52'<d, J=7.811z, 1t
l), 7.79(dt, J=7.8.2.0tlz
, 1ll), 7.98(brd, J=4.9!Iz
, 2H), 8.54 (brd, J=4.9Hz, L
H).

8.83 (brd, J=4.91 (z, 211),
13.48 (brS.

LH) Mass spectrum m/z (X) (EI:l :329(
M”, 37χ), 296 (20χ), 223 (
37χ), 106 (81χ), 92 (64χ).

7B (100χ) Example 16 2-nicotinoylamino-5-(2-pyridylmethylthio)-L3,4-thiadiazole (1) Nicotinic acid chloride hydrochloride Nicotinic acid 3.0 g and thionyl chloride 5.3 ml
The mixture was stirred under reflux for 1 hour. Petroleum ether was added to the reaction mixture under cooling, and the precipitated crystals were collected by filtration, washed with petroleum ether, and dried to give nicotinic acid chloride hydrochloride 2.9
Molecular formula obtained 58g (68,5%): C,)15c1
2NO (178) Melting point: 153-156°C Infrared absorption spectrum v ,,,Icm-' (KBr
) :3156°3120.3084.1730.14
64.1398.1274.1108.732 Proton nuclear magnetic resonance spectrum (200MZ) δ (mouth MSO
-d6) :8.04 (dd, J=8.1,5.4
tlz, IH), 8.80 (brd, J=8.
1Hz, 111), 9.06(brd, J=5.411
z, IH), 9.21 (brs, LH) (2) 2-nicotinoylamino-5-(2-pyridylmethylthio)-1
, 3,4-thiadiazole Under an argon atmosphere, 10 m of pyridine and 20 m of methylene chloride were added to a mixture of 1.276 g of 2-amino-5-(2-pyridylmethylthio)-L3.4-thiadiazole and 2.033 g of nicotinic acid chloride hydrochloride. was added and stirred at room temperature for 13 hours. The precipitated crystals in the reaction mixture were collected by filtration and recrystallized with methanol to give 2-nicotinoylamino-
1.2'76 g (67.6%) of 5-(2-pyridylmethylthio)-1,3,4-thiadiazole was obtained.

Molecular formula: Cl4HIINSO52 (329,39) Melting point: 222-223°C (dec,) Infrared absorption spectrum ν,..., Lcm-' (KBr): 1676, 1
596°1550.1416,1316.726 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-
db): 4.65(s, 2+D, 7.32(ddd
,,+7.3°4.9.1.0Hz, 1ll) ,
7.53 (d, J=1.8Hz, IH).

7.60 (dd, J=7.8, 4.9Hz, III),
7.80 (ddd.

J=7.8.7.3.2.0flz, 1tl), 8.
42 (ddd.

J=7.8.2.0.1.5Hz, IH), 8.54
(brd.

J=4.9Hz, LH), 8.81(dd, J=4.9
, 1.5Hz.

IH), 9.21 (d, J=2.0IIz, 18), 1
3.35 (brS.

II () Mass spectrum m/z (χ”) (EI): 329
(M”, 75X), 296 (31ri, 106 (100
X), 78 (7B Example 17 2-(4-acetoxy-3-methoxybenzoylamino)]5-(2-pyridylmethylthio)-1,3,4-thiadiazole (1) 4-acetoxy-3-methoxy Benzoic acid 4-hydroxybenzoic acid under argon atmosphere 5.1
3.67 rnl of acetic anhydride was added to a mixture of 8 g of chloroform (50) and 3.48 ml of pyridine, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was recrystallized from toluene to obtain 3.301 g (48.9%) of 4-acetoxy-3-methoxybenzoic acid.

Molecular formula: C5°H7°Os (210) Melting point: 145~
146°C Infrared absorption spectrum v,,,cm-' (KBr)
:1770.1692°1424.129B, 126
4.1214.1196.1174゜1108.760 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-d6): 2.29 (S, 3H), 3.84 (S
, 311), 7.22 (d, J=8.3Hz, 1l
l), 7.58(dd, J=8.3, 2.0fiz,
18), 7.61 (d, J=2.0Hz, l1l),
13.08 (brs, 111) Mass spectrum m/z (%) (El]: 210 (M
”, 5χ), 16B (100χ), 153 (43χ)
, 43(49χ)(2) 4-acetoxy-3-methoxybenzoyl chloride 4-acetoxy-3-methoxybenzoic acid 3
．． A mixture of 027 g and 3ff1/thionyl chloride was stirred under reflux for 1.25 hours. Excess thionyl chloride in the reaction mixture was distilled off under reduced pressure and dried to give 3.29 g of 4-acetoxy-3-methoxybenzoyl chloride (
100%) was obtained.

Molecular formula: C+o)IqCIOs Melting point: 52.5-53.5°C Infrared absorption spectrum v,,, cm-' (KBr)
:1764.1752゜1408.1274,126
2,1212.1150. 1120°972,762 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
Ch): 2.35 (S, 311), 3.91 (5, 31
1), 7.18 (d, J・8.3Hz, LH),
7.65 (d, J=2.2Hz, II(),
7.81 (dd, J = 8.3, 2.2 Hz, IH) mass spectrum m/z (χ) (El): 228 (M",
3″t), 186(25χ), 15H100χ), 12
3(14χ'), 43(65χ)(3)2-(
4-acetoxy-3-methoxybenzoylamino)-5
-(2-Pyridylmethylthio)-1,3,4-thiadiazole Under argon atmosphere, 2-amino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 1.
A mixture of 075 g of 4-acetoxy-3-methoxybenzoyl chloride, 1.612 g of pyridine, and 10 m of methylene chloride was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with toluene and water, and dried to give 2-(4-acetoxy-3
-methoxybenzoylamino)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 1.909 g
(95.6%).

Molecular formula CC11H16N4043z (416) Melting point: 195-200°C (dec,) Infrared absorption spectrum v,, Xcm-' (KBr): 1768.1
666°1538.1508.1310.1268,1
200.1172 proton nuclear magnetic resonance spectrum (20
0MZ) δ(DMSO-db): 2.30(S,
311), 3.89 (S, 3H), 4.77 (S, 2
H), 7.29 (d, J=8.3Hz, LH), 7
．． 61 (dd, J=7.6, 5.4Hz, III),
7.72 (dd, J=8.3.2.0Hz, 1)1
), 7.78 (d, J=7.8Hz, III)
.

7.88 (d, J=2.0Hz, LH), 8.14
(ddd, J=7.8.7.6.2.0Hz, l1l
), 8.70 (brd, J=5.4 summer 1z, LH)
, 13.2 (brS, LH) mass spectrum m/z
(X) (El): 416 (M”, 13χ), 3
74 (5χ), 151 (100χ), 123 (13χ"
), 93 (23χ).

92 (15%), 65 (15X), 43 (17%)
Example 18 2-(4-hydroxy-3-methoxybenzoylamino-5-(2-pyridylmethylthio)-1°3.4-thiadiazole hydrochloride 2-(4-acetoxy-3-methoxybenzoylamino)-5- A mixture of 915 mg of (2-pyridylmethylthio)-1,3,4-thiadiazole and 20 ml of 3N-hydrochloric acid was stirred under reflux for 1 hour. The precipitated crystals in the reaction mixture were collected by filtration, washed with water, and then recrystallized with methanol. 2-(4-hydroxy-3-methoxybenzoylamino)-5-(2
407 mg (41.6%) of -pyridylmethylthio)-1,3,4-thiadiazole (hydrochloride) was obtained.

Molecular formula: C+6HtsCINJ3Sz (410,
89) Melting point: 229-230°C (dec) Infrared absorption spectrum v m*xcm-' (KBr): 31
72.3112+1672.1594,1512,14
62. 1314. 1286°1272.1204.
1170 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-+:L): 3.86 (S, 3+1), 4.81
(S, 211), 5.50 (brS, IH), 6.9
4 (d, J=8.3Hz, 1tl), 7.65 (brd
, J=8.3Hz, 1t(), 7.71~? ,
, 77 (m, 2tl).

7.88 (d, J=7.8tlz, 18), 8.2
8 (m, 1tl), 8.77 (brd, J=5.9
Hz, 1ll), 12.90 (brS, III) Mass spectrum m/z (χ) (FD:l: 376.37
5,374 (M” of freebase) Example 19 2-(4-acetoxy-3-methoxycinnamoylamino)-5-(2-pyridylmethylthio)-1,3,4-
Thiadiazole (1) 4-acetoxy-3-methoxycinnamic acid Under an argon atmosphere, 5.7 g of 4-hydroxy-3-methoxycinnamic acid, 50-chloroform, and 3. pyridine.
Add 3.5-acetic anhydride to the mixture of 3rIi and stir at room temperature.
Stirred for 0.5 hour. The precipitated crystals in the reaction mixture were collected by filtration, washed with chloroform and dried to give 4-acetoxy-3-
Methoxycinnamic acid 3.899g (56,4
%) was obtained.

Molecular formula: C+J+zOs [236) Melting point: 193~
195°C Infrared absorption spectrum y maxcm-' (KBr)
: 1762+ 1690+1634.1422.1
262,1224.1198.1154° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d,)
: 2.27 (S, 3H), 3.83 (S, 3) 1),
6.59 (d, J=16.IHz, IH), 7.1
2(d, J=8.3Hz.

111), 7.27 (dd, J=8.3, 1.5Hz,
IH), 7.49 (d, J=1.5Hz, IH),
7.58 (d, J=16.1Hz.

LH) Mass spectrum m/z (χ) (EI, l: 23
6(M”, 3χ), 194(100″&), 179(
16χ), 43(28χ)(2)4-acetoxy-3-
Methoxycinnamoyl chloride 4-acetoxy-3-methoxycinnamic acid 3
．． A mixture of 0 g and 3.7 g of thionyl chloride was stirred under reflux for 1 hour. After cooling, petroleum ether was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with petroleum ether, and dried to obtain 3.095 g (95.8%) of 4-acetoxy-3-methoxycinnamoyl chloride.

Molecular formula: C1! HIIC104 (254,5:1 Melting point: 131-134°C Infrared absorption spectrum v @BCIm-' (KBr)
:1756.161(Li2O2,1510,126
4,1226,1200,1124° Proton nuclear magnetic resonance spectrum (200MZ) δ (CDCI 3): 2
．． 33 (S, 3) 1), 3.88 (S, 3H), 6.
59 (d, J=15.411z, LH), 7.0
8-7.22 (m, 3H), 7.79 (d, J
=15.411z, 10) Mass spectrum m/z (χ
) (Ell: 256,254(M”, 5χ).

214(13χ), 212(40χL 194(16χ
), 177(100χ), 145(32χ) (3) 2-(4-acetoxy-3-methoxycinnamoylamino)-5-(2-pyridylmethylthio)-1,
3,4-thiadiazole Under argon atmosphere, 2-amino-5-(2-pyridylmethylthio)' -1,3,4-
1.725 g of 4-acetoxy-3-methoxycinnamoyl chloride was added to a mixture of 1.014 g of thiadiazole, 10 d of pyridine, and 1 Qm of methylene chloride, and 1.6 g of 4-acetoxy-3-methoxycinnamoyl chloride was added at room temperature.
Stir for hours.

The precipitated crystals in the reaction mixture were collected by filtration, washed with benzene, and recrystallized with a mixed solvent of methanol/chloroform.
(4-acetoxy-3-methoxycinnamoylamino)
1.672 g (83.7%) of -5-(2-pyridylmethylthio)-1,3,4-thiadiazole was obtained.

Molecular formula: CzoH+5Na04St (442) Melting point: 230-233°C (dec,) Infrared absorption spectrum v □Xam-' (KBr): 1764, 1632° 1562.1354.1296.1262.1216.
1202°1182, 1156 Proton nuclear magnetic resonance spectrum (200MZ) δ (D
MSO-d6): 2.2B(S, 3H), 3.84(
S, 3H), 4.61 (S, 2tl), 6.89 (d
, J=15.6tlz, 111), 7.19(d,
J=8.3Hz, IH), 7.27 (dd,
J=8.3.1.5H2,1)1), 7.28~7.
35 (m, IB), 7.41 (d.

J=1.5Hz, IH), 7.51(d, J=7.8
Hz, IH).

7, 78 (d, J=15.6Hz, II),
7.75-7.83 (m.

IH), 8.53 (brd, J=4.9Hz, IH)
, 12.83 (S, IH) Mass spectrum m/z (χ) (El): 442 (M
”, 2X), 400 (5%).

226 (25χ), 150 (56χ), 92 (51%
), 65 (42χ'), 43 (58χ), 42
(100χ) Example 20 2-(4-hydroxy-3-methoxycinnamoylamino)-5-(2-pyridylmethylthio)--1,3,4
- Thiadiazole Hydrochloride Under an argon atmosphere, 6 rnl of water was added to a mixture of 672 mg of 2-(4-acetoxy-3-methoxycinnamoylamino)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole and 50 mg of methanol. Add 109 mg of sodium hydroxide (95%) dissolved in
Stir for hours. The reaction mixture was concentrated under reduced pressure, neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. The obtained crude crystals were recrystallized from IN-hydrochloric acid/methanol to give 2-(4-hydroxy-3-methoxycinnamoylamino)-5-(
2-Pyridylmethylthio)-1,3,4-thiadiazole (hydrochloride) 436B (65.8%) was obtained.

Molecular formula: Cl8H1? ClN403SZ (436,
933 Melting point: 223-225°C (dec,) Infrared absorption spectrum V maxCm-' (in Br): 1
632.1596°1552.1520.1300.1
244.1160 proton nuclear magnetic resonance spectrum (20
0MZ) δ (DMSO-db): 3.83 (S, 3H
), 4.79 (S, 2tl), 5.15 (brS.

IH), 6.78 (d, J=15.6Hz, IB),
6.88 (d, J=8.3Hz, LH), 7.12 (
dd, J=8.3, 1.511z, 111).

7.21 (d, J=1.5Hz, IH), 7.68 (d
, J=15.6Hz.

IH), 7.70-7.77 (m, 1tl), 7.8
8 (d, J=7.8Hz, LH), 8.27 (ddd,
J=7.8, 7.6, 1.5) 1z, 1! I).

8.77 (brd, J=5.4■z, LH),
12.76 (brs, IH) mass spectrum m/z
(2) (FD): 402 (26X), 401 (73
X).

400 (freebase M”, 100χ) Example 2
1 2- (3-(4-acetoxyphenyl)propionylamino)-5-(2-pyridylmethylthio)-1,3,
4-thiadiazole (1) 3-(4-acetoxyphenyl)propionic acid Under an argon atmosphere, acetic anhydride was added to a mixture of 5.507 g of 3-(4-hydroxyphenyl)propionic acid, 50 mZ of chloroform, and 3.75 g of pyridine at room temperature. Stirred for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and extracted with aqueous sodium bicarbonate solution. This alkaline aqueous solution was made acidic with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 3.126 g (45.4%) of 3-(4-acetoxyphenyl)propionic acid.

Molecular formula: Ct+H+z04 (208) Melting point: 97-9
8°C Infrared absorption spectrum v saxCm-' (KBr)
:2924,1756+1704.1510,142
2,1366, 1228. 1196°1168.9
14 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
Ch): 2.29 (S, 38), 2.67 (brt,
J=7.6)1z, 211).

2.95 (brt, J=7.6Hz, 2H), 7.0
1 (brd, J=8.8Hz, 2H), 7.23(br
d, J=8.8Hz, 2fl) Mass spectrum m/z (
χ”) (El): 208 (M”), 166 (41χ
).

107 (100χ), 43 (27%) (2) 3-(4-acetoxyphenyl)propionyl chloride 3-(4-acetoxyphenyl)propionic acid 100m
A mixture of 40 g and 0.2 rnl of thionyl chloride
Stirred at °C for 1 hour. Excess 1,000-onyl chloride in the reaction mixture was distilled off under reduced pressure, dried, and an oily 3-(4-
Acetoxyphenyl)propionyl chloride 108mg
(100%) was obtained.

Molecular formula: C11)lIlc103 (226,5)
Property 2 Oily infrared absorption spectrum I' smxC
m-' (NaC1): 1796+1762.15
10,1370,1216.1196.1168°10
18.910.632 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
C13): 2.29 (3,311), 3.00 (++
+, 2H), 3.20 (m, 2H).

7.02 (brd, J=8.8Hz, 2H), 7.
20 (brd.

J=8.8Hz, 2H) Mass spectrum m/z (χ) (EI): 228,
226 (M”, 22°5%), 186 (21%),
184 (662), 148 (36X).

120 (1002), 107 (46χ), 9N
21χ), 77(19χ), 43(74χ) (3) 2-(3-(4-acetoxyphenyl)propionylamino'))-5-(2-pyridylmethylthio)
-1,3,4-thiadiazole 105 mg of 2-amino-5-(2-pyridylmethylthio)-1,3,4-thiadiazole under argon atmosphere
A mixture of 1081 mg of 3-(4-acetoxyphenyl)propionyl chloride and 4d of pyridine was stirred at room temperature for 2 days. Pyridine in the reaction mixture was distilled off under reduced pressure, and the residue was recrystallized from methanol to give 2-(3-(
4-acetoxyphenyl)propionylamino)-5
-(2-pyridylmethylthio)-1,3,4-thiadiazole 55B (28.4%) was obtained.

Molecular formula: C+J+5N40:+Sz (414) Melting point: 173-174°C (dec,) Infrared absorption spectrum J/,,, cm-' (KBr): 2920
．． 1764°1694.1568.1508,1370
．． 1222.1196° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-di): 2.24 (S
, 3H) , 2.80 (m, 2H) , 2.90 (m.

2H), 4.59 (S, 2H), 7.03 (brd, J
=8.3Hz.

28), 7.25(brd, J=8.3Hz,
2H), 7.31 (m.

IH), 7.48 (d, J-7, 8) 1z, 11 ()
, 7.77 (dt.

J=7.8.2.0Hz, LH), 8.52(brd,
J=4.91(z.

111), 12.63 (S, IH) Mass spectrum m/z (X) [EI): 414 (M
”, 7χ), 38H8χ).

372 (11χ), 224 (15χ), 191 (16χ
), 125 (Look), 107 (69χ), 9
3 (40χ), 92 (29χ).

65(21χ), 43(22χ) Example 22 2-(3-(4-hydroxyphenyl)propionylamino)-5-(2-pyridylmethylthio)-L3.4
-thiadiazole 2-(3-(4-acetoxyphenyl)propionylamino)) -5-(2-pyridylmethylthio)-1,3
, 4-thiadiazole 44■, methanol 2d and 1%
A mixture of 0.5 m sodium hydroxide was stirred at room temperature for 1.5 hours. The reaction mixture was neutralized by adding hydrochloric acid, concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed with water, dried, and 2-
(3-(4-Hydroxyphenyl)propionylamino)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 29μ (72.5%) was obtained.

Molecular formula: C+J+1N40zSz (372,46)
Melting point: 213-214.5°C Infrared absorption spectrum! / ,,,cm-' (KBr
) :3440.3160゜2916.1702.15
60,1514.1440.1302° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-cL):
2.77 (m, 41 (), 4.58 (S, 2H),
6.65 (d, J=8.3Hz, 2H), 6.99 (d
, J=8.3Hz, 211).

7.30 (dd, J=7.3.4.911z, 1)1)
, 7.48 (d.

J・7.8Hz, IH), 7.77(ddd, J・7.
8.7.3°1.5Hz, IH), 8.51 (brd,
J=4.9Hz, IH,).

9, 18 (S, IH), 12.57 (S,
il+) Mass spectrum m/z (Z) (EI): 3
72 (M”, 16X), 339 (52), 22
4 (9χ), 191 (14%), 125 (
100χ).

107 (76%), 93 (54%), 92
(29χ), 77(11χ).

65 (23%) Example 23 2-(trans-4-(aminomethyl)cyclohexylcarbonylamino)-5-(2-pyridylmethylthio)
-1,3,4-Thiadiazole Hydrochloride (1) Trans-4-(aminomethyl)cyclohexanecarbonyl chloride hydrochloride Add 0 thionyl chloride to a mixture of 1.0 g of trans-4-(aminomethyl)cyclohexanecarboxylic acid and 10 mZ of benzene. .7 rnl was added and stirred at 60°C for 1 hour. Petroleum ether was added to the reaction mixture under cooling, and the precipitated crystals were collected by filtration, washed with petroleum ether, and dried to give 1.139 g (84.5%) of trans-4-(aminomethyl)cyclohexanecarbonyl chloride hydrochloride. Obtained.

Molecular formula: C, H15ChNO (212) Melting point: 234
~236°C Infrared absorption spectrum v,,,cm-' (KBr)
:3040.2940°1720.1614,150
2.1186.1140 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-di): 0.96 (
m, 2H), 1.26 (m, 2H), 1.55 (n+
, 18), 1.86 (m, 4H), 2.14 (m,
III).

2.62 (m, 2H), 8.10 (brs, 2H) (2
)2-()Lance-4-(aminomethyl)cyclohexylcarbonylamino)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole hydrochloride Under argon atmosphere, 2-amino-5-(2-pyridyl Methylthio)-1,3,4-thiadiazole 0.49g
SN, N-dimethylformamide 7 ml, pyridine 0
．． A mixture of 3 mZ and 0.69 g of trans-4-(aminomethyl)cyclohexanecarbonyl chloride hydrochloride was stirred at room temperature for 3 days. The precipitated crystals in the reaction mixture were collected by filtration, washed with toluene, recrystallized with methanol, and 2-[
trans-4-(aminomethyl)cyclohexylcarbonylamino)-5-(2-pyridylmethylthio)-1
, 3,4-thiadiazole hydrochloride 42 mg (4,8%)
I got it.

Molecular formula: C+6HtzCINsOSz (399,9
6) Melting point: 257-260° (: (dec,) Infrared absorption spectrum v,, Xcm-' (KBr):
3100.3020°2924.2852.168B,
1540.13B6.1294°1184, 1060 Proton nuclear magnetic resonance spectrum (200MZ) δ (D
MSO-d6): 1.01 (m, 2H), 1.38
(m, 2H), 1.56 (m, IH), 1.87 (m,
4B), 2.66 (d, J=6.3Hz.

2H), 7.30 (m, IH), 7.48 (d, J=7
．． 8Hz, III).

7.78 (dt, J=7.8, 2.0Hz, IH)
, 8.02 (brS.

2) 1), 8.52 (brd, J=4.9) 1z, I
H), 12.60 (brS, LH) Mass spectrum m/z (%) (FD): 366.
365,364.363 (free base M”) Example 24 2-(2-carboxybenzoylamino)-5-(2-
Pyridylmethylthio)-1,3,4-thiadiazole Under an argon atmosphere, 696 mg of phthalic anhydride was added to a mixture of 2.11 g of 2-amino-5-(2-pyridylmethylthio)-L3,4-thiadiazole and 20 m# of lysine. Stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, extracted with an aqueous potassium carbonate solution, and the alkali aqueous solution was made weakly acidic with hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and then recrystallized with methanol to give 2-(2-carboxybenzoylamino)-5-(2
893 mg (51.1%) of -pyridylmethylthio)-1,3,4-thiadiazole were obtained.

Molecular formula: C+JtJ4(hSz (372,42) Melting point = 174-175°C (dec,) Infrared absorption spectrum νsaxcm-' (KBr): 1678,1602
+1538.1302.1268.1248.1136
．． 740 proton nuclear magnetic resonance spectrum (200MZ)
δ (DMSO-d6): 4.63 (S, 28),
7.3Hddd, J・7.3゜4.9.1.0llz,
18), 7.52(d, J=7.8Hz, L
H).

7.57-7.73 (m, 3H), 7.79 (ddd
, J=7.8°7.3.2.0Hz, LH), 7.9
3(m, 1fl), 8.53(brdlJ=4.9f
lz, IH), 13.07 (brS, 2H) MS m
/z(X) (EI): 355 (97%), 321(
90χ), 190 (402).

182 (44X), 149 (43χ), 124 (45
χ), 104(56χ), 92(100X), 79(
39χ), 76(56χ).

65 (73χ) Example 25 2-amino-5-(3-pyridylmethylthio)-1,3
,4-thiadiazole Sodium hydroxide (95χN, 71
2-amino-5-mercapto-
1,3,4-thiadiazole 1.36g, benzene 3
0-,tetra-n-butylammonium bromide 322
Add B and 1.64 g of 3-picolyl chloride hydrochloride,
Stirred at room temperature for 24 hours. Crystals precipitated in the reaction mixture were collected by filtration, washed successively with water and benzene, and recrystallized with ethanol. The obtained crude crystals were treated with activated carbon and then recrystallized again from ethanol to obtain 1.027 g (45
, 8%).

Molecular formula: Cs1lsN4St (224,30) Melting point: 151~152°C Infrared absorption spectrum v ,,,cn+-' (Kll
r) ;3264.3088゜2948.1640.1
512,1480.1432.1416°113B, 1
026.710 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-da): 4.32 (S, 2H),? , 32 (
brS, 2) 1) , 7.35 (w, LH), 7.76
(m, IH), 8.46 (dd, J=1.5°4.9H
, z, 18), 8.5Hd, J=2.0Hz, LH
) Mass spectrum m/z (χ”) (El): 224
(M”, 26χ), 191 (19%), 149 (4
5%), 92 (100%), 65 (58χ) Example 26 2-Methyl-5-(2-quinolylmethylthio)-1,3
,4-thiadiazole under argon atmosphere, sodium hydroxide (95%) 1.
Dissolve 74 g in IQml of water, 1.32 g of 2-mercapto-5-methyl-1,3,4-thiadiazole, 322 mg of benzene 30d1 tetra-n-butylammonium bromide and 2.1 g of 2-chloromethylquinoline hydrochloride.
4 g was added and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 2-methyl-5-
2.047 g (75.0%) of (3-quinolylmethylthio)-1,3,4-thiadiazole was obtained.

Molecular formula: C+3H++N5Sz (273,37) Melting point: 80-81.5°C Infrared absorption spectrum v 5axC"l-' (KBr
) :1598.1504゜1426.1384,11
66.1062.102B, 826,784°762.
746,616 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
C1+): 2.70 (S, 38), 4.85 (S, 2
H), 7.53 (daa.

J=1.2.6.8.8.1Hz, 1)1), 7
．． 63 (d, J=8.5Hz, IH), 7.71 (d
dd, J=1.5.6.8, 8.5tlz.

LH), 7.80 (brd, J=8.111z, 1) 1
), 8.06 (brd, J=8.5Hz, 111)
, 8.12 (d, J=8.5Hz, 11()
Mass spectrum m/z (χ) (El): 273(
M”, 95%), 240 (84χ), 174 (41
χ), 142 (100χ), 129 (44χ).

116 (42%), 115 (66%) Example 27 2-phenyl-5-(2-pyridylmethylthio)-1,
3,4-thiadiazole (1) 2-phenyl-1,3,4-thiadiazolin-5
A mixture of 1,000 ml of penzonitrile, 20 ml of hydrazine hydrate, and 15 mf of methanol was allowed to stand at room temperature for 6 days.

Chloroform was added to the reaction mixture, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue were added 10 ml of ethanol and 1.2 ml of carbon disulfide, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in benzene and extracted with aqueous sodium hydroxide. This alkaline layer was adjusted to pH 3-4 with hydrochloric acid,
The precipitated crystals were collected by filtration. After washing with water and drying under reduced pressure, 2-phenyl-1,3,4-thiadiazolin-5-thione 17
7 mg (3.1%) was obtained.

Molecular formula: C5HJzSz (194) Melting point = 217
~219°C Infrared absorption spectrum v,,Xcm-' (KBr)
:3108.2876°1452.1290,128
0,1248,1064.740 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-di) near, 4
9-7.59 (m, 3H), 7.73-7.78 (m
, 2H), 14.76 (brS, 1N) mass spectrum m/z (X) (El): 194 (M”, 100χ
), 118 (80χ), 9N22%), ? ? (31χ)
(2) 2-phenyl-5-(2-pyridylmethylthio)
-1,3,4-thiadiazole under argon atmosphere, sodium hydroxide (95%) 180
mg in 3 d of water, 173 mg of 2-phenyl-1,3゜4-thiadiazolin-5-thousand ions, benzene 9+
n&, tetra-n-butylammonium bromide 32m
g and 259 mg of 2-picolyl chloride hydrochloride,
Stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 2-phenyl-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 223.
mg (88.1%) was obtained.

Molecular formula: C14HIIN3S2 (285,38) Melting point? 111.5-113°C Infrared absorption spectrum v I, 1. Xcm-'(KBr
): 1588, 156B.

1468.1458, 1434, 1364.1062.
1040°760, 684 Proton nuclear magnetic resonance spectrum (200MZ) δ (CD
Ch): 4.74 (S, 2H), 7.20 (ddd
, J・1.2.4.9°7-311z, LH), 7.2
7-7.49 (m+38), 7.54 (brd, J
=7.8Hz, LH), 7.66 (ddd,
J=2. sail? , 3,7.8Hz, LH), 7.84~
7.90 (m, 2) 1) 8.59 (ddd, J=1.0
, 2.0.4.9Hz, IH) mass spectrum m/z (
χ) (El): 285 (M”, 100%), 25
2 (51%), 149 (41ri, 121 (38%),
92 (51%).

8H34χ), 77 (25χ), 69 (74%
), 65 (38%) Example 28 2-(3-pyridyl)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole (1) 2-(3-pyridyl)-C3,4-thiadiazole A mixture of 6.44 g of -5-thione 3-pyridine carbonitrile, 43 ml of hydrazine hydrate, and 25 methanol was allowed to stand at room temperature for 3 days. Saturated brine was added to the reaction mixture, extracted with a mixed solvent of chloroform-methanol, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue were added 50% of ethanol and 2.8% of carbon disulfide, and the mixture was stirred at room temperature for 2.5 hours.

The precipitated crystals in the reaction mixture were collected by filtration, washed with water and methanol, and dried under reduced pressure to give 2-(3-pyridyl)-
1,3,4-thiadiazolin-5-thione 3.701g
(31.3%) was obtained.

Molecular formula: CJsNsSz (195) Melting point: 261~
264°C Infrared absorption spectrum v,,Xcm-' (KBr)
: 1502.1292°1264, 1062.73
6.650 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-cL) Near, 58 (ddd, J=1.0, 4.
9,8.3Hz, LH)+8.16(ddd, J=1
．． 5.2. ．． 4.8.3Hz, IH).

8.74 (dd, J=1.5, 4.9Hz, IH)
, 8.94 (dd.

J = 1.0.2.4Hz, LH) Mass spectrum m/z (χ) (EI): 195 (M
”, 100χ), 119(67χ), 92(14χ
), 78(42χ)(2)2-(3-pyridyl)-5
-(2-pyridylmethylthio)-1,3,4-thiadiazole under argon atmosphere, sodium hydroxide (95%) 1,
Dissolve 65g in 10m# of water, 2-(3-pyridyl)-
1.95 g of 1,3,4-thiadiazolin-5-thione.

Benzene 30ml1. TeI C n-butylammonium bromide 322 mg and 2-picolyl chloride hydrochloride 1
．． 64 g was added and stirred at room temperature for 31 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was recrystallized from a mixed solvent of methanol-hexane,
2-(3-pyridyl)-5-(2-pyridylmethylthio)-1,3,4-thiadiazole 1.56 g (36,
9%).

Molecular formula: C+sl(+oNnSz (286,37
) Melting point: 97.5-99°C Infrared absorption spectrum v,,, cm-' (KBr)
:1586.1568+1478, 1434.141
B, 1364.1080,974,754° Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d
&): 4.77 (S, 2H), 7.33 (dd d,
J=1.2゜4.9.7.3H,z,LH), 7.5
6-7.63 (n+, 2H).

7.81 (m, IH), 8.30 (ddd, J=1.
7.2.4°8.1Hz, 1)1), 8.55(ddd
, J=1.0, 1.7, 4.9Hz, IH), 8.7
4 (dd, J=1.5.4.9Hz, IH).

9.08 (dd, J = 0.7.2.4Hz, 111) Mass spectrum w+/z (χ) (EI): 286 (M
”, 100χ), 253(51χ), 136(35χ
), 124 (36χ), 122 (35χ).

92 (87χ'), 7B (37χ), 65
(63χ) Example 29 2-amino-5-((4-methylimidazol-5-yl)methylthio)-1,3,4-thiadiazole H3 3.43 g of 4-hydroxymethyl-5-methylimidazole hydrochloride and thionyl A mixture of 10 chlorides was stirred under reflux for 1 hour. Petroleum ether was added to the reaction mixture under cooling, and the precipitated crystals were collected by filtration, washed with petroleum ether, and dried under reduced pressure. Ethanol 40-1 to this crude crystal
2.24 g of 2-amino-5-mercapto-L3,4-thiadiazole and 2.06 g of sodium hydroxide (95%) dissolved in 10 ml of water were added and stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was neutralized by adding water and hydrochloric acid, and extracted with chloroform-methanol.

After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-amino-5-((4-methylimidazol-5-yl)methylthio]- 96 mg (1.8%) of 1°3.4-thiadiazole was obtained.

Molecular formula: CJJsSz (227,30) Melting point = 22
3~227°C (dec,) Infrared absorption spectrum ν1
1. xcm-' (KBr): 3276, 314B.

3044.1628.1574.1422.1040 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMS
O-da): 2.18 (S, 3), 5.11 (S,
2H), 7.19 (S, 2H), 7.42 (S,
IH) Mass spectrum m/z (χ) (ET): 22
7 (M”, 11%), 133 (432), 95 (10
0X), 94 (44%), 74 (13X).

67(19χ) Example 30 2-Amino-5-((2-methylthiazol-4-yl)methylthio)-1,3,4-thiadiazole (1) 4-chloromethyl-2-methylthiazole hydrochloride Argon atmosphere Bottom, 2.25g of thioacetamide.

A mixture of 20 m/s of 1,2-dichloroethane, 77 g of sodium bicarbonate and 3.1 g of 1,3-dichloroacetone was stirred at room temperature for 2.5 days. The solid matter in the reaction mixture was filtered off, washed with 1,2-dichloroethane, and the filtrate was collected. Add 2.4 thionyl chloride to this filtrate under water cooling.
ml and stirred at room temperature for 1.5 hours and under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration.

The crystals were washed with ethyl acetate, dried under reduced pressure, and 4.87 g of 4-chloromethyl-2-methylthiazole hydrochloride (
88.2%) was obtained.

Molecular formula: C5HtC1zNS (184) Melting point: 16
0~164°C Infrared absorption spectrum v @aXcm-' (KBr)
:3092,3076°3000.2540,248
4.1590.1418.13B4゜1284.121
4,978,726.706 Proton nuclear magnetic resonance spectrum (200?lZ) δ (DMSO-d6): 2.6
8 (S, 3B), 4.78 (S, 2H), 7.63 (
S, 11() (2) 2-amino-5-((2-methylthiazole-4
-yl)methylthio)-1,3,4-thiadiazole 2-amino-5-mercapto-1,3,
4-thiadiazole 1.36g, benzene 3k.

322 g of tetra-n-butylammonium bromide and 1.8 g of 4-chloromethyl-2-methylthiazole hydrochloride
4 g was added and stirred at room temperature for 3 days. The precipitated crystals in the reaction mixture were collected by filtration, washed with water and benzene, dried,
Brown crude crystals were obtained. This product was dissolved in a mixed solution of chloroform-methanol and extracted with dilute hydrochloric acid. The acidic layer was made alkaline with an aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration, washed with water, treated with activated carbon, and recrystallized with ethanol. 546 mg (22.4%) of 2-amino-5-((2-methylthiazol-4-yl)methylthio]-1,3,4-thiadiazole were obtained.

Molecular formula: C-, HaN4S3 (244,35) Melting point: 146-147.5°C Infrared absorption spectrum v maxCm-' (KBr)
:3272.3104゜296B, 1630,151
0.1190.1032 Proton nuclear magnetic resonance spectrum (200MZ) δ (DMSO-d6): 2.63 (S
, 3H), 4.32 (S, 2H), 7.29 (S, 2
H), 7.31 (S, IH) Mass spectrum m/z (χ) (EI): 244 (M”
, 43χ), 211 (9χ), 202 (15χ),
169 (14χ), 126 (-29χ).

112 (100Z), 71 (862) Example 31 2-(3-pyridyl)-5-(4-pyridylmethylthio)-1,3,4-thiadiazole Under an argon atmosphere, 850 μm of sodium hydroxide (95χ) was dissolved in water. Dissolved in 6 ml of 955 mg of 2-(3-pyridyl)-1゜3.4-thiadiazolin-5-thione, 161 mg of benzene 18d1 tetra-n-butylammonium bromide and 4-
882 mg of chloromethylpyridine hydrochloride was added, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 2-(3-pyridyl)-5-(4-pyridylmethylthio')-1,3,4-thiadiazole 3
94 mg (28.2%) was obtained.

Molecular formula: C+dl+. N, S2 (286,37) Melting point: 117-118°C Infrared absorption spectrum v maxCm-' (KBr)
:1600.1416°1370.1066.700
,566 Proton nuclear magnetic resonance spectrum C20C20O6 (DM
SO-da): 4.66 (S, 2H), 7.51 (b
rd, J = 6.1Hz.

2B), 7.59 (ddd, J=0.7, 4.9, 8.
1Hz, IH).

8.29 (ddd, J=1.7, 2.2+8.1Hz,
1ll), 8.55 (brd, J=6.1Hz, 21
1), 8.74 (dd, J=1.7°4.9Hz, I
H), 9.08(dd, J=0.7,2.211z
, IH) Mass spectrum m/z (χ) (El):
286CM”, 100χ), 253(19X)
, 149 (37X) , 122 (232) ,
92 (30ri.

65 (26χ) Example 32 2-(3-pyridyl)-5-(2-quinolylmethylthio)-1,3,4-thiadiazole Under an argon atmosphere, 740 mg of sodium hydroxide (95χ) was dissolved in 6 d of water, 766 mg of 2-(3-pyridyl)-1゜3.4-thiadiazolin-5-thione, 18 mf of benzene, 129 mg of tetra-n-butylammonium bromide and 2
-922 mg of chloromethylquinoline hydrochloride was added and stirred at room temperature for 24 hours. The precipitated crystals in the reaction mixture were collected by filtration, washed with benzene and water, and then recrystallized with methanol.
-(3-pyridyl)-5-(2-quinolylmethylthio)
-1,3,4-thiadiazole 684+++g (51
, 9%).

Molecular formula: CItHIzNaSt [336,43] Melting point: 147-148°C Infrared absorption spectrum l'maxCm-' (Br
): 1598.1566°1504, 1428.14
16,1360.1082,974,808°784.
772.750.698 Proton nuclear magnetic resonance spectrum (200MZ) δ (DM
SO-di): 4.97 (S, 2H), 7.55-7
．． 65 (m, 21 ().

7.71-7.81 (m, 2 old, 7.96-8.03 (
m, 2H).

8.29 (ddd, J=1.7, 2.2, 8.1Hz,
LH), 8.40 (brd, J=8.5Hz, LH)
, 8.74 (dd, J=1.7°4.9) 1z, 1B
), 9.08 (dd, J=0.7.2.2) 1z, 1)
1) Mass spectrum a+/z(2) (El): 33
6 (M”, 732), 303 (61χ), 199 (2
2%), 174 (24Z), 173 (27%).

168 (25%), 143 (412), 142 (100
X), 140 (25χ), 129 (38χ), 12
8 (28%), 116 (41χ).

115 (75X) Preparation Example 1 Preparation of Tablets (2) Milk Zero Tang
90g (3) Cornstarch 29g 1000 tablets
Mix 130g (1), (2) and 17g of cornstarch, granulate it with a paste made from 7g of cornstarch, add 5g of cornstarch and (4) to the granules, and compress the mixture with a compression tablet machine to form tablets. Per 1 tablet (1
) 1000 tablets containing 10 mg are manufactured.

Preparation Example 2 Preparation of capsules (1) 2-(3-pyridyl)-5-(2(2) lactose
150g (3) Cornstarch 100g
(4) Crystalline cellulose 40g (5
) Light anhydrous silicic acid 5g According to the usual method, mix the above ingredients and make granules into capsule 1.
000 capsules each weighing 500 mg are prepared.

Preparation Example 3 Preparation of injection (2) Sodium chloride 9g (3)
Chlorobutanol 5g (4) Sodium hydrogen carbonate 1g All ingredients in distilled water 100%
Dissolve the solution in 0- and dispense 1- into 1000 brown ampoules, replace with nitrogen gas, and seal. The entire process is carried out under aseptic conditions.

Preparation Example 4 Preparation of tablets (2) Lactose 100g
(3) Cornstarch 80g (
4) Crystalline cellulose 100g (5)
Polyvinylpyrrolidone 15g According to the usual method, mix the above ingredients, form granules, and compression mold to make 1 tablet.
Prepare 1000 tablets of 00 mg.

〔Effect of the invention〕

As described above, according to the present invention, a novel 1°3.4-
Provided are thiadiazole derivatives and highly effective anti-ulcer agents containing the derivatives as active ingredients.

1jhi>B enter; 噌;:i みU≧[i;
- Te Village - Turtle 1"l*'m Majesty: Sanriiri Ginsushi Chiki Yushun

Claims (2)

[Claims] (1) 1,3,4-thiadiazole derivatives represented by the general formula below: ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [In the formula, R_1 is alkylamino which may be substituted with an alkyl, amino, or methoxy group. , phenyl, pyridyl,
represents quinolyl or R~CONH- group; [in the formula, ~
means that R and the -CONH group are bonded directly or via a saturated or unsaturated carbon chain; R represents an alkyl, phenyl, pyridyl, cyclohexyl, or quinolyl group (provided that , these may be substituted with the following; an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, an amino group, an acyloxy group, or a halogen which may be substituted with an amino or alkoxy group)] R_2 is phenyl , pyridyl, quinolyl, or 5 having a heteroatom selected from the group consisting of nitrogen and sulfur.
Represents a membered heterocyclic group (which may be fused with a carbon ring or substituted with the following; an alkyl group, an alkoxy group, an amino group optionally substituted with an alkyl group) group, acylamino group, or
halogen). (However, compounds in which R_1 is an amino group and R_2 is a 2-pyridyl, 4-pyridyl, or 2-quinolyl group, and R_1 is 4-pyridyl and R_2 is a 2-
Excludes compounds when they are pyridyl. ). ] (2) Anti-ulcer agent whose active ingredient is a 1,3,4-thiadiazole derivative represented by the general formula below: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is an alkyl, amino, or methoxy group. alkylamino, phenyl, pyridyl, which may be substituted with
represents quinolyl or R~CONH- group; [in the formula, ~
means that R and the -CONH group are bonded directly or via a saturated or unsaturated carbon chain; R represents an alkyl, phenyl, pyridyl, cyclohexyl, or quinolyl group (provided that , these may be substituted with the following; an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, an amino group, an acyloxy group, or a halogen which may be substituted with an amino or alkoxy group)] R_2 is phenyl , pyridyl, quinolyl, or 5 having a heteroatom selected from the group consisting of nitrogen and sulfur.
represents a membered heterocyclic group [These may be fused with a carbocyclic ring or may be substituted with the following; an alkyl group, an alkoxy group, an amino group optionally substituted with an alkyl group; group, acylamino group, or halogen] (However, compounds where R_1 is an amino group and R_2 is 2-pyridyl, 4-pyridyl, or 2-quinolyl group, and compounds where R_1 is 4-pyridyl and R_2 are 2-
Excludes compounds when they are pyridyl. )]