JP3215042B2 - Thiadiazole amide derivative and anti-ulcer agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a thiadiazole amide derivative, particularly to a thiadiazole amide derivative having an antiulcer action.

[0002]

2. Description of the Related Art Various theories have been considered as causes of ulcers in humans. In particular, it has been revealed that stress and taking nonsteroidal anti-inflammatory drugs for the treatment of rheumatic diseases etc. are closely related to the development of ulcers, and these are caused by excessive acid secretion into the stomach and duodenum. It is said to be a major cause. Therefore, it is important to prevent and treat ulcer development by suppressing acid secretion.

[0003]

Various ulcer remedies have been developed so far, but few drugs have an effect of preventing the occurrence of stress ulcers. An object of the present invention is to provide a thiadiazole amide derivative having an excellent ulcer prevention effect and an antiulcer agent containing the same as a main component.

[0004]

Means for Solving the Problems As a result of diligent studies conducted by the present inventors to achieve the above object, a specific thiadiazole amide derivative is effective for various ulcers mainly by inhibiting acid secretion. The inventors have found this and completed the present invention. That is, a thiadiazole amide derivative and a salt thereof according to the present invention are characterized by comprising the following general formula (6).

[0005]

Embedded image (In the above formula 6, R ₁ and R ₂ represent any of a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, an alkenyloxy group, a piperidinoalkyl group, and a benzyloxy group. , if any of _R 1, _{R 2} is a hydrogen atom, the other is not a hydrogen atom .R ₃
Is a lower alkyl group, an aromatic ring, a pyridyl group, or -N
(R ₄₎ a group represented by R _5, R 4, R ₅ are means to form a lower alkyl group or a saturated heterocyclic group both bonded to 4- to 8-membered. However, R ₁ or R ₂
Is a lower alkoxy group, R ₃ is —N (R ₄ ) R
_The group represented by ₅ . n means the integer of 1-3. In addition, it is preferable that R ₁ and / or R ₂ is an alkenyloxy group, and it is more preferable that the alkenyloxy group is a geranyloxy group.

It is preferred that R ₁ and / or R ₂ be a lower alkyl group. Further, it is preferable that R ₁ and / or R ₂ be a lower alkoxy group. Further, for such R ₁ and R ₂ , R ₃ is a group represented by —N (R ₄ ) R ₅ (however, R ₄ and R ₅ are the same as in the above formula 6) or a pyridyl group. And R ₃ is preferably a piperidino group. In addition, R ₁ and / or R ₂
Is preferably an alkenyloxy group or a lower alkyl group, R ₃ is preferably a lower alkyl group, and R ₃ is preferably an aromatic ring. Further, the thiadiazole amide derivative and the salt thereof according to the present invention,
It is preferable to be represented by the following general formula 7.

[0007]

Embedded image (In the above Chemical Formula 7, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group. However, when either R ₁ or R ₂ is a hydrogen atom, the other is a lower alkyl group. R ₄ , R ₅ and n are the same as those in Chemical formula 6.) In Chemical formula 7, either R ₁ or R ₂ is preferably a hydrogen atom, and n is preferably 2. Further, the thiadiazole amide derivative and the salt thereof according to the present invention,
It is preferably represented by the following general formula 8.

[0008]

Embedded image (In Chemical Formula 8, R ₁ represents a lower alkoxy group or a lower alkylamino group. R ₄ , R ₅ and n are the same as those in Chemical Formula 6.) In Chemical Formula 8, n is 2. Is preferred. In addition, the thiadiazole amide derivative and the salt thereof according to the present invention are preferably represented by the following general formula (9).

[0009]

Embedded image (In the above chemical formula 9, R ₁ is an alkenyloxy group, and R ₃ is —N
(R ₄ ) means a group represented by R ₅ or a pyridyl group.
In addition, R ₄ , R ₅ and n are the same as those in the above formula 6. In the above chemical formula 9, R ₁ is a geranyloxy group , R ₃
Is preferably a group represented by —N (R ₄ ) R ₅ (where R ₄ and R ₅ are the same as those in Chemical formula 6). The thiadiazole amide derivative and the salt thereof according to the present invention are preferably represented by the following general formula (10 ).

[0010]

Embedded image (In Chemical Formula 10, R ₁ represents an alkenyloxy group. R ₃ represents a lower alkyl group or an aromatic ring.) In Chemical Formula 10, R ₁ is preferably a geranyloxy group. It is. Further, according to the present invention,
The azizolamide derivative and its salt are
R ₁ is a piperidinoalkyl group, R ₂ is a hydrogen atom
And R ₃ is —N (R ₄ ) R ₅ (R ₄ and R ₅ are the same as defined above)
It is preferable that R _{1 is the same as}
Is preferably a piperidinomethyl group. Also,
Thiadiazole amide derivative and salt thereof according to the present invention
In the above formula 6, R ₁ is a benzyloxy group.
R ₂ is preferably a lower alkyl group;
R ₁ is a fluorobenzyloxy group, R ₂
Is preferably an isobutyl group. In addition, R ₄ and
And R ₅ is preferably an ethyl group. Also, n is
Preferably, it is 2. Further, the antiulcer agent according to the present invention is characterized in that the thiadiazole amide derivative or a pharmaceutically acceptable salt thereof is used as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound of the present invention, R ₁ , R ₂
Is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl,
Examples include n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, etc., but a stable anti-ulcer effect is obtained. From the viewpoint, it is preferably a branched lower alkyl group, particularly preferably an isopropyl group or a t-butyl group.

The lower alkoxy group found in R ₁ and R ₂ means an alkoxy group derived from the above lower alkyl group, preferably a branched lower alkoxy group, particularly preferably an isopropyloxy group. , T-butoxy group. In the definition of R ₁ and R ₂ ,
The alkenyl group of the “alkenyloxy group” means a linear or branched alkenyl group having 2 to 20 carbon atoms containing at least one double bond, and is preferably a branched alkenyl group from the viewpoint of effect. is there. As the branched alkenyl group,
Examples thereof include a prenyl group, a geranyl group, a neryl group, and a farnesyl group, and a geranyl group is particularly preferred.

Further, R ₁ and R ₂ can be a piperidinoalkyl group or a benzyloxy group in addition to the above substituents. Examples of the piperidinoalkyl group include a piperidinomethyl group and a piperidinoethyl group, and the lower alkyl group may be used as the alkyl group of the piperidinoalkyl group. The piperidinoalkyl group and the benzyloxy group may have a substituent on the ring . As a preferred substituent
Is, for example, a halogen atom such as fluorine.

Next, the same lower alkyl groups as those described above for R ₃ can be exemplified, but a preferable example of R ₃ is a methyl group, an ethyl group or an isopropyl group.
Pill group . In R ₃ , the aromatic ring or pyridyl group may be unsubstituted or have a substituent on the unsaturated ring, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a naphthyl group, and a pyridyl group. . As the lower alkyl group found in R ₄ and R ₅ , the same as those described above can be exemplified, and a preferred alkyl group in R ₄ and R ₅ is an ethyl group. R ₄ and R ₅ can be combined to form a 4- to 8-membered saturated heterocyclic group. In such a case, R ₃ includes, for example, a piperidino group.

Compound 6 of the present invention can be produced by the reaction formula shown in FIG. 1, but is not limited thereto. In the reaction formula A shown in FIG. 1, the general formula (II)
From the carboxylic acid represented by the general formula (III) and the substituted thiadiazole by the mixed acid anhydride method, the acid chloride method, DC
By using a known amide bond forming reaction such as the method C, the CDI method or the azide method, a thiadiazole amide derivative of the present invention represented by the general formula (I) can be obtained. In reaction formula A, R ₁ , R _2, R ₃ and n are as defined above.

In the case of the mixed acid anhydride method, carboxylic acid (II) is used as an activator using, for example, diphenylphosphinic chloride, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride, or the like. After conversion to the corresponding acid anhydride, it is reacted with compound (III). As the additive, for example, an organic base such as triethylamine, pyridine, or N-methylmorpholine is used. As the solvent, for example, dichloromethane, halogenated hydrocarbons such as chloroform, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide and dimethylacetamide are used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within a range from -15 ° C to the reflux temperature of the solvent.

In the case of the acid chloride method, the carboxylic acid (II) is converted into its corresponding acid chloride using, for example, phosphorus pentachloride, phosphorus trichloride, thionyl chloride or the like as an activator. And compound (III). As an additive, for example, an organic base such as triethylamine, pyridine, N
-Methylmorpholine and the like are used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and amides such as dimethylformamide and dimethylacetamide. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

In the case of the DCC method, for example, dicyclohexylcarbodiimide (DCC), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI) and the like are used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran and dioxane; and amides such as dimethylformamide and dimethylacetamide. This reaction may be performed by adding 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) as necessary. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

In the case of the CDI method, the carboxylic acid (II) is converted into its corresponding N-acyl derivative using, for example, N, N'-carbonyldiimidazole as an activator, and then the compound (III) ). As additives, for example, organic bases triethylamine, pyridine,
N-methylmorpholine and the like, and inorganic bases such as sodium hydride and potassium hydride are used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran and dioxane; and amides such as dimethylformamide and dimethylacetamide. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

In the case of the azide method, carboxylic acid is used by using, for example, diphenylphosphoryl azide as an activator.
After converting (II) to its corresponding azide, the compound
(III). As the additive, for example, an organic base such as triethylamine, pyridine, or N-methylmorpholine is used. As the solvent, for example, dichloromethane, halogenated hydrocarbons such as chloroform, benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and dioxane, and amides such as dimethylformamide and dimethylacetamide are used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

Specifically, for example, diphenylphosphinic chloride, pivaloyl chloride or the like is used as an activator for the mixed acid anhydride method, and triethylamine is used as an additive in a solvent such as chloroform or dimethylformamide. The purpose is achieved by performing the reaction in the range of -15 ° C to room temperature. The compound (II) as a raw material of the reaction formula A can be synthesized, for example, according to a reaction formula B shown in FIG.

In the reaction formula B, A represents —O— or —NH—
And compound (V) represents R ₇ —OH, R ₇ —X, or R ₇
Represents an alkene having a skeleton. Here, R ₇ is a branched lower alkyl group or a branched alkenyl group. Also, X
Represents a halogen atom. R ₆ represents a carboxyl protecting group, and a lower alkyl group such as a methyl group, an ethyl group, or a tertiary butyl group, unless a problem occurs in a subsequent reaction;
A phenacyl group or a trichloroethyl group can be used. In reaction formula B, compound (IV) is replaced with (V)
The carboxylic acid (II-a) can be synthesized by reacting with a compound represented by the following formula, followed by hydrolysis.

In the first step of the present reaction, when the compound (V) is R ₇ —OH or an alkene having R ₇ in the skeleton, the reaction can be carried out under acidic conditions. A method using a mineral acid, an organic acid such as p-toluenesulfonic acid, or a Lewis acid such as boron trifluoride etherate can be used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic compounds such as benzene, toluene, xylene and pyridine, ethers such as tetrahydrofuran and dioxane, N, N-dimethylformamide, and N, N-dimethylacetamide. Amides are used. Also,
When compound (V) is an alcohol, it can itself be used as a solvent. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent. Specifically, for example, the objective is achieved by performing a reaction under ice-cooling in a solvent such as dichloromethane using 95% sulfuric acid or the like as an acidic catalyst.

When compound (V) is R ₇ -X in the first step of the reaction, the reaction can be carried out in the presence of a base, and can be carried out in the presence of sodium amide, triethylamine, sodium hydride, sodium hydroxide, potassium carbonate. , Barium oxide, silver oxide and the like are used. Also, a catalytic amount of potassium iodide can be added. As the solvent, for example, alcohols such as methanol, ethanol, butanol, benzene, toluene, xylene, aromatic compounds such as pyridine, diethyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethylformamide,
Amides such as dimethylacetamide and ketones such as dimethylsulfoxide and acetone are used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

Specifically, for example, the compound (IV) is dissolved in tetrahydrofuran, N, N'-dimethylformamide, etc.
After adding sodium hydride or the like as a base and stirring, alkenyl halide is added and the reaction is carried out at room temperature to the reflux temperature of the solvent to achieve the object. In the second step, the carboxylic acid (II) is hydrolyzed in the presence of an acid or a base to hydrolyze the ester compound (VI).
-a) can be synthesized. Acids include hydrochloric acid, sulfuric acid,
As a base such as p-toluenesulfonic acid, sodium hydroxide, potassium hydroxide, potassium t-butoxide and the like are used. As the solvent, carboxylic acids such as formic acid and acetic acid, alcohols such as methanol and ethanol, water, and a mixed solvent thereof are used. Reaction temperature,
The reaction time may be changed according to the starting compound used, but the reaction is usually carried out within the range of 0 ° C. to the reflux temperature of the solvent.

Specifically, for example, the ester compound (VI)
Is dissolved in an alcohol such as methanol or ethanol, an aqueous solution of sodium hydroxide or potassium hydroxide is added, and the reaction is carried out at a temperature from room temperature to a reflux temperature.

As the starting compound (II) in the reaction formula A, the compound (XI) or the compound (II-b) synthesized by the reaction formula C or the reaction formula D in FIG. 3 or FIG. 4 can be used. It is. First, in Reaction Formula C, X represents a halogen atom. R ₆ represents a carboxyl-protecting group, and a methyl group, an ethyl group,
A lower alkyl group such as a tertiary butyl group, a phenacyl group or a trichloroethyl group can be used. In the first step of the reaction formula C, the methyl group of the compound represented by the general formula (VII) is converted into a halide to form the compound represented by the general formula (VII)
The benzyl halide represented by I) is obtained.

As the reagent used in this reaction, for example, N
-Bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-halogenocaprolactam, 1,3-
Dihalogeno-5,5-dimethylhydantoin and the like can be used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic compounds such as benzene, toluene, xylene, and pyridine; ethers such as tetrahydrofuran and dioxane; and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. Are used. This reaction may be carried out by adding a peroxide such as benzoyl peroxide as needed. Reaction temperature,
The reaction time may be changed according to the starting compound used, but it is usually in the range of 0 ° C. to the reflux temperature of the solvent.
Specifically, for example, the object is achieved by dissolving compound (VII) in dichloromethane or the like, adding N-bromosuccinimide in the presence of a catalyst, and performing the reaction at reflux temperature.

In the second step of the reaction formula C, the general formula (I
The compound represented by the general formula (X) is obtained by reacting the piperidine represented by the general formula (X) with a benzyl halide represented by the general formula (VIII) in the presence of a base. In the second step of the reaction between the halide and the amine in this reaction, the reaction can be carried out under the same conditions as the reaction conditions in the first step of Reaction Formula B. In the third stage hydrolysis reaction of the present reaction, the reaction can be carried out under the same conditions as the reaction conditions in the second stage of Reaction Formula B.

Next, in the reaction formula D of FIG.
A carboxylic acid represented by the general formula (II-b) is obtained by reacting a hydroxy compound represented by the formula (XII) with a benzyl halide represented by the general formula (XIII) in the presence of a base, followed by hydrolysis. Can be In reaction formula D, R ₁ is as defined above. Further, X represents a halogen atom, R ₈
Represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a lower alkyl group, or a lower alkoxy group. R ₆ represents a carboxyl protecting group, and a lower alkyl group such as a methyl group, an ethyl group or a tert-butyl group, a phenacyl group, a trichloroethyl group, or the like can be used unless a problem occurs in the subsequent reaction.

In the benzylation reaction of the first step in this reaction, the reaction can be carried out under the same conditions as the reaction conditions in the second step of Reaction Formula C. In the hydrolysis reaction of the second step, The reaction can be carried out under the same conditions as in the second step of formula B. In the reaction formula D, the starting compound represented by the general formula (XII) is commercially available, or the compound (XVII) of the general formula (XII) wherein R ₁ is a lower 2-alkenyl group is FIG.
The compound (XVII) can be produced by the reaction formula F shown in FIG.
Compound (XVIII) wherein R ₁ is a lower alkyl group can be produced by the method (I).

In the first step of the reaction formula E, the general formula (IV)
-a) is reacted with a halide represented by the general formula (XV) in the presence of a base to obtain a compound represented by the general formula (XVI)
The compound represented by is obtained. In reaction formula E, R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ represent a hydrogen atom or a lower alkyl group, and X represents a halogen atom. Also, R ₆
Represents a carboxyl-protecting group, and a lower alkyl group such as a methyl group, an ethyl group, or a tert-butyl group, a phenacyl group, a trichloroethyl group, or the like can be used unless a problem occurs in the subsequent reaction. As the base in this reaction, for example, an inorganic base such as potassium carbonate, potassium hydroxide, sodium hydroxide, or sodium hydride, or an organic base such as triethylamine or pyridine is used. Specifically, for example, potassium carbonate is used as a base, and the reaction is carried out in a solvent such as acetone or dimethylformamide at a temperature ranging from room temperature to the reflux temperature of the solvent, thereby achieving the object.

In the second step of the reaction formula E, the general formula (XV
By subjecting the compound represented by I) to a Claisen rearrangement reaction, a compound represented by the general formula (XVII) is obtained.
This reaction is carried out in a high boiling solvent or in the absence of a solvent, at normal pressure or under pressure. As the solvent, for example, phenyl ether, N, N-dimethylaniline and the like are used. The reaction temperature and the reaction time may be changed according to the starting compound used, but the reaction is usually carried out in the range of 100 ° C to 200 ° C.

As shown in a reaction formula F shown in FIG. 6, a compound represented by the general formula (XVIII) can be obtained by hydrogenating the compound (XVII) obtained in the above reaction formula E. In reaction formula F, R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R
₁₃ and R ₆ are the same as defined in the above Reaction Formula E. When this reaction is performed under catalytic reduction conditions, for example, palladium, platinum, nickel, rhodium, ruthenium and the like can be used as a catalyst. Specifically, for example, palladium-carbon is used in a hydrogen gas atmosphere in a solvent such as ethanol, ethyl acetate, and tetrahydrofuran at room temperature to the reflux temperature of the solvent to achieve the object.

The compound (III), which is the other starting material of the reaction formula A, can be produced, for example, as shown in a reaction formula G shown in FIG. Incidentally, in the reaction formula G,
R ₃ and n are as defined in Chemical formula 6, and X represents a halogen atom. In the reaction formula G, the compound represented by the general formula (III) is obtained by reacting the compound represented by the general formula (XIX) with a halide represented by the general formula (XX) in the presence of a base. In this reaction, the reaction can be carried out under the same conditions as the reaction conditions in the second step of reaction formula C. Incidentally, among the starting compounds used in each of the above reaction schemes, compounds not particularly described are commercially available or can be easily synthesized using a known method.

Examples of the acid addition salts of the thiadiazole amide derivative of the present invention represented by the general formula (I) include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and acetic acid. And salts with organic acids such as propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and methanesulfonic acid. These salts can be easily produced by a usual method.

The thiadiazole amide derivative according to the present invention has a strong antistress ulcer action and an excellent gastric acid secretion inhibitory action, and is highly safe. Therefore, it is useful as an agent for treating / preventing peptic ulcer in humans or animals.
When the compound of the present invention is administered as a therapeutic or prophylactic agent for peptic ulcer, it may be administered orally as tablets, powders, granules, capsules, syrups, etc., or as suppositories, injections, or external preparations. It may also be administered parenterally as drops.
Depending on the degree of symptoms, individual differences, age, type of ulcer, etc., the dose may be administered outside the following range, but of course, it must be adjusted to suit the individual situation in each specific case. No. Usually about 0.01 to 200 mg / kg, preferably 0.05 to 50 mg / day for an adult per day.
kg, more preferably 0.1 to 10 mg / kg is administered once or several times a day.

At the time of formulation, it is manufactured by an ordinary method using a usual formulation carrier, but if necessary, pharmacologically and pharmaceutically acceptable additives may be added. That is, when preparing an oral solid preparation, an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, if necessary, and then a tablet is prepared in a conventional manner. , Coated tablets, granules, powders, capsules and the like.

As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose,
Silicon dioxide and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose,
Methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc.
Disintegrators include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and the like, and lubricants such as magnesium stearate, talc, polyethylene glycol, silica , Hardened vegetable oils and the like are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint brain,
Aromatic acids, peppermint oil, dragon brain, cinnamon powder and the like are used. These tablets and granules can be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjuster, a buffer, a stabilizing agent, a solubilizing agent and the like are added to the main ingredient as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method. . Hereinafter, the present invention will be described in more detail with reference to specific examples. Note that the present invention is not limited to these.
First, a test method used for evaluation as an anti-ulcer agent in each example will be described.

WIS: Water Immersion Restraint Stress Ulcer Inhibition Test <Significance> The degree of inhibition of ulcer occurrence due to stress is verified. <Method> 6-7 week old Crj: SD male rat or S
lc: SD male rats were fasted overnight (water is free),
The test drug (100 mg / 10 ml / kg) dissolved or suspended in 0.3% sodium carboxymethylcellulose or 0.05% Tween 80 aqueous solution was orally administered to 5 to 8 animals per group. The subject was administered only the base. 10
Minutes later, the rats were placed in a medicinal stress cage of the University of Tokyo, and
It was immersed up to the xiphoid process in a constant temperature water bath at ℃. 7 from the start of water immersion
After time, the rats were taken out of the aquarium, immediately sacrificed with ether or carbon dioxide, and the stomach was removed. After injecting 10 ml of 5% neutral formalin buffer into the stomach and immersing it in 1% neutral formalin buffer for 30 minutes or more and fixing it, the incision was made along the greater curvature of the stomach and the gland developed in the stomach. The length of the erosion was measured using a vernier caliper under a stereoscopic microscope. The total length of erosions per rat was taken as the ulcer index. <Evaluation Criteria> The effect at the time of administration of the test drug at 100 mg / kg was expressed as an ulcer occurrence inhibition rate (%). Ulceration inhibition rate (%) = (1- (ulcer coefficient of test drug group / ulcer coefficient of target group)) × 100

VOL, TAO: Acid secretion inhibition test (in
Vivo) <Significance> The inhibitory effect of acid secretion in vivo is confirmed. <Method> Seven-week-old Crj: Donryu male rats were fasted overnight (free to drink), and 8 to 10 rats per group were used under urethane anesthesia (1.25 g / kg). 0.5% sodium carboxymethylcellulose aqueous solution or 0.0
A test drug (100 mg / 10 ml / kg) dissolved or suspended in a 5% Tween 80 aqueous solution was orally administered, and 30 minutes later, a median incision was made and the pylorus was ligated. 30
Minutes later, histamine 30 mg / kg dissolved in physiological saline
Was subcutaneously administered, and three hours later, stratified with carbon dioxide. The stomach was immediately removed and the stored gastric juice was collected, and the gastric fluid volume was measured. Gastric fluid was titrated with 0.1 N NaOH to calculate total acid excretion.

<Evaluation Criteria> The effect of administration of the test drug at 100 mg / kg was expressed in terms of gastric fluid volume (VOL) and total acid excretion (TAO) in terms of the inhibition rate (%). Each inhibition rate (%) = (1− (value of test drug / value of control group)) × 100

CAP: Acid secretion inhibition test (in vitro
o) <Significance> To examine the ability to suppress acid secretion at the cellular level. It can also be used to study the mechanism of action. <Method> First, a free fundic gland specimen was prepared. Male Japanese white rabbits (2.5-3 kg) were anesthetized and killed with Nembutal, and the stomach was immediately removed by midline incision, and the pylorus and cardia were excised and cut along the greater curvature to cut into two pieces. divided. The stomach contents adhering to the mucosal surface were washed away with ice-cold PBS (-), and then carefully washed in ice-cold PBS (-). Spread the stomach wall on a cork board with the mucous membrane facing up and feed with sterile gauze.
The mucus was completely removed. The mucous membrane was peeled off with a spatula and collected in ice-cold PBS (-). After washing twice with PBS (-), the cells were cut with scissors. Further, it was washed twice with a nutrient solution. The composition of the nutrient solution was NaCl 132.4 mM, KCl 5.4.
mM, Na ₂ HPO ₄ .12H ₂ O ₅ mM, NaH ₂ PO ₄
・ 2H ₂ O 1 mM, MgSO ₄ 1.2 mM, CaCl
_Two

1 mM, HEPES 25 mM, gluc
ose 2 mg / ml and BSA 1 mg / ml.
The mucosal fragments were dispersed in 70 ml of a nutrient solution containing 1 mg / ml of collagenase, and placed in an Erlenmeyer flask.
Stir vigorously with a stirrer for 60 minutes. During this time, 100
% O ₂ is sprayed on the surface of the nutrient solution, and the pH is measured as appropriate.
Was adjusted. A nutrient solution was added to the reaction solution to make about 200 ml, filtered through a mesh and dispensed into a 50 ml centrifuge tube.
The fundic glands were allowed to settle for 5 minutes. The fundus gland was washed three times by repeatedly removing the supernatant with an aspirator, dispersing in a nutrient solution, and allowing to stand. At this time, instead of pipetting, the dispersion was performed by alternately repeatedly pouring into two centrifuge tubes. The number of cells was counted under a microscope, and 1.6 × 10 ⁶ c
cells / ml.

Next, an experiment of incorporation of [ ¹⁴ C] -aminopyrine was performed. After weighing the Eppendorf tube, 10 μl of histamine (final concentration: 10 ⁻⁵ M) dissolved in the above-described nutrient solution, and 10 μl of the test drug dissolved in DMSO
l (final concentration 10 ^-5 M), diluted with nutrient solution [ ¹⁴ C]-
Aminopyrine 10 μl (final concentration 0.05 μCi / m
l) was added, 970 μl of the free fundus gland prepared above was added, and the mixture was shaken at 37 ° C. at 125 times / min for 40 minutes. After centrifugation for 30 seconds using a tabletop centrifuge, 200 μl of the supernatant was placed in a mini vial, and the remainder was removed with an aspirator. The precipitate was put in a dryer at 80 ° C. overnight with the lid of the tube opened, completely dried, and then returned to room temperature and weighed. Then, 100 μl of 1N KOH was added, and the plate was capped and heated at 60 ° C.
Treated for 2 hours to dissolve and transferred to mini vials. 4ml Atomite in mini vial containing supernatant or sediment
Was added, and the radioactivity was measured with a liquid scintillation counter. The radioactivity of the precipitate was corrected using 20 mM NaSCN to cancel the hydrogen ion concentration gradient, and the accumulation rate of aminopyrine specifically trapped in the precipitate was calculated. This experiment was performed in duplicate.

Here, the principle will be briefly described. In the free fundic glands, acid accumulates in the space from the secretory tubules to the glandular cavities. Aminopyrine is a weak base (pKa = 5.0) and non-ionic in a neutral solution and freely passes through the cell membrane. In an acidic solution, it is ionized and cannot pass through the cell membrane due to electric charge. Utilizes the property that aminopyrine accumulates in a closed acidic space. The accumulation rate (R) of aminopyrine is calculated by the following equation. R = ((corrected radioactivity of the precipitate) / (radioactivity of the supernatant)) × (200 / (mg dry weight of the precipitate)) <Criterion> The effect of the test drug at a final concentration of 10 ⁻⁵ M is as follows: It was expressed as acid secretion inhibition rate (%). Acid secretion inhibition rate (%) = (1− (R of test drug / R of control group)) × 100

PD: Gastric mucosal damage test <Significance> The possible mechanism of action of the compound that was effective in the experimental ulcer model includes a compatible cytoprotective effect (weak mucosal necrotic substance is an endogenous prostaglandin in the gastric mucosa) By increasing the amount, an apparent anti-ulcer effect may be considered). In this case, the test drug has mucosal damage and is unsuitable as an anti-ulcer agent. Thus, by measuring gastric mucosal potential difference (PD) that reflects the health of the gastric mucosa, it is confirmed that the test drug has no gastric mucosal damage (toxicity at the gastric mucosal level).

<Method> Crj: SD male rats aged 7 to 8 weeks were fasted overnight (water was free), and urethane (1.2) was used.
(5 g / kg, ip) Under anesthesia, the patient was fixed in a supine position on a cork plate, and a midline incision was made. A small incision was made in the anterior stomach, and the stomach was washed with physiological saline heated to 37 ° C. An incision was made along the greater curvature from the anterior stomach to the end of the gastroduodenal artery and right gastric omental artery at the center of the stomach so as not to damage the blood vessels. After adjusting the height by placing the cork board on the jack, ex.
The stomach was attached to the vivo chamber. The gastric mucosa area exposed in this chamber is 2.5 cm ² . The inside of the chamber was perfused with physiological saline heated to 37 ° C. using a microtube pump, and the potential difference between the inside of the chamber and the intraperitoneal cavity was measured with a PD meter using an agar bridge containing 3M-KCl. The rectal temperature was measured over time to control the body temperature. After the PD has stabilized sufficiently, stop the perfusion of saline,
A test drug 100 mg / 10 ml / kg dissolved or suspended in a 0.5% aqueous solution of sodium carboxymethylcellulose or a 0.05% aqueous solution of Tween 80 was administered into the chamber, and the PD was recorded for 60 minutes. In addition, only the base was administered to the control.

<Judgment Criteria> The change in PD for 60 minutes after the administration of 100 mg / kg of the test drug was comprehensively considered, and the results were classified into five levels with reference to a positive control. 5: Same as control, showing no impairment. 4: PD slightly decreased, suggesting a possibility of some mucosal damage, but no problem. 3: There is a slight decrease in PD and a possibility of mild mucosal damage is recognized, but there is almost no problem. 2: There is moderate decrease in PD and mucosal damage is recognized. 1: There is severe decrease in PD, and remarkable mucosal damage is observed.

AT: Preliminary single-dose toxicity test <Method> Five-week-old Slc: ICR male mice were grouped in groups of 3
Used in ~ 5 animals. Test drug 20 dissolved or suspended in 0.5% sodium carboxymethylcellulose aqueous solution after fasting for 4 to 5 hours from 9:00 am on the day of the test (water is free).
00 mg / 10 ml / kg was orally administered. In addition, only the base was administered to the control. Behavior and symptoms were observed at 15 minutes, 30 minutes, 1 hour, 2 hours, and 3 hours after administration, and daily follow-up was continued until one week later. Body weight was measured before and after fasting and at the same time every day except on holidays. Necropsy was immediately performed on the death cases, and the organs were visually observed. Surviving cases were also sacrificed one week after administration with ether or carbon dioxide, and the organs were visually observed.

<Judgment Criteria> The toxicity of a single dose of 2000 mg / kg of the test drug was classified into five levels and expressed. 5: 0% mortality, no toxicity observed in behavior or organs. 4: 0% mortality, no toxicity to organs, but slight toxicity to behavior or weight gain. 3: There are fatal cases (not all fatalities), but no toxicity is found in the organs. 2: Organs are toxic regardless of death. 1: All cases died

MTT: cytotoxicity / protection test <Meaning> It is confirmed that there is no toxicity at the cell level. Those that are toxic at the cellular level are also unsuitable as anti-ulcer agents. In addition, it can be confirmed that the effect of the test drug in other cell-level tests is not due to toxicity.

<Method> Male Japanese white rabbits (2.5-3
kg) was anesthetized with Nembutal, and the stomach was immediately removed. Incision is made in the greater curvature of the stomach to remove gastric contents,
After washing with BSS (Hanks' balanced salt solution), they were transported to the laboratory in ice-cold HBSS. The antrum vestibule is removed, the stomach body mucosa is peeled off with subtilis, and BME is removed.
After minced into 2 to 3 mm ² in (BasalMedium Eagle), dispase 280 U / ml and collagenase 30~50U / ml
(Medium: 60 ml of BME) at 37 ° C for 15 minutes 1
Shake 20 to 130 times / min. In addition, the collagenase concentration was appropriately changed every time the lot was changed by checking the state of the cells. EBSS (Earle's Balanced Sal) containing 1 mM EDTA
t Solution), then wash with ME containing 1 mM EDTA
M (Minimum Essential Medium) for 5 minutes at 37 ° C. Next, the mixture was shaken with the same concentration of dispase collagenase for 15 minutes to remove the supernatant.
The mixture was shaken at 37 ° C for 120 minutes / 120 to 130 times / minute. Then, after washing twice with HBSS, 2% Ultrocer
1 × 10 ⁶ Cells / ml in Ham F12 containing G,
Each 200 μl was dispensed into a 96-well plate. 37 ℃ ・ 5
After reaching confluence by incubating for 3 days in 95% air with% CO ₂ , it was used for the MTT assay.

The test drug was DMSO so as to have a concentration of 10 ^-2 M.
And 2% Ultr to a final concentration of 10 ^-4 M.
diluted with HBSS containing ocG. 8 wells / group, MTT reagent 1 immediately after replacing with 100 μl of medium
0 μl was added. After incubating at 37 ° C., 5% CO ₂ , 95% air for 4 hours, centrifuge and discard the supernatant, add 100 μl of 100% ethanol to dissolve formazan, and absorbance with a microplate reader (OD570-630).
Was measured. This is a method utilizing the phenomenon that the MTT is changed to MTT formazan by only the mitochondria of living cells and the color changes.

<Judgment Criteria> The cytotoxicity or cytoprotective activity of the test drug at a final concentration of 10 ⁻⁴ M was expressed as a cytotoxicity rate (%). Cytotoxicity (%) = (1− (absorbance of test drug group / absorbance of control group) × 100 Therefore, a smaller number is preferable.

Based on the above effect test and safety test,
The anti-ulcer action and safety of the compounds according to the examples of the present invention were examined.

Compound Group 1 This compound group has the structure shown in the above-mentioned Chemical Formula 7, and the following example compounds were tested as thiadiazole amide derivatives corresponding to this compound group 1. Table 1 shows the results of the effect test and the safety test. [Example 1]

Embedded image [Example 2]

Embedded image [Example 3]

Embedded image [Example 4]

Embedded image [Example 5]

Embedded image [Example 6]

Embedded image

[0059]

[Table 1] ─────────────────────────── Antiulcer test safety Example WIS CAP PD AT MTT ─────── １ 1 83 101 3 22 ───────────────────────── ── 2 80 100 5 5 -77 ３ 3 96 104 -75 ───────── ４ 4 79 100 3 22 ─────────────────────────── 5 63 100 -19 ６ 6 81 100 58 ─────────────

As is clear from the above Examples 1 to 6, the compounds having the general formula shown in Chemical Formula 7 are superior in the results of the water immersion restraint stress ulcer test (WIS) and the acid secretion inhibition test (CAP) in the results of the anti-ulcer test. It is understood that it has an action and an acid secretion inhibitory action. These compounds were also excellent in safety. In addition, as for R ₁ and R ₂ , when one lower alkyl group is introduced on the benzene ring as shown in Examples 1 to 5, it generally has a high anti-ulcer effect. Thus, even when two alkyl groups are introduced, a sufficient effect is exhibited.

Compound Group 2 In contrast to Compound Group 1 in which R ₁ is a lower alkyl group, the thiadiazole amide derivative of Compound Group 2 is characterized in that R ₁ is a lower alkoxy group or It has a basic skeleton that is an alkylamino group.
The following compounds were tested as thiadiazole amide derivatives corresponding to compound group 2. Table 2 shows the results. [Example 7]

Embedded image Example 8

Embedded image [Example 9]

Embedded image

[0062]

[Table 2] ──────────────────────────── Antiulcer test safety Example WIS CAP MTT ──────── ７ 7 76 97 46 ────────────────────────── ８ 8 66 99 -11 ──────────────────────────── 9 51 2 -107 ──────────明 ら か As is clear from the above examples, even when R ₁ is a lower alkoxy group or a lower alkylamino group, sufficient anti-ulcer properties, Acid secretion inhibitory action and safety are obtained.

Compound Group 3 The thiadiazole amide derivative according to Compound Group 3 is
R ₁ is an alkenyloxy group, and R ₃ is a group having a nitrogen atom such as a group represented by —N (R ₄ ) R ₅ or a pyridyl group. The following are examples of thiadiazole amide derivatives corresponding to compound group 3. [Example 10]

Embedded image [Example 11]

Embedded image [Example 12]

Embedded image Example 13

Embedded image [Example 14]

Embedded image

[0064]

[Table 3] 抗 Anti-ulcer test Safety Example WIS VOL TAO CAP PD AT MTT １０ 10 48 36 44 100 5 5 17 ── ────────────────────────────────── 11 65 100 48 ──────────── ──────────────────────── 12 44 99 5 5 12 ──────────────────── ──────────────── 13 51 100 41 ────────────────────────────── ────── 14 30 45 5 5 -13 ──────────────────────────────────── Above As is clear from each example, the compound group No. 3 has a high anti-ulcer effect, and particularly when R ₃ is —N (R ₄ ) R ₅ , is also excellent in acid secretion inhibitory effect. Further, the compounds of the compound group 3 are also excellent in safety.

Compound Group 4 The thiadiazole amide derivative according to Compound Group 4 is
In the compound group 3, R ₃ is a group represented by —N (R ₄ ) R ₅ or a pyridyl group, whereas R ₃ is a lower alkyl group or an aromatic group. A group of compounds that are aromatic rings. In addition, the following are mentioned as a thiadiazole amide derivative corresponding to compound group 4. [Example 15]

Embedded image [Example 16]

Embedded image [Example 17]

Embedded image [Example 18]

Embedded image

[0066]

[Table 4] 抗 Anti-ulcer test Safety Example WIS VOL TAO CAP PD AT MTT ──────────────────────────────────── 15 43 10 19 17 5 5 1 ── １６ 16 53 14 ───────────── ─────────────────────── 17 46 -4 ─────────────────────── １８ 18 32 18 ──────────────────────────────────明 ら か As is clear from the above examples, even when R ₃ is a lower alkyl group or an aromatic ring, sufficient anti-ulcer properties can be obtained.

[0067]

The methods for producing the compounds according to the above Examples will be described below. First, a method for synthesizing an intermediate used in the production of Examples described later is described below in Reference Examples 1 to 13.
As shown.

Reference Example 1 Synthesis of 4-geranyloxybenzoic acid Methyl 4-hydroxybenzoate (7.6 g), geranyl bromide (10.9 g), and potassium carbonate (13.8 g) were added to 80 ml of acetone in 6 ml of acetone.
The mixture was stirred and refluxed for an hour. Water was added to the reaction solution, and extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of methanol, and potassium hydroxide 3.
9 g and 10 ml of water were added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized by adding hydrochloric acid, and extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. By recrystallizing the obtained solid (n-hexane-ethanol),
9.8 g of the title compound were obtained.

REFERENCE EXAMPLE 2 Synthesis of 3-piperidinomethylbenzoic acid 45.0 g of methyl 3-methylbenzoate, 53.4 g of N-bromosuccinimide and a catalyst amount of azobisisobutyronitrile were stirred and refluxed in 500 ml of carbon tetrachloride for 24 hours. Filter the reaction,
The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1),
An oil was obtained. This was dissolved in 1.5 l of dimethylformamide, 63.2 g of piperidine and 205 g of potassium carbonate were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain an oil. 78.0 g of potassium hydroxide, 325 ml of water and 325 ml of ethanol were added thereto, and the mixture was stirred and refluxed for 2 hours. Acetic acid was added to the reaction solution to neutralize it, chloroform was added and the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained solid is washed with ethanol,
24.4 g of the title compound were obtained.

Reference Example 3 Synthesis of 4-tert-butyloxybenzoic acid 16.6 g of ethyl 4-hydroxybenzoate, 25 g of isobutene,
0.5 ml of 95% sulfuric acid was stirred in 300 ml of dichloromethane at 0 ° C. overnight. The reaction solution was washed with 20% aqueous sodium carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 32 ml of ethanol, 7.5 g of potassium hydroxide and 6 ml of water were added, and the mixture was stirred and refluxed for 2 hours. The reaction solution was neutralized with hydrochloric acid, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (ethyl acetate) to obtain 9.3 g of the title compound.

Reference Example 4 Synthesis of 4-tert-butylaminobenzoic acid 165 g of ethyl 4-aminobenzoate and 24.5 g of 95% sulfuric acid were added to tert-butyl.
The mixture was stirred and refluxed in 560 ml of butanol for 16 hours. 2 in the reaction solution
After neutralization with 8% aqueous ammonia, the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate (4: 1) gave an oil. This was dissolved in 100 ml of ethanol, and 23.5 g of potassium hydroxide and 2
0 ml was added and the mixture was stirred and refluxed for 2 hours. The reaction solution was neutralized with hydrochloric acid, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (ethyl acetate) to give 23.5 g of the title compound.

Reference Example 5 Synthesis of 4- (4-fluorobenzyloxy) -3-isobutylbenzoic acid 50.0 g of ethyl 4-hydroxybenzoate, 32.6 g of methallyl chloride
g of potassium carbonate and 45.6 g of potassium carbonate were stirred and refluxed in 150 ml of acetone for 40 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 150 ml of toluene, and the mixture was washed with 2% sodium hydroxide solution and water. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain an oily substance. This was dissolved in N, N-dimethylaniline (80 ml) and refluxed with stirring for about 10 hours. The reaction solution was acidified by adding concentrated hydrochloric acid under ice cooling, and extracted with toluene. After the extract was extracted with a 10% aqueous sodium hydroxide solution, the aqueous layer was made acidic by adding concentrated hydrochloric acid, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid substance. Dissolve this in 580 ml of ethanol and add 10% palladium charcoal
Using 6.0 g, catalytic reduction was carried out in a hydrogen gas atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain a solid substance. This was dissolved in 350 ml of acetone, 73.8 g of potassium carbonate and 60.6 g of 4-fluorobenzyl bromide were added, and the mixture was stirred and refluxed for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was concentrated under reduced pressure, 120 ml of water, 29.9 g of potassium hydroxide and 250 ml of ethanol were added to the residue obtained, and the mixture was stirred and refluxed for 2 hours. Water was added to the reaction solution, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 71.5 g of the title compound.

Reference Example 6 Synthesis of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole 13.3 g of 2-amino-5-mercapto-1,3,4-thiadiazole,
17.2 g of diethylaminoethyl chloride hydrochloride and 11.2 g of potassium hydroxide were stirred in 200 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure.
The obtained solid was recrystallized (n-hexane-ethanol) to give 19.0 g of the title compound.

Reference Example 7 Synthesis of 2-amino-5-diethylaminopropylthio-1,3,4-thiadiazole 4.7 g of 1-bromo-3-chloropropane, 2.2 g of diethylamine
g of potassium carbonate and 8.3 g of potassium carbonate were stirred in 150 ml of acetone at room temperature for 4 days. Water was added to the reaction solution, which was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of methanol, and 2-amino-5-mercapto-1,
4.0 g of 3,4-thiadiazole and 1.7 g of potassium hydroxide were added, and the mixture was stirred and refluxed for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid is subjected to silica gel column chromatography (chloroform: methanol = 3:
Purification in 1) gave 2.8 g of the title compound.

Reference Example 8 Synthesis of 2-amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole 4.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole
6.0 g of diisopropylaminoethyl chloride hydrochloride,
3.4 g of potassium hydroxide was stirred in 100 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. Recrystallize the obtained solid (n-hexane-ethanol)
This gave 6.1 g of the title compound.

Reference Example 9 Synthesis of 2-amino-5-piperidinoethylthio-1,3,4-thiadiazole 4.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole
6.0 g of piperidinoethyl chloride hydrochloride and 3.4 g of potassium hydroxide were stirred in 100 ml of methanol at room temperature overnight.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 6.1 g of the title compound.

Reference Example 10 Synthesis of 2-amino-5-piperidinopropylthio-1,3,4-thiadiazole 13.3 g of 2-amino-5-mercapto-1,3,4-thiadiazole,
18.4 g of piperidinopropyl chloride hydrochloride and 11.2 g of potassium hydroxide were stirred in 300 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 13.9 g of the title compound.

Reference Example 11 Synthesis of 2-amino-5-isobutylthio-1,3,4-thiadiazole 2.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole
2.1 g of isobutyl bromide and 0.8 g of potassium hydroxide were stirred in 50 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 1.1 g of the title compound.

Reference Example 12 Synthesis of 2-amino-5-benzylthio-1,3,4-thiadiazole 2.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole,
2.6 g of benzyl bromide and 0.8 g of potassium hydroxide were stirred in 50 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 2.4 g of the title compound.

Reference Example 13 Synthesis of 2-amino-5- (2-pyridinomethyl) thio-1,3,4-thiadiazole 2.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole
2.5 g of 2-chloromethylpyridine hydrochloride, 1.7 of potassium hydroxide
g was stirred in 50 ml of methanol at room temperature overnight. The reaction solution was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 1.3 g of the title compound.

Examples of the compound of the present invention are shown below.

Example 1 Synthesis of 2- (4-isopropylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diethylaminoethylthio-1,3,3 2.3 g of 4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 1.6 g of 4-isopropylbenzoic acid and 1.8 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 3.5 g of the title compound.
I got ¹ H-NMR (CDCl ₃ ) δ: 8.15 (2H, d, J = 8.3 Hz), 7.39 (2H, d, J =
(8.3Hz), 3.39 (2H, t, J = 6.8Hz), 3.00 (1H, s7, J = 7.3Hz), 2.85
(2H, t, J = 6.8Hz), 2.55 (4H, q, J = 7.3Hz), 1.30 (6H, d, J = 7.3H
z), 1.00 (6H, t, J = 6.8Hz).

Example 2 Synthesis of 2- (4-isopropylbenzoyl) amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diisopropylaminoethylthio-1, 2.6 g of 3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. 1.6 g of 4-isopropylbenzoic acid, 1.8 g of carbonyldiimidazole
Was stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran.
This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1). Recrystallize the resulting solid (n-
Hexane-ethanol) to give the title compound 2.3
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 12.40 (1 H, bs), 8.17 (2 H, d, J = 8.8 H
z), 7.38 (2H, d, J = 8.8Hz), 3.35 (2H, t, J = 6.8Hz), 3.00 (3H, s
7, J = 6.8Hz), 2.82 (2H, t, J = 6.8Hz), 1.30 (6H, d, J = 6.8Hz),
0.98 (12H, d, J = 6.8Hz).

[0084]Example 3  2- (4-isopropylbenzoyl) amino-5-diisopropyl
Of laminoethylthio-1,3,4-thiadiazole hydrochloride
2- (4-isopropylbenzoyl) amino-5-diisopropyl
1.2 g of L-aminoethylthio-1,3,4-thiadiazole
Dissolve in 50 ml of knoll,Hydrochloric acid-methanol 10mlAnd add 1
Stirred at room temperature for 0 minutes. The reaction solution was concentrated under reduced pressure to obtain
Recrystallization of solid (n-hexane-ethanol)
Thus, 1.3 g of the title compound was obtained.¹ H-NMR (CDCl_Three) δ: 11.78 (1H, bs), 8.13 (2H, d, J = 8.3H)
z), 7.41 (2H, d, J = 8.3Hz), 4.02-3.93 (2H, m), 3.74-3.65
(2H, m), 3.48-3.36 (2H, m), 3.00 (2H, s7, J = 6.8Hz), 1.57
(6H, d, J = 6.8Hz), 1.46 (6H, d, J = 6.8Hz), 1.28 (12H, t, J = 6.8Hz)
Hz).

Example 4 Synthesis of 2- (4-tert-butylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diethylaminoethylthio-1, 2.3 g of 3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. 1.8 g of 4-tert-butylbenzoic acid and 1.8 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). By recrystallizing the obtained solid (n-hexane-ethanol), 1.7 g of the title compound was obtained.
I got ¹ H-NMR (CDCl ₃ ) δ: 8.17 (2H, d, J = 8.3 Hz), 7.54 (2H, d, J =
(8.3Hz), 3.40 (2H, t, J = 6.8Hz), 2.84 (2H, t, J = 6.8Hz), 2.55
(4H, q, J = 7.3Hz), 1.37 (12H, s), 1.00 (6H, t, J = 7.3Hz).

Example 5 Synthesis of 2- (4-tert-butylbenzoyl) amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diisopropylaminoethylthio- 2.6 g of 1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 4-tert
-Butyl benzoic acid 1.8 g, carbonyl diimidazole 1.8
g was stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 2.2 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 12.47 (1 H, bs), 8.19 (2 H, d, J = 8.8 H
z), 7.54 (2H, d, J = 8.8Hz), 3.35 (2H, t, J = 6.8Hz), 3.00 (2H, s
7, J = 6.4Hz), 2.83 (2H, t, J = 6.8Hz), 1.37 (9H, s), 0.97 (12H,
d, J = 6.4Hz).

Example 6 Synthesis of 2- (3,5-di-tert-butylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diethylaminoethyl 2.3 g of thio-1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. 3,5-di-tert-
2.3 g of butyl benzoic acid, 1.8 g of carbonyldiimidazole
Was stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran. This was added to the previous reaction solution and stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 1.5 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, d, J = 1.5 Hz), 7.69 (2H, t, J =
1.5Hz), 3.33 (2H, t, J = 6.8Hz), 2.83 (2H, t, J = 6.8Hz), 2.56
(4H, q, J = 7.3Hz), 1.35 (18H, s), 1.02 (6H, t, J = 7.3Hz).

Example 7 Synthesis of 2- (4-isopropyloxybenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diethylaminoethylthio-1,3 2.3 g of 1,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 1.8 g of 4-isopropyloxybenzoic acid, 1.8 g of carbonyldiimidazole
g was stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 2.4 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.22 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J =
8.8Hz), 4.67 (1H, s7, J = 5.9Hz), 3.37 (2H, t, J = 6.8Hz), 2.83
(2H, t, J = 6.8Hz), 2.54 (4H, q, J = 7.3Hz), 1.38 (6H, d, J = 5.9H
z), 1.00 (6H, t, J = 7.3Hz).

Example 8 Synthesis of 2- (4-tert-butyloxybenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-diethylaminoethylthio-1 2.3 g of 3,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 4-tert-butyloxybenzoic acid 1.9 g, carbonyldiimidazole 1.8
g was stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 3.1 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.16 (2H, d, J = 8.8 Hz), 7.10 (2H, d, J =
8.8Hz), 3.37 (2H, t, J = 6.8Hz), 2.83 (2H, t, J = 6.8Hz), 2.56
(4H, q, J = 7.3Hz), 1.44 (9H, s), 1.01 (6H, t, J = 7.3Hz).

Example 9 Synthesis of 2- (4-tert-butylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole 1.9 g of 4-tert-butylaminobenzoic acid was added while cooling with ice. The mixture was added to thionyl chloride (20 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 2.3 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole and 30 ml of chloroform were added, and the mixture was stirred at room temperature for 3 hours. A 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform: methanol).
= 15: 1) to give 3.0 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.03 (2H, d, J = 8.8 Hz), 6.70 (2H, d, J =
8.8Hz), 4.29 (1H, s), 3.36 (2H, t, J = 6.8Hz), 2.83 (2H, t, J =
6.8Hz), 2.55 (4H, q, J = 7.3Hz), 1.43 (9H, s), 1.00 (6H, t, J =
(7.3Hz).

[0091]Example 10  2- (4-geranyloxybenzoyl) amino-5-diethyla
Synthesis of minoethylthio-1,3,4-thiadiazole 0.4 g of sodium hydride, 2-amino-5-Diethylamino
Ethylthio1.4 g of -1,3,4-thiadiazole in tetrahydro
The mixture was stirred in 30 ml of furan under ice cooling for 30 minutes. 4-geranillo
1.6 g of xybenzoic acid and 1.1 g of carbonyldiimidazole
The mixture was stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran.
This was added to the previous reaction solution and stirred at room temperature for 4 hours. reaction
The solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. Nothing
After drying over sodium hydrogen sulfate, the mixture was concentrated under reduced pressure. Residue
Kagel column chromatography (chloroform: meta
(Nol = 20: 1). Recrystallize the resulting solid (n-
Hexane-ethanol) to give the title compound 2.5
g was obtained.¹ H-NMR (CDCl_Three) δ: 8.19 (2H, d, J = 8.8Hz), 7.01 (2H, d, J =
8.8Hz), 5.53-5.47 (1H, m), 5.18-5.06 (1H, m), 4.62 (2H, d, J
= 6.4Hz), 3.26 (2H, t, J = 7.3Hz), 2.81 (2H, t, J = 7.3Hz), 2.58
(4H, t, J = 7.3Hz), 2.18-2.04 (4H, m), 1.76 (3H, s), 1.68 (3H,
s), 1.61 (3H, s), 1.03 (6H, d, J = 7.3Hz).

Example 11 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-diethylaminopropylthio-1,3,4-thiadiazole 0.4 g of sodium hydride, 2-amino-5-diethylaminopropylthio-1,3 1.5 g of 1,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 1.8 g of 4-geranyloxybenzoic acid, 1.1 g of carbonyldiimidazole
Was stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran. This was added to the previous reaction solution and stirred at room temperature for 4 hours.
The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 3.1 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.18 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J =
8.8Hz), 5.54-5.44 (1H, m), 5.12-5.04 (1H, m), 4.62 (2H, d, J
= 6.4Hz), 3.30 (2H, t, J = 7.3Hz), 2.56 (2H, t, J = 7.3Hz), 2.52
(4H, q, J = 7.3Hz), 2.20-2.14 (4H, m), 1.92 (2H, q5, J = 7.3H
z), 1.76 (3H, s), 1.67 (3H, s), 1.61 (3H, s), 1.01 (6H, t, J = 7.
3Hz).

Example 12 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-piperidinoethylthio-1,3,4-thiadiazole 0.4 g of sodium hydride, 2-amino-5-piperidinoethylthio 1.5 g of -1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 1.6 g of 4-geranyloxybenzoic acid and 1.1 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 2.3 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.21 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J =
8.8Hz), 5.50 (1H, t, J = 6.3Hz), 5.12-5.06 (1H, m), 4.61 (2H,
d, J = 6.3Hz), 3.40 (2H, t, J = 7.3Hz), 2.71 (2H, t, J = 7.3Hz),
2.44-2.32 (4H, m), 2.19-2.06 (4H, m), 1.76 (3H, s), 1.68 (3
H, s), 1.61 (3H, s), 1.59-1.49 (4H, m), 1.46-1.34 (2H, m).

Example 13 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-piperidinopropylthio-1,3,4-thiadiazole 0.4 g of sodium hydride, 2-amino-5-piperidinopropylthio 1.6 g of -1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. 1.6 g of 4-geranyloxybenzoic acid and 1.1 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). The obtained solid was recrystallized (n-hexane-ethanol) to give 2.1 g of the title compound.
I got ¹ H-NMR (CDCl ₃ ) δ: 8.16 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J =
8.8Hz), 5.49 (1H, t, J = 6.4Hz), 5.14-5.06 (1H, m), 4.62 (2H,
d, J = 6.4Hz), 3.29 (2H, t, J = 7.3Hz), 2.41 (2H, t, J = 7.3Hz),
2.33-2.22 (4H, m), 2.18-2.01 (4H, m), 1.95 (2H, q5, J = 7.3H
z), 1.76 (3H, s), 1.68 (3H, s), 1.61 (3H, s), 1.60-1.47 (4H,
m), 1.45-1.33 (2H, m).

Example 14 Synthesis of 2- (4-geranyloxybenzoyl) amino-5- (2-pyridylmethyl) thio-1,3,4-thiadiazole 0.3 g of sodium hydride, 2-amino-5- (2- 1.3 g of (pyridylmethyl) thio-1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. 1.5 g of 4-geranyloxybenzoic acid and 1.0 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature.
This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). Recrystallize the resulting solid (n-
Hexane-ethanol) to give the title compound 1.9
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 12.58 (1 H, bs), 8.55 (1 H, dd, J = 1.0 H
z, 4.9Hz), 8.22 (2H, d, J = 8.8Hz), 7.59 (1H, d, J = 7.3Hz), 7.2
9 (2H, d, J = 7.3Hz), 7.17 (1H, dd, J = 1.0Hz, 4.9Hz), 7.01 (2H,
d, J = 8.8Hz), 5.45 (1H, t, J = 6.8Hz), 5.08 (1H, t, J = 6.8Hz),
4.62 (2H, s), 4.57 (2H, t, J = 6.8Hz), 2.18-2.02 (4H, m), 1.71
(3H, s), 1.68 (3H, s), 1.60 (3H, s).

Example 15 2- (4-geranyloxybenzoyl) amino-5-ethylthio-
Synthesis of 1,3,4-thiadiazole It was dissolved in 2.2 g of 4-geranyloxybenzoic acid, 1.0 g of pyridine and 40 ml of benzene. Thionyl chloride while cooling on ice 1.
Add 4 g and stir at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and 30 ml of tetrahydrofuran and 1.3 g of pyridine were added to the residue. 2-dissolved in tetrahydrofuran while cooling with ice
1.3 g of amino-5-ethylthio-1,3,4-thiadiazole was added,
Stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (chloroform: methanol = 15: 1) and recrystallized (n-hexane-ethanol) to obtain 2.3 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 8.08 (2H, d, J = 9.3 Hz), 7.01 (2H, d, J =
9.3Hz), 5.53-5.43 (1H, m), 5.14-5.04 (1H, m), 4.63 (2H, d, J
= 6.8Hz), 3.27 (2H, q, J = 7.3Hz), 2.13-2.11 (4H, m), 1.76 (3
H, s), 1.67 (3H, s), 1.61-1.59 (3H, m), 1.45 (3H, t, J = 7.3H
z).

Example 16 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-propylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-propylthio-
1.2 g of 1,3,4-thiadiazole in 30 ml of tetrahydrofuran
The mixture was stirred under ice-cooling for 30 minutes. 1.9 g of 4-geranyloxybenzoic acid and 1.3 g of carbonyldiimidazole were stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 1).
5: 1). Recrystallize the obtained solid (n-hexane-
Ethanol) gave 1.3 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 12.24 (1 H, bs), 8.19 (2 H, d, J = 8.8 H
z), 7.01 (2H, d, J = 8.8Hz), 5.49 (1H, t, J = 6.4Hz), 5.12-5.04
(1H, m), 4.62 (2H, d, J = 6.4Hz), 3.22 (2H, d, J = 7.3Hz), 2.19-
2.03 (4H, m), 1.80 (2H, s6, J = 7.3Hz), 1.75 (3H, s), 1.68 (3H,
s), 1.61 (3H, s), 1.04 (3H, t, J = 7.3Hz).

Example 17 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-isobutylthio-1,3,4-thiadiazole Sodium hydride 0.4 g, 2-amino-5-isobutylthio
1.1 g of -1,3,4-thiadiazole in 30 ml of tetrahydrofuran
The mixture was stirred under ice-cooling for 30 minutes. 1.6 g of 4-geranyloxybenzoic acid and 1.1 g of carbonyldiimidazole were stirred in 30 ml of tetrahydrofuran for 30 minutes at room temperature. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The obtained solid was recrystallized (n-hexane-ethanol) to give 1.9 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 12.46 (1H, bs), 8.21 (2H, d, J = 8.8H)
z), 7.01 (2H, d, J = 8.8Hz), 5.49 (1H, t, J = 6.4Hz), 5.14-5.04
(1H, m), 4.62 (2H, d, J = 6.4Hz), 3.15 (2H, d, J = 6.8Hz), 2.26-
2.12 (4H, m), 2.11 (1H, s7, J = 6.8Hz), 1.76 (3H, s), 1.68 (3H,
s), 1.61 (3H, s), 1.04 (6H, d, J = 6.8Hz).

Example 18 Synthesis of 2- (4-geranyloxybenzoyl) amino-5-benzylthio-1,3,4-thiadiazole 0.6 g of sodium hydride, 2-amino-5-benzylthio-
1.6 g of 1,3,4-thiadiazole in 30 ml of tetrahydrofuran
The mixture was stirred under ice-cooling for 30 minutes. 1.9 g of 4-geranyloxybenzoic acid and 1.3 g of carbonyldiimidazole were stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran. This was added to the previous reaction solution and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. Recrystallization (n-hexane-
Ethanol) gave 0.7 g of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 12.85 (1H, bs), 8.09 (2H, d, J = 8.8H)
z), 7.42-7.19 (5H, m), 7.07 (2H, t, J = 8.8Hz), 5.44 (1H, t, J =
6.4Hz), 5.10-5.01 (1H, m), 4.65 (2H, d, J = 6.4Hz), 4.50 (2H,
s), 2.16-2.02 (4H, m), 1.72 (3H, s), 1.63 (3H, s), 1.57 (3H,
s).

Example 19 Synthesis of 2- (3-piperidinomethylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

[0101]

Embedded image 2.2 g of 3-piperidinomethylbenzoic acid was added to 20 ml of thionyl chloride while cooling with ice, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 2.3 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole and 30 ml of chloroform were added, and the mixture was stirred at room temperature for 3 hours. A 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform: methanol).
= 15: 1) to give 1.7 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 10.11 (1H, s), 8.12 (1H, d, J = 8.3 Hz),
8.07 (1H, s), 7.61 (1H, d, J = 8.3Hz), 7.47 (1H, t, J = 8.3Hz),
3.56 (2H, s), 3.32 (2H, t, J = 6.8Hz), 2.81 (2H, t, J = 6.8Hz),
2.54 (4H, q, J = 7.3Hz), 2.48-2.34 (4H, m), 1.64-1.58 (4H,
m), 1.56-1.38 (2H, m), 1.00 (6H, t, J = 7.3Hz).

Example 20 Synthesis of 2- [4- (4-fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-diethylaminoethylthio-1,3,4-thiadiazole

[0103]

Embedded image 0.8 g of sodium hydride and 3.3 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole were stirred in 30 ml of tetrahydrofuran under ice-cooling for 30 minutes. 2.1 g of 4- (4-fluorobenzyloxybenzoic acid) and 1.3 g of carbonyldiimidazole were stirred at room temperature for 30 minutes in 30 ml of tetrahydrofuran, added to the above reaction solution and stirred at room temperature for 4 hours. The mixture was concentrated, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1). (N-hexane-ethanol) to give 3.2 g of the title compound ¹ H-NMR (CDCl ₃ ) δ: 12.47 (1H, S), 8.06 (1H, d, J = 8.8 Hz),
7.91 (1H, S), 7.40 (2H, d, J = 8.8Hz), 7.09 (2H, t, J = 8.3H
z), 7.01 (1H, d, J = 8.3Hz), 5.12 (2H, s), 3.90-3.86 (2H,
m), 3.52-3.46 (2H, m), 3.35-3.13 (4H, m), 2.59 (2H, d, J = 6.8
Hz), 1.87-2.05 (1H, m), 1.41 (6H, t, J = 7.3Hz), 0.91 (6H,
d, J = 6.4Hz).

[0104]

As described above, the thiadiazole amide derivative according to the present invention exhibits an excellent anti-ulcer effect.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram showing an example of a production process of a thiadiazole amide derivative according to the present invention.

FIG. 2 is an explanatory diagram showing an example of a production process of a raw material compound of a thiadiazole amide derivative according to the present invention.

FIG. 3 is an explanatory diagram showing an example of a production process of a raw material compound of a thiadiazole amide derivative according to the present invention.

FIG. 4 is an explanatory diagram showing an example of a production process of a raw material compound of a thiadiazole amide derivative according to the present invention.

FIG. 5 is an explanatory view showing one example of a production process of a raw material compound of a thiadiazole amide derivative according to the present invention.

FIG. 6 is an explanatory view showing one example of a production process of a starting compound of a thiadiazole amide derivative according to the present invention.

FIG. 7 is an explanatory view showing one example of a production process of a raw material compound of a thiadiazole amide derivative according to the present invention.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hirotada Fukunishi 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside Shiseido Daiichi Research Center (72) Inventor Nao Kojima 7-5-5 Ginza, Chuo-ku, Tokyo Shiseido Co., Ltd. (56) References JP-A-1-160976 (JP, A) JP-A-63-190886 (JP, A) JP-A-1-233282 (JP, A) JP-A-59-21624 (JP) , A) J. Drug Res. (1974), 6 (3), p. 203-207 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 285/00-285/38 CA (STN) REGISTRY (STN)

Claims (24)

(57) [Claims] 1. A thiadiazolamide derivative represented by the following general formula 1 and a salt thereof. Embedded image (In the above Chemical Formula 1, R ₁ and R ₂ represent any of a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, an alkenyloxy group, a piperidinoalkyl group, and a benzyloxy group. , if any of _R 1, _{R 2} is a hydrogen atom, the other is not a hydrogen atom .R ₃
Is a lower alkyl group, an aromatic ring, a pyridyl group, or -N
(R ₄₎ a group represented by R _5, R 4, R ₅ are means to form a lower alkyl group or a saturated heterocyclic group both bonded to 4- to 8-membered. However, R ₁ or R ₂
Is a lower alkoxy group, R ₃ is —N (R ₄ ) R
_The group represented by ₅ . n means the integer of 1-3. ) 2. The compound according to claim 1, wherein R ₁ and / or R ₂ is an alkenyloxy group, and a thiadiazole amide derivative and a salt thereof. 3. The thiadiazole amide derivative according to claim 2, wherein the alkenyloxy group is a geranyloxy group, and a salt thereof. 4. The compound according to claim 1, wherein R ₁ and / or R ₂ is a lower alkyl group, and a thiadiazole amide derivative and a salt thereof. 5. The thiadiazole amide derivative according to claim 1, wherein R ₁ and / or R ₂ is a lower alkoxy group, and a salt thereof. 6. The compound according to any one of claims 1 to 5, wherein R ₃ is a group represented by —N (R ₄ ) R ₅ (provided that:
R ₄ and R ₅ are the same as those in the above formula 1) or a pyridyl group, and a thiadiazole amide derivative and a salt thereof. 7. The compound of claim 6, wherein R ₃ is a piperidino group, and a thiadiazole amide derivative and a salt thereof. 8. The thiadiazole amide derivative and a salt thereof, wherein R ₃ is a lower alkyl group in the compound according to claim 1. 9. The thiadiazole amide derivative and a salt thereof, wherein R ₃ is an aromatic ring in the compound according to any one of claims 1 to 4. 10. The thiadiazole amide derivative and a salt thereof, which are represented by the following general formula 2 in the compound according to claim 1. Embedded image (In the above Chemical Formula 2, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group. However, when either R ₁ or R ₂ is a hydrogen atom, the other is a lower alkyl group. R ₄ , R ₅ and n are the same as those in the above formula 1.) 11. The compound according to claim 10, wherein R
A thiadiazole amide derivative and a salt thereof, wherein either _one of R ₁ and R ₂ is a hydrogen atom, and n is 2. 12. The thiadiazole amide derivative according to claim 1, which is represented by the following general formula 3, and a salt thereof. Embedded image (In the above formula 3, R ₁ represents a lower alkoxy group or a lower alkylamino group. R ₄ , R ₅ and n are the same as those in the above formula 1.) 13. The compound according to claim 12, wherein n
Is 2 and a thiadiazole amide derivative and a salt thereof. 14. A thiadiazole amide derivative and a salt thereof, which are represented by the following general formula 4 in the compound according to claim 1. Embedded image (In the above chemical formula 4, R ₁ is an alkenyloxy group, and R ₃ is —N
(R ₄ ) means a group represented by R ₅ or a pyridyl group.
Note that R ₄ , R ₅ and n are the same as those in the above formula 1. ) 15. The compound according to claim 14, wherein R
₁ is a geranyloxy group, and R ₃ is a group represented by —N (R ₄ ) R ₅ (wherein R ₄ and R ₅ are the same as those in the above formula 1), and a thiadiazole amide derivative and a thiadiazole amide derivative thereof. salt. 16. The thiadiazole amide derivative and a salt thereof, which are represented by the following general formula 5 in the compound according to claim 1. Embedded image (In the above formula 5, R ₁ represents an alkenyloxy group.
R ₃ represents a lower alkyl group or an aromatic ring. ) 17. The compound according to claim 16, wherein R
A thiadiazole amide derivative and a salt thereof, wherein ₁ is a geranyloxy group. 18. The compound of claim 1, wherein R ₁
Is a piperidinoalkyl group, R ₂ is a hydrogen atom, and R ₃ is —N (R ₄ ) R ₅ (where R ₄ and R ₅ are the same as those in the above formula 1). And its salts. 19. The compound according to claim 18, wherein R
A thiadiazole amide derivative and a salt thereof, wherein ₁ is a piperidinomethyl group. 20. The compound according to claim 1, wherein R ₁
Is a benzyloxy group, and R ₂ is a lower alkyl group, and a thiadiazole amide derivative and a salt thereof. 21. The compound according to claim 20, wherein R
A thiadiazole amide derivative and a salt thereof, wherein ₁ is a fluorobenzyloxy group and R ₂ is an isobutyl group. 22. The thiadiazole amide derivative and a salt thereof, wherein R ₄ and R ₅ are an ethyl group in the compound according to any one of claims 18 to 21. 23. A thiadiazole amide derivative and a salt thereof, wherein n is 2 in the compound according to any one of claims 18 to 22. 24. An anti-ulcer agent comprising the thiadiazole amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.