JPH08169881A - Arylthiadiazole derivative and antiviral agent containing the same - Google Patents

Abstract

PURPOSE: To obtain the subject new compound, excellent in antiviral actions, especially anti-human immunodeficiency viral actions and useful for preventive or therapeutic treatment of humans infected with a virus or in fear of infection therewith. CONSTITUTION: A compound of formula I Y<1> and W are each O or S; one of R<1> to R<3> is a (mono- or di-1-6C alkyl-substituted)amino, carboxyl, etc.; other two are each H, a halogen, a [OH, a (1-4C alkoxy-substituted)1-4C alkoxy, etc.,-substituted[1-6C alkyl, CF3 , etc.; R<4> and R<5> are each H, a 1-4C alkoxy, a (1-4C alkoxy, OH, CN, etc.,-substituted)1-6C alkyl, etc.} or its salt, e.g. N,N- dimethyl[3-(3-amino-2,6-dichlorophenyl)-1,2,5-thiadiazol-4-yl]carbamate. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (Q is Cl, I or Br) in the presence of a base such as pyridine in a solvent such as hexane at 0-150 deg.C temperature.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to aryl thiadiazole derivatives having antiviral activity and salts thereof.

[0002]

2. Description of the Related Art Up to now, JP-A-3-193773, JP-A-4-103575, and JP-A-4-1-1.
In 17372, certain thiadiazoles are described and these are reported to have herbicidal activity.
In addition, JP-A-4-182403, JP-A-4-18
2405 discloses that certain thiadiazoles are useful as agricultural fungicides. On the other hand, as an antiviral agent, acyclovir (anti-herpes agent),
Amantadine (anti-influenza agent), azidothymidine (anti-HIV agent, HIV: Human immunode)
ficentivirus) and the like are known.

[0003]

At present, there is no satisfactory therapeutic drug for viral diseases, and there is a demand for the development of a new antiviral agent. In particular, the development of a drug having an anti-HIV action is an urgent need. Has become.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the aryl thiadiazole derivative has excellent antiviral activity, and completed the present invention.

That is, the feature of the present invention is that the general formula [I]

[0006]

[Chemical 17]

[Wherein Y ¹ is an oxygen atom or a sulfur atom, W is an oxygen atom or a sulfur atom, R ¹ , R ² and R ³
One of them is an amino group (which may be independently substituted by one or two alkyl groups having 1 to 6 carbon atoms), a carboxyl group, (substituted by an alkoxy group having 1 to 4 carbon atoms).
Carbonyl group, carbamoyl group (which may be independently substituted by one or two alkyl groups having 1 to 6 carbon atoms), cyano group or {hydroxy group, alkoxy group having 1 to 4 carbon atoms, (having 1 carbon atom) Substituted with an alkoxy group having 1 to 4 carbon atoms) or an alkoxy group having 1 to 4 carbon atoms or substituted with a silyloxy group (3 independently substituted with an alkyl group having 1 to 6 carbon atoms); The remaining two of the alkyl groups, R ¹ , R ² and R ³ are the same or different and are a hydrogen atom, a halogen atom, a {hydroxy group, an alkoxy group having 1 to 4 carbon atoms, Alkoxy group having 1 to 4 carbon atoms (substituted by alkoxy group) or (having 1 to 6 carbon atoms)
May be substituted with a silyloxy group, which may be independently substituted with 3 alkyl groups of 3), an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, a carboxyl group, (carbon Carbonyl group (substituted by an alkoxy group having 1 to 4 carbon atoms), carbamoyl group (which may be independently substituted by 1 or 2 alkyl groups having 1 to 6 carbon atoms), cyano group, hydroxy group, hydroxymethyl group A nitro group or an amino group (which may be independently substituted by one or two alkyl groups having 1 to 6 carbon atoms), R ⁴ and R
⁵ are the same or different and are a hydrogen atom, an alkoxy group having 1 to 4 carbon atoms, {an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a cyano group, a carboxyl group, a carbamoyl group, or (an alkoxy group having 1 to 4 carbon atoms. (Substituted) carbonyl group may be substituted} alkyl group having 1 to 6 carbon atoms,

[0008]

Embedded image

Or R ⁴ and R ⁵ are connected to each other

[0010]

[Chemical 19]

R ⁶ , R ⁷ and R ⁸ are the same or different, and a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R ⁹ and R ¹⁰ are the same or different. A hydrogen atom or an alkyl group having 1 to 6 carbon atoms, E is —CH ₂ — or an oxygen atom, and n ¹ is an integer of 0 to 2. ] The aryl thiadiazole derivative represented by or its salt.

The present invention also resides in an antiviral agent containing an arylthiadiazole derivative represented by the general formula [I] or a salt thereof as an active ingredient.

The present invention further provides

[0014]

Embedded image

[0015]

[Chemical 21]

[0016]

[Chemical formula 22]

[0017]

[Chemical formula 23]

Or

[0019]

[Chemical formula 24]

(Wherein n ² is 1 or 2, n ³ is 0 or 1 Y ¹ is an oxygen atom or a sulfur atom, W is an oxygen atom or a sulfur atom, and R ¹¹ , R ¹² and R ¹³ are the same or different. Hydrogen atom, halogen atom, alkyl group having 1 to 6 carbon atoms, trifluoromethyl group, alkoxy group having 1 to 4 carbon atoms, hydroxy group, nitro group, R ¹⁴ is hydrogen atom, alkyl group having 1 to 6 carbon atoms or A phenyl group (which may be substituted with a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 4 carbon atoms), R ¹⁸ is {hydroxy group, cyano group, carboxyl group, carbamoyl group or (number of carbon atoms 1
Substituted with ~ 4 alkoxy groups were) substituted with a carbonyl group} alkyl group having 1 to 6 carbon atoms, R ¹⁹ may be substituted with a hydrogen atom or an (alkoxy group having 1 to 4 carbon atoms) carbon atoms The alkyl groups of 1 to 6 are shown.

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R
¹⁰ , E and n ¹ have the same meanings as described above.

(However, in Chemical formula 24, n ³ represents 0, and R ¹¹ , R ¹² and R ¹³ do not represent a hydrogen atom at the same time), and the arylthiadiazole derivative or a salt thereof.

Furthermore, the present invention provides the general formula [II]

[0024]

[Chemical 25]

[Where A is

[0026]

[Chemical formula 26]

-Y ¹ -SO ₂ NR ⁹ R ¹⁰ ,

[0028]

[Chemical 27]

[0029]

[Chemical 28]

[0030]

[Chemical 29]

Or

[0032]

Embedded image

R ¹⁵ and R ¹⁶ are the same or different and each is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or an alkyl group having 1 to 6 carbon atoms (which may be substituted by a halogen atom). J is -CH = or -N =, Y ²
, R ¹⁷ is a halogen atom or ^{-NR 14 -R 19, R 11,} R 12, R 13, - an oxygen atom, a sulfur atom or -NR ¹⁴ are
R ¹⁴ , R ¹⁸ , R ¹⁹ , n ² , n ³ , R ⁴ , R ⁵ , R ⁹ , R
¹⁰ , R ¹⁴ , Y ¹ and W have the same meanings as described above. ] It is an antiviral agent containing the aryl thiadiazole derivative represented by these or its salt as an active ingredient.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below.

In the general formulas [I] and [II], examples of the alkyl group having 1 to 6 carbon atoms as the substituent include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group. , Isobutyl group, s-butyl group, t
-Butyl group, n-pentyl group, cyclopentyl group, n-
A straight chain, branched or cyclic alkyl group having 1 to 6 carbon atoms such as a hexyl group and a cyclohexyl group can be mentioned.
As the alkoxy group having 1 to 4 carbon atoms, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-
Examples thereof include butoxy group, isobutoxy group, s-butoxy group and t-butoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

A typical method for producing the aryl thiadiazole derivative represented by the general formulas [I] and [II] is shown below.

(Production method 1)

[0038]

[Chemical 31]

(In the reaction formula, Q is a chlorine atom, a bromine atom or an iodine atom, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above.) General formula [ The aryl thiadiazole derivative represented by the formula [I] is obtained by converting the derivative represented by the formula [III] into the formula [IV]
It can be produced by reacting with a carbamoyl derivative represented by

The reaction is carried out in the presence of a base in a solvent in the range of 0 to 15
It is performed at 0 ° C., preferably 20 to 100 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [II
[I] to 1 equivalent of the derivative represented by the general formula [I
V] is 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is 1 to 5 equivalents, preferably 1 to
It is 3 equivalents.

As the solvent, hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, polar solvents such as acetonitrile, methanol, ethanol, isopropanol, Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 1-1) In the general formula [I], R
^At least one of ¹ , R ² and R ³ is a C 1-6 alkyl group substituted with a hydroxy group,
⁴ , R ⁵ , Y ¹ and W have the same meanings as described above, and the aryl thiadiazole derivative can be represented by the following formula:
^At least one of ¹ , R ² and R ³ is {carbon number 1
To alkoxy groups, C1 to C4 alkoxy groups (substituted with C1 to C4 alkoxy groups) or (silyloxy groups independently substituted with three C1 to C6 alkyl groups). And an aryl thiadiazole derivative in which R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above and are an alkyl group having 1 to 6 carbon atoms.

The reaction is carried out in a solvent in the presence of an acid or a base,
0 to 120 ° C, preferably 20 to 100 ° C, several minutes to 12
The time is preferably 1 to 6 hours.

The amount of the reagent used in the reaction is 1 to 50 equivalents, preferably 1 to 50 equivalents of the acid or base, relative to 1 equivalent of the substrate.
It is 20 equivalents.

As the solvent, hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, phosphoric acid hexamethyltriamide, polar solvents such as acetonitrile, methanol, ethanol , Alcohols such as isopropanol and tert-butanol, and water.

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. Examples of the acid include protic acids such as acetic acid, trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, aluminum chloride, titanium tetrachloride, boron trifluoride, boron tribromide, zinc bromide, trimethylsilyl iodide, and fluorine. Lewis acids such as tetrabutylammonium chloride can be mentioned.

(Production Method 1-2) In the general formula [I], R
^At least one of ¹ , R ² and R ³ is a carboxyl group, and R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above, and the aryl thiadiazole derivative has the general formula [I]
In the above, at least one of R ¹ , R ² and R ³ is a carbonyl group (substituted with an alkoxy group having 1 to 4 carbon atoms), and R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above. The aryl thiadiazole derivative represented by can also be produced by hydrolysis.

The reaction is carried out in a solvent in the presence of an acid or a base,
0 to 120 ° C, preferably 20 to 100 ° C, several minutes to 12
The time is preferably 1 to 6 hours.

The amount of the reagent to be used in the reaction is 1 to 50 equivalents, preferably 1 to 50 equivalents of acid or base with respect to 1 equivalent of the substrate.
It is 20 equivalents.

As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone,
Hexamethyltriamide phosphoric acid, polar solvents such as acetonitrile, methanol, ethanol, isopropanol,
Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. You can

Examples of the acid include acetic acid, trifluoroacetic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trimethylsilyl chloride, boron tribromide, aluminum chloride and the like.

(Production Method 1-3) In the general formula [I], R
^At least one of ¹ , R ² and R ³ is (carbon number 1
The aryl thiadiazole derivative represented by the general formula is an amino group in which each of the alkyl groups of 6 to 6 may be independently substituted by 1 or 2) and R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above. In [I], at least one of R ¹ , R ² and R ³ is a nitro group, and R ⁴ , R ⁵ , Y ¹ and W have the same meanings as described above, and an aryl thiadiazole derivative is used as a catalyst (platinum oxide, It can also be produced by reducing with hydrogen in the presence of platinum, platinum carbon, platinum sulfide carbon, palladium-carbon, etc. Further, if necessary, the obtained amino group may be reacted with an alkylating agent having 1 to 6 carbon atoms to produce an amino group having a substituent.

The reduction reaction is carried out in a solvent in the presence or absence of an acid at 0 to 80 ° C., preferably 10 to 50 ° C. for several minutes to
It is carried out for 24 hours, preferably 1 to 12 hours.

The amount of the reagent to be used in the reaction is 0.01 to 1 part by weight, preferably 0.0 to 1 part by weight, relative to 1 part by weight of the substrate.
3 to 0.3 parts by weight, the acid is 0.1 to 10 parts by weight, preferably 0.5 to 3 parts by weight, and the hydrogen pressure is 1 to 5 atm, preferably 1 to 2 atm.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , N,
N-dimethylformamide, dimethyl sulfoxide,
Examples include polar solvents such as 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, acetonitrile and ethyl acetate, alcohols such as methanol, ethanol, isopropanol and tert-butanol, acetic acid and water. it can.

Examples of the catalyst include platinum oxide, platinum, platinum carbon, platinum sulfide carbon, palladium-carbon and the like.

As the acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid,
Oxalic acid, trifluoroacetic acid, etc. can be mentioned.

The reaction between the obtained amino group and the alkylating agent having 1 to 6 carbon atoms is carried out in a solvent in the presence or absence of a base at 0 to 130 ° C., preferably 20 to 100 ° C. for several minutes to It is carried out for 24 hours, preferably 1 to 12 hours.

The amount of the reagent used for the reaction is 0.5 to 5 equivalents of the alkylating agent having 1 to 6 carbon atoms per 1 equivalent of the substrate,
It is preferably 1 to 3 equivalents.

Examples of the alkylating agent include alkyl halides and alkyl sulfates.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , N,
N-dimethylformamide, dimethyl sulfoxide,
Polar solvents such as 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, acetonitrile and ethyl acetate, alcohols such as methanol, ethanol, isopropanol and tert-butanol, pyridine, triethylamine, N, N- Examples thereof include amines such as diisopropylethylamine and water.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 2)

[0067]

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(In the reaction formula, R ¹ , R ² , R ³ , R ⁴ and R
⁵ , Y ¹ and W have the same meanings as described above. The aryl thiadiazole derivative represented by the general formula [I] is obtained by reacting the derivative represented by the general formula [III] with a carbonylating agent, and then reacting with an amine represented by the general formula [V]. It can also be manufactured by

The carbonylation reaction is carried out in a solvent in the presence or absence of a base at 0 to 100 ° C, preferably 10 to 5 ° C.
It is carried out at 0 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [II
The carbonylating agent is 1 to 3 equivalents, preferably 1 to 2 equivalents, and the base is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the derivative represented by [I].

Examples of the carbonylating agent include phosgene, thiophosgene, trichloromethyl chloroformate, bis (trichloromethyl) carbonate, 1,1'-thiocarbonyldiimidazole, 1,1'-carbonyldiimidazole and dimethyl carbonate. be able to.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. Etc. can be mentioned.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

The subsequent reaction with the amines represented by the general formula [V] is carried out in a solvent in the presence or absence of a base in the range of 0 to 1
It is carried out at 00 ° C., preferably 10 to 50 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of reagents used in the reaction is determined by the formula [II
The amine represented by the general formula [V] is 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the derivative represented by [I]. Is.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. Etc. can be mentioned.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 3)

[0079]

[Chemical 33]

(In the reaction formula, R ¹ , R ² , R ³ , R ⁴ , Y
¹ and W have the same meanings as described above. The aryl thiadiazole derivative represented by the general formula [Ia] is obtained by converting the derivative represented by the general formula [III] into the general formula [V
It can also be produced by reacting with an isocyanate represented by I].

The reaction is carried out without solvent or in the presence or absence of a base at 0 to 150 ° C., preferably 20 to 1 ° C.
It is carried out at 00 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [II
The isocyanate represented by the general formula [VI] is equivalent to 1 to 30 equivalents, preferably 1 equivalent to 1 equivalent of the derivative represented by [I].
-10 equivalents, the base is 0.01-3 equivalents, preferably 0.1.
It is 01 to 1 equivalent.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, polar solvents such as acetonitrile, and the like.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 4)

[0086]

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(In the reaction formula, R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R
¹³ and R ¹⁴ have the same meaning as described above. The aryl thiadiazole derivative represented by the general formula [II-a] is obtained by reacting the amide derivative represented by the general formula [VII] with phosphorus oxychloride, and then reacting with the amine derivative represented by the general formula [VIII]. It can be produced by reacting.

The reaction with phosphorus oxychloride is carried out in a solvent at 0-
100 ° C, preferably 10 to 50 ° C, several minutes to 24 hours,
It is preferably carried out for 3 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [VI
I]] to 1 equivalent of the amide derivative, 0.3 to 1.5 equivalents of phosphorus oxychloride, preferably 0.5 to 1.1
It is equivalent.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. Etc. can be mentioned.

The subsequent reaction with the amine derivative represented by the general formula [VIII] is carried out in the solvent used for the reaction with phosphorus oxychloride at 10 to 130 ° C., preferably 50 to 90 ° C. for several minutes to
The time is 12 hours, preferably 1 to 6 hours.

The amount of the reagent used in the reaction is determined by the formula [VI
[E] to one equivalent of the amide derivative represented by the general formula [V
III] represented by 0.25 to 1 equivalent, preferably 0.5 to 1.0 equivalent.

(Production method 5)

[0094]

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(In the reaction formula, R ¹¹ , R ¹² , R ¹³ , n ³ and Q have the same meanings as described above.) The carboxylic acid derivative represented by the general formula [X] is represented by the general formula [IX]. It can be produced by reacting the represented halogen compound with a cyanating agent and then hydrolyzing it with an acid or a base.

The reaction with the cyanating agent is carried out in a solvent in an amount of 10 to 1
80 ° C, preferably 50 to 150 ° C, several minutes to 24 hours,
It is preferably carried out for 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [IX]
The cyanating agent is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the halogen compound represented by.

As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone,
Examples thereof include polar solvents such as phosphoric acid hexamethyltriamide and acetonitrile.

Examples of the cyanating agent include sodium cyanide, potassium cyanide, copper cyanide and the like.

The subsequent hydrolysis reaction is carried out in the presence of an acid or a base in a solvent at 0 to 120 ° C., preferably 20 to 100 ° C.
It is carried out at a temperature of several minutes to 12 hours, preferably 1 to 6 hours.

The amount of the reagent to be used in the reaction is 1 to 50 equivalents, preferably 1 to 50 equivalents of acid or base with respect to 1 equivalent of the substrate.
It is 20 equivalents.

Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone,
Hexamethyltriamide phosphoric acid, polar solvents such as acetonitrile, methanol, ethanol, isopropanol,
Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. You can

Examples of the acid include formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, bromic acid, sulfuric acid and the like.

(Production method 6)

[0106]

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(In the reaction formula, R ⁴ , R ⁵ , R ¹¹ , R ¹² , R
¹³ and n ³ have the same meanings as described above. The aryl thiadiazole derivative represented by the general formula [II-b] is reacted with the carboxylic acid derivative represented by the general formula [X] with a chlorinating agent to obtain an acid chloride represented by the general formula [XI]. After that, it can be produced by reacting with an amine represented by the general formula [V].

The reaction with the chlorinating agent is carried out without solvent or in a solvent at 0 to 100 ° C., preferably 10 to 80 ° C. for several minutes to 1
It is carried out for 2 hours, preferably 1 to 6 hours.

The amount of the reagent used in the reaction is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of the carboxylic acid derivative [X].

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, and hexamethyltriamide phosphate.

Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride and the like.

Not only a chlorinating agent but also a brominating agent or an iodizing agent can be used for the reaction.

The subsequent reaction with the amines represented by the general formula [V] is carried out in a solvent in the presence or absence of a base at 0-5.
It is performed at 0 ° C., preferably 0 to 20 ° C. for several minutes to 6 hours, preferably 0.5 to 2 hours.

The amount of the reagent used in the reaction is determined by the formula [XI]
The amine represented by the general formula [V] is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the acid chloride represented by
The base is 1 to 5, preferably 1 to 3 equivalents.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert. Examples thereof include alkali metal alkoxides such as butoxide.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, polar solvents such as acetonitrile, water and the like. it can.

(Production method 7)

[0118]

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(In the reaction formula, R ⁴ , R ⁵ , R ¹¹ , R ¹² , R
¹³ and n ³ have the same meanings as described above. The aryl thiadiazole derivative represented by the general formula [II-c] can be produced by reacting the aryl thiadiazole derivative represented by the general formula [II-b] with a sulfiding agent.

The reaction is carried out in a solvent at 20 to 150 ° C., preferably 50 to 100 ° C. for several minutes to 6 hours, preferably 0.5.
~ 2 hours.

The amount of the reagent used in the reaction is determined by the formula [II-
The amount of the sulfurizing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the aryl thiadiazole derivative represented by b].

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, amines such as pyridine and triethylamine. .

Examples of the sulfiding agent include phosphorus pentasulfide and Lawesson's reagent.

(Production method 8)

[0125]

[Chemical 38]

(In the reaction formula, R ¹¹ , R ¹² , R ¹³ , R ¹⁷ , Y
¹ and n ² have the same meaning as described above. The aryl thiadiazole derivative represented by the general formula [II-d] is obtained by converting the derivative represented by the general formula [XII] into the general formula [X
It can be produced by reacting with a halogen compound represented by III].

The reaction is carried out in the presence of a base in a solvent in the range of 0 to 15
It is performed at 0 ° C., preferably 20 to 100 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [XI
[I]] to 1 equivalent of the derivative represented by the general formula [XII
The halogen compound represented by [I] is 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is 1 to 5 equivalents, preferably 1 to 3 equivalents.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, polar solvents such as acetonitrile, methanol, ethanol, isopropanol, Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 9)

[0132]

[Chemical Formula 39]

(In the reaction formula, R ¹¹ , R ¹² , R ¹³ , R ¹⁹ , Y
¹ , Y ² , n ² and Q have the same meanings as described above. ) The aryl thiadiazole derivative represented by the general formula [II-f] is produced by reacting the aryl thiadiazole derivative represented by the general formula [II-e] with the compound represented by the general formula [XIV]. be able to.

The reaction is carried out in the presence of a base in a solvent in the range of 0 to 15
It is performed at 0 ° C., preferably 20 to 100 ° C. for several minutes to 24 hours, preferably 1 to 12 hours.

The amount of the reagent used in the reaction is determined by the formula [II-
[E] to 1 equivalent of the aryl thiadiazole derivative, the compound represented by the general formula [XIV] is 1 to 5 equivalents, preferably 1 to 3 equivalents, and the base is 1 to 5 equivalents, preferably 1 to It is 3 equivalents.

Examples of the solvent include hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. , Pyridine, amines such as triethylamine, N, N-dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethyltriamide phosphate, polar solvents such as acetonitrile, methanol, ethanol, isopropanol, Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include organic bases such as pyridine, triethylamine and N, N-diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, sodium methoxide and sodium ethoxy. And alkali metal alkoxides such as potassium tert-butoxide and the like.

(Production method 10)

[0139]

[Chemical 40]

General formula [II-g] (in the formula, R ¹¹ , R ¹² , R
¹³ , R ¹⁴ , R ¹⁸ , Y ¹ and W have the same meanings as described above. The aryl thiadiazole derivative represented by) can be produced by the same reaction as the production method 1, 2 or 3.

(Production Process 10-1) In the general formula [II-g], R ¹⁸ is an alkyl group having 1 to 6 carbon atoms (substituted by a carboxyl group or a carbamoyl group), R ¹¹ , R ¹² and R
^An aryl thiadiazole derivative in which ¹³ , R ¹⁴ , Y ¹ and W have the same meanings as described above is represented by the following formula [II-g]:
R ¹⁸ represents an alkyl group having 1 to 6 carbon atoms substituted with a cyano group, and R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , Y ¹ and W have the same meanings as described above, and are hydrolyzed aryl thiadiazole derivatives. It can also be manufactured by

The reaction is carried out in a solvent in the presence of an acid or a base,
0 to 120 ° C, preferably 20 to 100 ° C, several minutes to 12
The time is preferably 1 to 6 hours.

The amount of the reagent to be used in the reaction is 1 to 50 equivalents, preferably 1 to 50 equivalents of the acid or base with respect to 1 equivalent of the substrate.
It is 20 equivalents.

As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone,
Hexamethyltriamide phosphoric acid, polar solvents such as acetonitrile, methanol, ethanol, isopropanol,
Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. You can

Examples of the acid include formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, bromic acid, sulfuric acid and the like.

(Production Process 10-2) In the general formula [II-g], R ¹⁸ is an alkyl group having 1 to 6 carbon atoms substituted with a carbonyl group (substituted with an alkoxy group having 1 to 4 carbon atoms). The aryl thiadiazole derivative in which R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , Y ¹ and W have the same meanings as described above is a compound represented by the general formula [II-g], in which R ¹⁸ is substituted with a carboxyl group. 1 to 6 are alkyl groups, R ¹¹ , R ¹² ,
It can also be produced by reacting an aryl thiadiazole derivative in which R ¹³ , R ¹⁴ , Y ¹ and W have the same meanings as described above with an alcohol having 1 to 4 carbon atoms.

The reaction is carried out in the presence of an acid in a solvent in the range of 0 to 120.
C., preferably 20 to 100.degree. C., several minutes to 12 hours, preferably 1 to 6 hours.

The amount of the reagent to be used in the reaction is 1 to 50 equivalents, preferably 1 to 20 equivalents, for 1 equivalent of the substrate.

As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone,
Hexamethyltriamide phosphoric acid, polar solvents such as acetonitrile, methanol, ethanol, isopropanol,
Examples thereof include alcohols such as tert-butanol, water and the like.

Examples of the acid include formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, bromic acid, sulfuric acid and the like.

Specific examples of the aryl thiadiazole derivatives represented by the general formulas [I] and [II] are shown in Tables 1 to 26, but the present invention is not limited to these compounds.

[0153]

[Table 1]

[0154]

[Table 2]

[0155]

[Table 3]

[0156]

[Table 4]

[0157]

[Table 5]

[0158]

[Table 6]

[0159]

[Table 7]

[0160]

[Table 8]

[0161]

[Table 9]

[0162]

[Table 10]

[0163]

[Table 11]

[0164]

[Table 12]

[0165]

[Table 13]

[0166]

[Table 14]

[0167]

[Table 15]

[0168]

[Table 16]

[0169]

[Table 17]

[0170]

[Table 18]

[0171]

[Table 19]

[0172]

[Table 20]

[0173]

[Table 21]

[0174]

[Table 22]

[0175]

[Table 23]

[0176]

[Table 24]

[0177]

[Table 25]

[0178]

[Table 26]

The aryl thiadiazole derivatives represented by the general formulas [I] and [II] and salts thereof have useful pharmacological properties, particularly antiviral action, and a pharmaceutical composition containing them is It is useful for prophylactic or therapeutic treatment of humans infected or at risk of being infected with the virus.

Examples of viruses to which the antiviral agent of the present invention is applied include, in the case of DNA type viruses, Herpes simplex virus type 1 (Herpes simplex vi) of the Herpesvirus family (Herpesviridae).
Rus type 1), Herpes simplex virus type 2 (Herpes simplex virus type)
e 2), human cytomegalovirus (Human
cytomegalovirus, Epstein-Barr virus
s), Varicella zoster virus (Varicella z)
oster virus, herpes virus type 6 (H
human apesvirus 6), human adenovirus of the adenovirus family (Adenoviridae), hepatitis B virus of the Hepadnaviridae family (Hepatitis B virrue)
s), papovaviridae (Papovavirida)
e) human papillomavirus (Human papi)
Illoma virus) and the like.

[0181] In addition, the RNA viruses of the present invention include Rubella virus of the Togaviridae family and Japanese encephalitis virus.
is virus), hepatitis C virus (Hepati)
tis C virus), Paramyxoviridae (P
aramyxoviridae measles virus (M
easys virus), RS virus (Resp
iratery syncy virus),
Mumps virus, Orthomyxoviridae (Orthomyxovirid)
ae) influenza virus (Influenza)
virus, Rhabdoviridae (Rhabdovi)
rabies virus (Rabies vir)
us), Retroviridae (Retrovirida)
e) T cell leukemia virus (Human T-lym)
phototropic virus, human immunodeficiency virus (Human immunodeficiency)
virus), Picornavirus family (Picorna)
human poliovirus (Human)
Polio virus, hepatitis A virus (Hep)
atitis A virus) and the like. Among them, it is particularly effective against human immunodeficiency virus (HIV).

When the aryl thiadiazole derivative represented by the general formula [I] and / or [II] and / or a salt thereof is used as an antiviral agent, oral administration, parenteral administration (subcutaneous, intravenous, intramuscular, sternum injection) Etc.) or rectal administration. In this case, the aryl thiadiazole derivative represented by the general formula [I] and / or [II] and / or a salt thereof is administered in the form of a preparation prepared by mixing with an appropriate pharmaceutical carrier. As the form of the preparation, tablets, granules, fine granules, powders, capsules, injections, eye drops, eye ointments or suppositories are used. The amount of active ingredient contained in the formulation is about 0.01-99.99%. The dose varies depending on the type of virus to be treated, symptoms, age, and administration method, but is usually about 0.
It is 01 to 500 mg / kg / day.

[0183]

INDUSTRIAL APPLICABILITY The aryl thiadiazole derivatives represented by the general formulas [I] and [II] and salts thereof have an antiviral action and are useful as an antiviral agent.

[0184]

EXAMPLES Next, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

Example 1 N, N-Dimethyl [3- (3-amino-2,6-dic
Lolophenyl) -1,2,5-thiadiazol-4-i
L] Carbamate Production (Compound No. 70) N, N-Dimethyl [3- (2,6-dichloro-3-
Nitrophenyl) -1,2,5-thiadiazole-4-
[Ill] carbamate (100 mg) dissolved in ethanol (10 ml) was added with platinum oxide (10 mg) and acetic acid (0.1 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere. After 2 hours, the reaction mixture was filtered through Celite. The filtrate is concentrated and then purified by silica gel preparative thin layer chromatography to obtain N, N
80 mg of dimethyl [3- (3-amino-2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate were obtained.

Melting point: 120 to 123 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
2.90 (s, 3H), 2.95 (s, 3H), 4.3
(Br s, 2H), 6.80 (d, J = 9 Hz, 1
H), 7.16 (d, J = 9 Hz, 1H) IR (KBr, cm ^-1 ): 3480, 3460, 339
0,3350,1740,1620,1460,137
0, 1325, 1220, 1150, 815 Examples 2 to 5 show physical properties of representative compounds obtained by the same method as in Example 1.

Example 2 N, N-dimethyl [3- (5-amino-2-chlorophenyl)
Phenyl) -1,2,5-thiadiazol-4-yl] ca
-Bamate (Compound No. 21) Melting point: 121-124 ° C ¹ H-NMR (solvent: CDCl ₃ , unit: δppm):
2.93 (s, 3H), 3.03 (s, 3H), 3.4
(Br s, 2H), 6.70 (dd, J = 3, 8.5
Hz, 1H), 6.76 (d, J = 3Hz, 1H),
7.22 (d, J = 8.5 Hz, 1H) IR (KBr, cm ⁻¹ ): 3440, 3340, 173
0,1595,1455,1375,1160,810

Example 3 N-methyl-N-propyl [3- (3-amino-2-
Chloro-6-fluorophenyl) -1,2,5-thiadi
Azol-4-yl] carbamate (Compound No. 99) oily substance ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.80 (t, J = 7.5 Hz), 0.81 (t, J
= 7.5 Hz), 3H)], [1.48 (sexte
t, J = 7.5 Hz), 1.50 (sextet, J =
7.5 Hz), 2 H), [2.91 (s), 2.95.
(S), 3H], [3.20 (t, J = 7.5 Hz),
3.25 (t, J = 7.5 Hz), 2H], 3.9 (b
rs, 2H), 6.7 to 7.1 (m, 2H) IR (neat, cm ^-1 ): 3470, 3360, 17
35, 1475, 1385, 1210, 1150

Example 4 N-methyl-N-propyl [3- (3-amino-2,
6-dichlorophenyl) -1,2,5-thiadiazole
-4-yl] Carbamate (Compound No. 71) Oil ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.75 (t, J = 7.5 Hz), 0.76 (t, J
= 7.5 Hz), 3H)], [1.44 (sexte
t, J = 7.5 Hz), 1.45 (sextet, J =
7.5 Hz), 2H], [2.89 (s), 2.90.
(S), 3H], [3.16 (t, J = 7.5 Hz),
3.21 (t, J = 7.5 Hz), 2H], 4.26
(Br s, 2H), [6.78 (d, J = 9 Hz),
6.79 (d, J = 9 Hz), 1H], 7.14 (d,
J = 9 Hz, 1H) IR (neat, cm ⁻¹ ): 3480, 3360, 17
40, 1620, 1460, 1380, 1220, 11
Fifty

Example 5 N-Methyl-N-propyl [3- (5-amino-2-
Chlorophenyl) -1,2,5-thiadiazole-4-
Yl] carbamate (Compound No. 22) oil ¹ H-NMR (solvent: CDCl _3, unit: [delta] ppm):
[0.81 (t, J = 7.5 Hz), 0.83 (t, J
= 7.5 Hz), 3H)], [1.50 (sexte
t, J = 7.5 Hz), 1.53 (sextet, J =
7.5 Hz), 2 H), [2.91 (s), 2.99
(S), 3H], [3.20 (t, J = 7.5 Hz),
3.29 (t, J = 7.5 Hz), 2H], 3.70
(Br s, 2H), [6.68 (dd, J = 3, 8.
5 Hz), 6.74 (d, J = 3 Hz), 6.75
(D, J = 3 Hz), 1H], 7.20 (d, J = 8.
5 Hz, 1 H) IR (neat, cm ^-1 ): 3460, 3360, 17
35, 1460, 1390, 1305, 1210, 11
Fifty

Example 6 N1-diethyl-N2- [3- (2,6-dichlorophene)
Nyl) -1,2,5-thiadiazol-4-yl] phor
Production of Muamidine (Compound No. 130) 0.2 g of N, N-diethylformamide was added to 1 m of benzene.
0.15 g of phosphorus oxychloride was added to the solution dissolved in 1 and stirred at room temperature for 12 hours. 0.12 g of 3- (2,6-dichlorophenyl) -4-amino-1,2,5-thiadiazole was added to the reaction mixture, and the mixture was heated under reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into water and extracted with ether. The ether layer was washed twice with 10% sodium hydrogen carbonate and water, respectively. The extract was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography to give N1-diethyl-N2- [3- (2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] formamidine. 0.15 g was obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
1.00 (t, J = 7 Hz, 3H), 1.17 (t, J
= 7 Hz, 3 H), [3.28 (q, J = 7 Hz),
3.30 (q, J = 7 Hz), 4H], 7.2-7.4
(M, 3H), 8.32 (s, 1H) IR (neat, cm ^-1 ): 1610, 1485, 14
60, 1425, 1395, 1360, 1125, 79
5 Physical properties of representative compounds obtained by the same method as in Example 6 are shown in Examples 7 to 10.

Example 7 N ¹ -Dimethyl-N ^2- [3- (2,6-dichlorophenyl)
L) -1,2,5-thiadiazol-4-yl] form
Amidine (Compound No. 127) Melting point: ^{100 to} 103 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
2.88 (s, 3H), 3.04 (s, 3H), 7.2
~ 7.4 (m, 3H), 8.35 (s, 1H) IR (KBr, cm ^-1 ): 1630, 1505, 147
0, 1430, 1390, 1120, 1105, 795

Example 8 N ¹ -methyl-N ¹ -propyl-N ^2- [3- (2,6-
Dichlorophenyl) -1,2,5-thiadiazole-4
-Yl] formamidine (Compound No. 128) oily substance ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
0.73 (t, J = 7Hz, 1H), 0.88 (t, J
= 7 Hz, 2H), 1.4 to 1.7 (m, 2H), 2.
86 (s, 2H), 3.02 (s, 1H), 3.25
(Q, J = 7 Hz, 2H), 7.2-7.4 (m, 3
H), 8.35 (s, 1H) IR (neat, cm ^-1 ): 1615, 1490, 14
65, 1430, 1390, 1125, 795

Example 9 N ¹ -Diethyl-N ^2- [3- (2,6-dichlorophenyl)
Ru) -1,2,5-thiadiazol-4-yl] aceto
Amidine (Compound No. 131) Melting point: 39-40 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
0.85 (br s, 3H), 1.11 (br s, 3)
H), 2.20 (s, 3H), 3.29 (q, J = 7H
z, 4H), 7.2-7.4 (m, 3H) IR (KBr, cm ^-1 ): 1560, 1550, 142
5,1390,1355,790

Example 10 N ¹ -Diethyl-N ^2- [3- (2,6-dichlorophenyl)
Le) -1,2,5-thiadiazol-4-yl] benz
Amidine (Compound No. 132) Melting point: 54-55 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
0.99 (t, J = 7 Hz, 6H), 3.03 (br
q, J = 7 Hz, 2H), 3.49 (br q, J = 7)
Hz, 2H), 7.1-7.5 (m, 8H) IR (KBr, cm ^-1 ): 1565, 1555, 142
5,1390,1360,790,780

Example 11 4- (2-chlorophenyl) -1,2,5-thiadiazo
Production of benzyl-3 -carboxylic acid (Compound No. 163) 3-Bromo-4- (2-chlorophenyl) -1,2,5
-Thiadiazole 280 mg, copper cyanide 180 mg in 1,3-dimethyl-2-imidazolidinone, 150
The mixture was stirred at C for 12 hours. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with diluted sodium hydroxide and water. It is dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography to give 3- (2-chlorophenyl) -4.
120 mg of -cyano-1,2,5-thiadiazole was obtained. Then, the obtained 3- (2-chlorophenyl) -4-
Cyano-1,2,5-thiadiazole 120 mg, 5%
6 ml of sodium hydroxide was heated to reflux in 2 ml of ethanol for 1 hour. After allowing to cool, the reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed with water. Dry over anhydrous magnesium sulfate, concentrate and then purify by silica gel column chromatography.
4- (2-Chlorophenyl) -1,2,5-thiadiazole-3-carboxylic acid (100 mg) was obtained.

Melting point: 112 to 114 ° C. IR (KBr, cm ⁻¹ ): 3600 to 2400,170
5,1270,1240,1165,750 Elemental analysis (%): Calculated as C ₉ H ₅ ClN ₂ O ₂ S: C; 44.92, H; 2.09, N; 11.6
4 Found: C; 44.64, H; 2.19, N; 11.5.
2 Physical properties of representative compounds obtained by the same method as in Example 11 are shown in Examples 12 to 22.

Example 12 4- (3-chlorophenyl) -1,2,5-thiadiazo
Ol -3-carboxylic acid (Compound No. 164) Melting point: 163-165 [deg.] C. IR (KBr, cm < ^-1 >): 3200-2400,170
0, 1460, 1270, 1160, 770 Elemental analysis (%): Calculated as C ₉ H ₅ ClN ₂ O ₂ S: C; 44.92, H; 2.09, N; 11.6
4 Found: C; 44.94, H; 2.38, N; 11.8.
Four

Example 13 4- (4-chlorophenyl) -1,2,5-thiadiazo
Ol -3-carboxylic acid (Compound No. 165) Melting point: 157-158 [deg.] C. IR (KBr, cm < ^-1 >): 3300-2400,170
0,1465,1440,1295,1160,109
0,820 Elemental analysis (%): Calculated as C ₉ H ₅ ClN ₂ O ₂ S: C; 44.92, H; 2.09, N; 11.6
4 Found: C; 44.68, H; 2.32, N; 11.5.
1

Example 14 4- (2-Tolyl) -1,2,5-thiadiazole-3
-Carboxylic acid (Compound No. 166) Melting point: 119 to 121 ° C IR (KBr, cm ^-1 ): 3300 to 2400, 170
0, 1460, 1450, 1260, 1155, 85
0,765,745 Elemental analysis (%): Calculated as C ₁₀ H ₈ N ₂ O ₂ S: C; 54.53, H; 3.66, N; 12.7
2 Found: C; 54.29, H; 3.89, N; 12.7.
1

Example 15 4- (3-tolyl) -1,2,5-thiadiazole-3
-Carboxylic acid (Compound No. 167) Melting point: 118-120 ° C IR (KBr, cm ^-1 ): 3200-2400, 170
0,1460,1450,1280,1140,770 Elemental analysis _{(%): C 10 H 8} N 2 O 2 S Calculated: C; 54.53, H; 3.66 , N; 12.7
2 Found: C; 54.42, H; 3.56, N; 12.7.
1

Example 16 4- (4-tolyl) -1,2,5-thiadiazole-3
-Carboxylic acid (Compound No. 168) Melting point: 128-130 ° C IR (KBr, cm ^-1 ): 3300-2400, 170
0, 1455, 1435, 1295, 1150 Elemental analysis (%): Calculated as C ₁₀ H ₈ N ₂ O ₂ S: C; 54.53, H; 3.66, N; 12.7
2 Found: C; 54.33, H; 3.62, N; 12.5.
9

Example 17 4- (3-Fluorophenyl) -1,2,5-thiadia
Sol -3-carboxylic acid (Compound No. 170) Melting point: 153-156 ° C. IR (KBr, cm ⁻¹ ): 3200-2400,170
0,1460,1210,870,855,770 Elemental analysis (%): Calculated as C ₉ H ₅ FN ₂ O ₂ S: C; 48.21, H; 2.25, N; 12.4
9 Found: C; 48.04, H; 2.54, N; 12.6.
9

Example 18 4- (4-Fluorophenyl) -1,2,5-thiadia
Zol-3-carboxylic acid (Compound No. 171) Melting point: 165 to 166 [deg.] C. IR (KBr, cm < ^-1 >): 3300 to 2400,170
0,1460,1440,1220,1160,830 Elemental analysis (%): Calculated as C ₉ H ₅ FN ₂ O ₂ S: C; 48.21, H; 2.25, N; 12.4
9 Found: C; 47.97, H; 2.47, N; 12.4.
8

Example 19 4- (3-trifluoromethylphenyl) -1,2,5
-Thiadiazole-3-carboxylic acid (Compound No. 17
3) Melting point: 122 to 124 ° C. IR (KBr, cm ⁻¹ ): 3200 to 2400, 170
0, 1325, 1295, 1155, 1110 Elemental analysis (%): Calculated as C ₁₀ H ₅ F ₃ N ₂ O ₂ S: C; 43.80, H; 1.84, N; 10.2
2 Found: C; 43.63, H; 2.13, N; 10.4.
1

Example 20 4- (4-trifluoromethylphenyl) -1,2,5
-Thiadiazole-3-carboxylic acid (Compound No. 17
4) Melting point: 135 to 137 ° C. IR (KBr, cm ⁻¹ ): 3200 to 2400, 170
0, 1460, 1320, 1160, 1110 Elemental analysis (%): Calculated as C ₁₀ H ₅ F ₃ N ₂ O ₂ S: C; 43.80, H; 1.84, N; 10.2
2 Found: C; 43.56, H; 2.06, N; 10.2
0

Example 21 4- (3-Nitrophenyl) -1,2,5-thiadiazo
Ol -3-carboxylic acid (Compound No. 176) Melting point: 193-194 [deg.] C. IR (KBr, cm < ^-1 >): 3400-2400,170
5,1525,1465,1340 Elemental analysis _{(%): C 9 H 5} N 3 O 4 S Calculated: C; 43.03, H; 2.01 , N; 16.7
3 Found: C; 42.86, H; 2.29, N; 16.9.
Two

Example 22 4- (4-methoxyphenyl) -1,2,5-thiadia
Sol -3-carboxylic acid (Compound No. 180) Melting point: 118-120 ° C. IR (KBr, cm ⁻¹ ): 3200-2400,170
0,1605,1460,1440,1250,115
5 Elemental analysis (%): Calculated as C ₁₀ H ₈ N ₂ O ₃ S: C; 50.84, H; 3.41, N; 11.8
6 Found: C; 50.60, H; 3.64, N; 11.8.
5

Example 23 N-methyl-N-propyl 4- (2-chlorophenyl)
) -1,2,5-thiadiazole-3-carboxaal
Preparation of amide (Compound No. 195) 50 mg of 4- (2-chlorophenyl) -1,2,5-thiadiazole-3-carboxylic acid was added to 1 ml of dichloromethane.
70 mg of thionyl chloride was added to the solution dissolved in and stirred for 1 hour. After allowing to cool to room temperature, unreacted thionyl chloride was distilled off under reduced pressure, 1 ml of dichloromethane and 73 mg of methylpropylamine were added to the residue, and the mixture was stirred at room temperature. After 6 hours, the reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed twice with diluted hydrochloric acid, 10% sodium hydrogen carbonate and water, respectively. The extract was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel preparative thin layer chromatography to obtain N-methyl-N-propyl 4-.
50 mg of (2-chlorophenyl) -1,2,5-thiadiazole-3-carboxamide was obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.85 (t, J = 7.5 Hz), 0.88 (t, J
= 7.5 Hz), 3 H], 1.5 to 1.8 (m, 2
H), [3.02 (s), 3.03 (s), 3H),
[3.21 (t, J = 7.5 Hz), 3.21 (dd,
J = 6,9 Hz), 1H], [3.43 (t, J = 7.
5 Hz), 3.43 (dd, J = 6,9 Hz), 1
H], 7.3 to 7.6 (m, 4H) The physical properties of representative compounds obtained by the same method as in Example 23 are shown in Examples 24 to 25.

Example 24 N-methoxy-N-methyl 4-phenyl-1,2,5
-Thiadiazole-3-carboxamide (compound number
194) ¹ H-NMR (solvent: CDCl ₃ , unit: δppm):
3.3 (s, 3H), 3.5 (s, 3H), 7.2-
7.9 (m, 5H) IR (KBr, cm ^-1 ): 1655, 1480, 143
0,1360,970,750

Example 25 N- (4-chloro-2-fluorophenyl) 4- (4
-Chlorophenyl) -1,2,5-thiadiazole-3
-Carboxamide (Compound No. 198) ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
7.0-7.8 (m, 6H), 8.3 (t, J = 8H
z, 1H), 9.1 (br s, 1H) IR (KBr, cm ⁻¹ ): 1690, 1590, 152
0,1480,1410,820

Example 26 {3- (2-chlorophenyl) -1,2,5-thiadia
Preparation of Zol-4-yl} acetic acid (Compound No. 185) 3-Bromomethyl-4- (2-chlorophenyl) -1,
290 mg of 2,5-thiadiazole and 49 mg of sodium cyanide were added to 90% in N, N-dimethylformamide.
The mixture was stirred at ℃ for 3 hours. After cooling, the reaction mixture was poured into water,
It was extracted with diethyl ether. The diethyl ether layer was washed with diluted sodium hydroxide and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to obtain 150 mg of 3- (2-chlorophenyl) -4-cyanomethyl-1,2,5-thiadiazole. Then, the obtained 3- (2-chlorophenyl) -4
-Cyanomethyl-1,2,5-thiadiazole 150 m
g, 5% sodium hydroxide 6 ml, ethanol 2 ml
The mixture was heated under reflux for 1 hour. After allowing to cool, the reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed with water. The extract was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography to obtain {3- (2-chlorophenyl) -1,2,5-
120 mg of thiadiazol-4-yl} acetic acid was obtained. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
3.95 (s, 2H), 7.3 to 7.6 (m, 3H),
8.4 (br s, 1H)

Example 27 N-methyl-N-propyl [3- (2-chlorophenyl
Ru) -1,2,5-thiadiazol-4-yl] aceto
Preparation of amide (Compound No. 202) 30 mg of [3- (2-chlorophenyl) -1,2,5-thiadiazol-4-yl] acetic acid was added to 1 m of dichloromethane.
To the solution dissolved in 1 was added thionyl chloride 60 mg, 1
Stirred for hours. After allowing to cool to room temperature, unreacted thionyl chloride was distilled off under reduced pressure, 1 ml of dichloromethane and 73 mg of methylpropylamine were added to the residue, and the mixture was stirred at room temperature. 6
After hours, the reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed twice with diluted hydrochloric acid, 10% sodium hydrogen carbonate and water, respectively. The extract was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel preparative thin layer chromatography to give N-methyl-N-propyl [3
20 mg of-(2-chlorophenyl) -1,2,5-thiadiazol-4-yl] acetamide was obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.82 (t, J = 7.5 Hz), 0.83 (t, J
= 7.5 Hz), 3H], 1.3 to 1.6 (m, 2
H), [2.86 (s), 2.97 (s), 3H],
[3.21 (t, J = 7.5 Hz), 3.28 (t, J
= 7.5 Hz), 2H], 3.92 (s, 2H), 7.
3 to 7.6 (m, 4H)

Example 28 N- (3-carboxypropyl) -N-methyl [3-
(2,6-dichlorophenyl) -1,2,5-thiadia
[Zol-4-yl] carbamate (Compound No. 2
22) 3- (2,6-dichlorophenyl) -4-hydroxy-
170 mg of pyridine was added to a solution prepared by dissolving 490 mg of 1,2,5-thiadiazole and 210 mg of bis (trichloromethyl) carbonate in 10 ml of dichloromethane, and the mixture was stirred at room temperature. After 12 hours, 340 mg of 4- (methylamino) butyric acid hydrochloride and 570 mg of N, N-diisopropylethylamine were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane.
The dichloromethane layer was washed with diluted hydrochloric acid and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to give N- (3-carboxypropyl) -N-methyl [3- (2,6-dichlorophenyl) -1,2,5-thiadiazole- 4-yl] carbamate (510 mg) was obtained.

Melting point: 125-126 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
1.6-1.9 (m, 2H), 2.1-2.3 (m, 2)
H), [2.90 (s), 2.95 (s), 3H],
[3.26 (t, J = 7.0 Hz), 3.32 (t, J
= 7.0 Hz), 2H], 7.2-7.5 (m, 3
H), 8.5 (brs, 1H) IR (KBr, cm ^-1 ): 3400 to 2400, 174
0, 1700, 1430, 1380, 1295, 123
0,1180,790 Physical properties of representative compounds obtained by the same method as in Example 28 are shown in Example 29.

Example 29 N- (cyanomethyl) -N-methyl [3- (2,6-
Dichlorophenyl) -1,2,5-thiadiazole-4
-Yl] carbamate (Compound No. 218) Melting point: 106-107 ° C ¹ H-NMR (solvent: CDCl ₃ , unit: δppm):
[3.02 (s), 3.09 (s), 3H], [4.20 (s), 4.25 (s), 2H], 7.3 ~ 7.
5 (m, 3H) IR (KBr, cm ^-1 ): 2250, 1745, 143
0, 1380, 1280, 1230, 1205, 113
5,790,770

Example 30 N- (2-Cyanoethyl) -N-methyl [3- (2,
6-dichlorophenyl) -1,2,5-thiadiazole
Preparation of -4-yl] carbamate (Compound No. 219) 3- (2,6-dichlorophenyl) -4-hydroxy-
1,98 g of 1,2,5-thiadiazole and 0.8 g of bis (trichloromethyl) carbonate were added to dichloromethane 5
0.7 g of pyridine was added to the solution dissolved in 0 ml, and the mixture was stirred at room temperature. After 12 hours, N- (2-cyanoethyl)
1.51 g of -N-methylamine was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with diluted hydrochloric acid, 10% sodium hydrogen carbonate and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to give N- (2-cyanoethyl) -N-methyl [3
2.8 g of-(2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate were obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[2.46 (t, J = 6.5 Hz), 2.51 (t, J
= 6.5 Hz), 2H], [3.04 (s), 3.12
(S), 3H], [3.49 (t, J = 6.5 Hz),
3.59 (t, J = 6.5 Hz), 2H], 7.3-
7.55 (m, 3H) IR (neat, cm ^-1 ): 2250, 1740, 14
30, 1380, 1230, 1195, 1125, 79
0 Physical properties of representative compounds obtained by the same methods as in Example 30 are shown in Example 31.

Example 31 N- (2-hydroxyethyl) -N-methyl [3-
(2,6-dichlorophenyl) -1,2,5-thiadia
Zol-4-yl] carbamate (Compound No. 220) Melting point: 105-106 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
2.1 (br s, 1H), [2.97 (s), 3.0
2 (s), 3H], [3.36 (t, J = 5.5H
z), 3.41 (t, J = 5.5 Hz), 2H], 3.
64 (t, J = 5.5 Hz, 2H), 7.3 to 7.5
(M, 3H) IR (KBr, cm ^-1 ): 3550, 1725, 143
0, 1380, 1220, 1130, 790 The physical properties of the compound obtained by the same method as in Example 30 are shown in Examples 32 and 33.

Example 32 N-methyl-N-propyl [3- (2,6-dichloro
-3-Cyanophenyl) -1,2,5-thiadiazole
-4-yl] carbamate (Compound No. 87) Oil ¹ H-NMR (solvent: CDCl ₃ , unit: δppm):
[0.76 (t, J = 7.4 Hz), 0.80 (t, J
= 7.4 Hz), 3H], [1.46 (sextet,
J = 7.4 Hz), 1.50 (sextet, J = 7.
4Hz), 2H], [2.89 (s), 2.96.
(S), 3H], [3.18 (t, J = 7.4 Hz),
3.25 (t, J = 7.4 Hz), 2H], 7.55
(D, J = 8.5 Hz, 1H), [7.71 (d, J =
8.5 Hz), 7.73 (d, J = 8.5 Hz), 1
H] IR (neat, cm ^-1 ): 2230, 1740, 13
95, 1365, 1145

Example 33 N-methyl-N-propyl [3- (2,6-dichloro
-3-Methoxycarbonylphenyl) -1,2,5-thi
Asiazol-4-yl] carbamate (Compound No. 9
1) Oily substance ¹ H-NMR (solvent: CDCl ₃ , unit: δppm): [0.
75 (t, J = 7.4 Hz), 0.77 (t, J = 7.
4Hz), 3H], [1.40 (t, J = 7.4Hz,
3H), 1.45 (sextet, J = 7.4Hz, 2
H), [2.90 (s), 2.93 (s), 3H],
[3.18 (t, J = 7.4 Hz), 3.22 (t, J
= 7.4 Hz), 2H], 4.41 (q, J = 7.4H)
z, 2H), 7.48 (d, J = 8.4Hz, 1H),
[7.83 (d, J = 8.4 Hz), 7.85 (d, J
= 8.4 Hz), 1H] IR (neat, cm ^-1 ): 1750, 1745, 13
95, 1365, 1300, 1280, 1220, 11
80,1145

Example 34 N-methyl-N-propyl [3- (3-carbamoyl)
-2,6-Dichlorophenyl) -1,2,5-thiadia
[Zol-4-yl] carbamate (Compound No. 9
3) 3- (3-carbamoyl-2,6-dichlorophenyl)
-4-Hydroxy-1,2,5-thiadiazole 80m
g, potassium carbonate 41 mg, and N-methyl-N-propylcarbamoyl chloride 41 mg in acetonitrile,
The mixture was heated under reflux for 2 hours. After allowing to cool, the reaction mixture was poured into dilute hydrochloric acid and extracted with ether. The ether layer was washed with water and saturated saline. Dry over anhydrous magnesium sulfate, concentrate and then purify by silica gel column chromatography.
41 mg of N-methyl-N-propyl [3- (3-carbamoyl-2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate were obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.78 (t, J = 7.3 Hz, 3H), 1.48
(Sextet, J = 7.3 Hz, 2H), [2.90
(S), 2.94 (s), 3H], [3.18 (t, J
= 7.3 Hz), 3.23 (t, J = 7.3 Hz), 2
H], [6.21 (bs), 6.31 (bs), 2
H], 7.50 (d, J = 8.4 Hz, 1H), [7.
78 (d, J = 8.4 Hz), 7.80 (d, J = 8.
4 Hz), 1H] IR (neat, cm ^-1 ): 3450, 3330, 32
00, 1735, 1670, 1400, 1360, 12
25,1150 The physical properties of the compound obtained by the same method as in Example 34 are shown in Example 35.

Example 35 N-methyl-N-propyl [3- (3-carboxyl
-2,6-Dichlorophenyl) -1,2,5-thiadia
Zol-4-yl] carbamate (Compound No. 89) Oil ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[0.66 (t, J = 7.6 Hz), 0.71 (t, J
= 7.6 Hz), 3 H], 1.2 to 1.5 (m, 2
H), [2.69 (s), 2.83 (s), 3H],
2.9 to 3.2 (m, 2H), 7.26 (d, J =
8.1 Hz, 1 H), 7.5-7.7 (m, 1 H) IR (neat, cm ^-1 ): 3700-3100, 17
40, 1600, 1400, 1390, 1360, 12
30,1150

Example 36 N- (2-carbamoylethyl) -N-methyl [3-
(2,6-dichlorophenyl) -1,2,5-thiadia
[Zol-4-yl] carbamate (Compound No. 2
23) N- (2-cyanoethyl) -N-methyl [3- (2,
6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate (360 mg) with ethanol (3 m)
6 ml of concentrated hydrochloric acid was added to the solution dissolved in l,
Stirred for hours. The reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with diluted hydrochloric acid and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography to give N- (2-carbamoylethyl) -N-methyl [3- (2,6-dichlorophenyl) -1,2,5-thiadiazole- 4-yl] carbamate 240 mg was obtained.

Melting point: 160 to 161 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[2.40 (t, J = 7.0 Hz), 2.44 (t, J
= 7.0 Hz), 2H], [2.95 (s), 3.00
(S), 3H], [3.52 (t, J = 7.0 Hz),
3.59 (t, J = 7.0 Hz), 2H], [5.43]
(Br s), 5.81 (br s), 2H], 7.3.
~ 7.5 (m, 3H) IR (KBr, cm ^-1 ): 3440, 3300, 320
0,1735,1680,1620,1455,143
0, 1380, 1305, 1230, 1190, 113
0,790,780

Example 37 N- (2-carboxyethyl) -N-methyl [3-
(2,6-dichlorophenyl) -1,2,5-thiadia
[Zol-4-yl] carbamate (Compound No. 2
21) N- (2-cyanoethyl) -N-methyl [3- (2,
6-Dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate (360 mg), concentrated hydrochloric acid (10 m)
1 was added, and the mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with diluted hydrochloric acid and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to give N- (2-carboxyethyl) -N-methyl.
280 mg of [3- (2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate was obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
[2.52 (t, J = 7.0 Hz), 2.53 (t, J
= 7.0 Hz), 2H], [2.96 (s), 3.01
(S), 3H], [3.49 (t, J = 7.0 Hz),
3.58 (t, J = 7.0 Hz), 2H], 7.3-
7.5 (m, 3H), 9.4 (br s, 1H) IR (neat, cm ^-1 ): 3600 to 2400, 17
60-1700, 1430, 1380, 1230, 11
90, 1120, 790

Example 38 N- {2- (ethoxycarbonyl) ethyl} -N-methyl
Ru [3- (2,6-dichlorophenyl) -1,2,5
-Thiadiazol-4-yl] carbamate
Compound number 224) N- (2-carboxyethyl) -N-methyl [3-
0.2 ml of concentrated hydrochloric acid was added to a solution of 200 mg of (2,6-dichlorophenyl) -1,2,5-thiadiazol-4-yl] carbamate dissolved in 5 ml of ethanol,
The mixture was stirred at 60 ° C for 6 hours. The reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with 10% sodium hydrogen carbonate and water. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to give N- {2- (ethoxycarbonyl) ethyl} -N-methyl [3- (2,6-dichlorophenyl) -1,2,5. 180 mg of thiadiazol-4-yl] carbamate were obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
1.23 (t, J = 7.0 Hz, 3H), [2.43
(T, J = 7.0 Hz), 2.44 (t, J = 7.0H
z), 2H], [2.92 (s), 2.98 (s), 3
H], [3.47 (t, J = 7.0 Hz), 3.56
(T, J = 7.0 Hz), 2H], 4.10 (q, J =
7.0 Hz, 2 H), 7.3 to 7.5 (m, 3 H) IR (neat, cm ⁻¹ ): 1760 to 1720, 14
30, 1380, 1230, 1190, 1120, 79
0

Example 39 3- (2-Bromoethoxy) -4- (2,6-dichloro)
Production of phenyl) -1,2,5-thiadiazole (compound
No. 160) 3- (2,6-dichlorophenyl) -4-hydroxy-
0.49 g of 1,2,5-thiadiazole, 0.3 g of potassium carbonate and 1.9 g of 1,2-dibromoethane were stirred in acetonitrile at 80 ° C. for 1 hour. After allowing to cool, the reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with diluted hydrochloric acid, 10% sodium hydrogen carbonate and water. After drying over anhydrous magnesium sulfate, concentrating and purifying by silica gel column chromatography, 3- (2
1.04 g of -bromoethoxy) -4- (2,6-dichlorophenyl) -1,2,5-thiadiazole was obtained.

Melting point: 60 to 61 ° C. ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
3.63 (t, J = 6.5 Hz, 2H), 4.77
(T, J = 6.5 Hz, 2H), 7.3 to 7.5 (m,
3H) IR (KBr, cm ^-1 ): 1485, 1430, 141
0, 1360, 1290, 1245, 790

Example 40 3- (2,6-Dichlorophenyl) -4- {2- (N-
Methyl-N-propylamino) ethoxy} -1,2,5
-Production of thiadiazole (Compound No. 161) 0.35 g of 3- (2-bromoethoxy) -4- (2,6-dichlorophenyl) -1,2,5-thiadiazole,
0.3 g of N-methyl-propylamine was stirred in dimethoxyethane at 50 ° C. for 6 hours. After concentrating the reaction mixture,
Purified by silica gel column chromatography, 3-
0.2 g of (2,6-dichlorophenyl) -4- {2- (N-methyl-N-propylamino) ethoxy} -1,2,5-thiadiazole was obtained.

Oily ¹ H-NMR (solvent: CDCl ₃ , unit: δ ppm):
0.81 (t, J = 7.5 Hz, 3H), 1.41 (s
extet, J = 7.5 Hz, 3H), 2.25 (s,
3H), 2.32 (t, J = 7.5Hz, 2H), 2.
76 (t, J = 6.0 Hz, 2H), 4.53 (t, J
= 6.0 Hz, 2H), 7.2 to 7.45 (m, 3H) IR (neat, cm ^-1 ): 3000 to 2700, 15
20, 1490, 1430, 1245, 1025, 79
0

Example 41 Antiviral Testing Against HIV 20 mM Hepes buffer, 10% fetal bovine serum, and 2
RPMI 1640 containing 0 μg / ml gentamicin
3 × 10 ⁴ MT-4 cells (cells that die when infected with HIV) in the medium were infected with 0.02 HIV per cell, and immediately the thiadiazole derivative having the compound number shown in Table 2 was infected. Add a specified amount of the sample containing
It was cultured in. Five days after the culture, the living cells were measured by the MTT method to determine the compound concentration (EC ₅₀ ) required to prevent the cell death of MT-4 cells by 50%. Further, the cells were cultured in the same manner as above without being infected with HIV, and the compound concentration (CC ₅₀ ) at which 50% of MT-4 cells were killed was determined. Furthermore, from the EC ₅₀ and CC ₅₀ , the safety factor (SI (= CC ₅₀ / E
C ₅₀ )) was determined. The results are shown in Tables 27 and 28.

[0239]

[Table 27]

[0240]

[Table 28]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 417/12 211 211 213 // (C07D 417/12 213: 16) (C07D 417/12 211: 14) (72) Inventor Tomoyuki Yokota 20-1 Kitashitasato, Hirano, Iizaka-cho, Fukushima-shi, Fukushima Prefecture (72) Hiromitsu Takayama 3-7-15 Todoroki, Inage-ku, Chiba-shi 4-102 (72) ) Inventor Shinichiro Sakai 1075-13 Hoshikuki, Chuo-ku, Chiba City, Chiba Prefecture (72) Inventor Yasuaki Hanasaki 4-26-5, Shonandai, Fujisawa City, Kanagawa Prefecture Sun Palace 204 204 (72) Teruhiko Ide Shonandai, Fujisawa City, Kanagawa Prefecture 4-26-5 Sun Palace Shonan 403 (72) Inventor Hiroyuki Watanabe 2-15-4-208 Doi, Shinnanyo-shi, Yamaguchi Prefecture Inventor Kimio Katsuura 2-23-3 Nishiochiai, Shinjuku-ku, Tokyo

Claims (8)

[Claims] 1. A compound represented by the general formula [I]: [Wherein Y ¹ is an oxygen atom or a sulfur atom, W is an oxygen atom or a sulfur atom, and ^one of R ¹ , R ² and R ³ is (an alkyl group having 1 to 6 carbon atoms and Or may be replaced by two)
Amino group, carboxyl group, carbonyl group (substituted by alkoxy group having 1 to 4 carbon atoms), (may be independently substituted by 1 or 2 by alkyl group having 1 to 6 carbon atoms)
Carbamoyl group, cyano group or {hydroxy group, alkoxy group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms (substituted by alkoxy group having 1 to 4 carbon atoms) or (alkyl having 1 to 6 carbon atoms) Substituted by a silyloxy group), the alkyl group having 1 to 6 carbon atoms, the remaining two of R ¹ , R ² and R ³ are the same or different and are hydrogen atoms, Halogen atom, {hydroxyl group, alkoxy group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms (substituted by alkoxy group having 1 to 4 carbon atoms) or (alkyl group having 1 to 6 carbon atoms independently And may be substituted with a silyloxy group).
Alkyl group, trifluoromethyl group, alkoxy group having 1 to 4 carbon atoms, carboxyl group, carbonyl group (substituted by alkoxy group having 1 to 4 carbon atoms), (carbon number 1 to 6)
A carbamoyl group, cyano group, hydroxy group, hydroxymethyl group, nitro group or one or two independently substituted with an alkyl group having 1 to 6 carbon atoms. Amino groups, R ⁴ and R ⁵ may be the same or different and each is a hydrogen atom, carbon number 1
~ 4 alkoxy group, {alkoxy group having 1 to 4 carbon atoms,
A hydroxy group, a cyano group, a carboxyl group, a carbamoyl group or a carbonyl group (which may be substituted with an alkoxy group having 1 to 4 carbon atoms) may be substituted} an alkyl group having 1 to 6 carbon atoms, Or R ⁴ and R ⁵ are linked to each other R ⁶ , R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or 1 carbon atom.
To 4 alkoxy groups, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, E is -CH ₂ - or an oxygen atom, n ¹ is an integer of 0 to 2. ] The aryl thiadiazole derivative or its salt represented by these. 2. An antiviral agent containing the aryl thiadiazole derivative or its salt according to claim 1 as an active ingredient. 3. A compound represented by the formula: (In the formula, R ⁹ and R ¹⁰ are the same or different and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ¹¹ , R ¹² and R ¹³ are the same or different and are a hydrogen atom, a halogen atom, and a carbon number 1 to 6 Alkyl group, trifluoromethyl group, alkoxy group having 1 to 4 carbon atoms, hydroxy group, nitro group, R ¹⁴ is a hydrogen atom, alkyl group having 1 to 6 carbon atoms or (halogen atom, alkyl group having 1 to 6 carbon atoms). Group or carbon number 1
An aryl thiadiazole derivative or a salt thereof, which represents a phenyl group which may be substituted with an alkoxy group of 4 to 4). 4. A compound represented by the formula: (In the formula, n ³ is 0 or 1, W is an oxygen atom or a sulfur atom, R ⁴ and R ⁵ are the same or different and are a hydrogen atom, and a carbon number is 1.
~ 4 alkoxy group, {alkoxy group having 1 to 4 carbon atoms,
Optionally substituted with a hydroxy group, a cyano group, a carboxyl group, a carbamoyl group or a carbonyl group (substituted with an alkoxy group having 1 to 4 carbon atoms); an alkyl group having 1 to 6 carbon atoms; Or R ⁴ and R ⁵ are linked to each other R ⁶ , R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or 1 carbon atom.
To 4 alkoxy groups, R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, E is -CH ₂ - or an oxygen atom, n ¹ is an integer of 0 to 2. R ¹¹ , R ¹² and R ¹³ are the same or different and each is a hydrogen atom, a halogen atom or a carbon number of 1 to
Represents an alkyl group, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a nitro group) or a salt thereof. 5. embedded image (In the formula, Y ¹ is an oxygen atom or a sulfur atom, W is an oxygen atom or a sulfur atom, R ¹¹ , R ¹² and R ¹³ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, tri Fluoromethyl group, alkoxy group having 1 to 4 carbon atoms, hydroxy group, nitro group, R ¹⁴ is hydrogen atom, alkyl group having 1 to 6 carbon atoms or (halogen atom, alkyl group having 1 to 6 carbon atoms or 1 carbon atom)
A phenyl group (which may be substituted with an alkoxy group of 4 to 4), R ¹⁸ is substituted with a hydroxy group, a cyano group, a carboxyl group, a carbamoyl group or a carbonyl group (which is substituted with an alkoxy group having 1 to 4 carbon atoms). Aryl thiadiazole derivative represented by the formula (1) represents an alkyl group having 1 to 6 carbon atoms or a salt thereof. 6. embedded image (In the formula, Y ¹ is an oxygen atom or a sulfur atom, n ² is 1 or 2, and R ¹¹ , R ¹² and R ¹³ are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, trifluoro Methyl group, alkoxy group having 1 to 4 carbon atoms, hydroxy group, nitro group, R ¹⁴ is hydrogen atom, alkyl group having 1 to 6 carbon atoms or (halogen atom, alkyl group having 1 to 6 carbon atoms or 1 carbon atom)
A phenyl group, which may be substituted with an alkoxy group having 4 to 4 carbon atoms, and R ¹⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, which may be substituted with an alkoxy group having 1 to 4 carbon atoms).
An aryl thiadiazole derivative represented by or a salt thereof. 7. embedded image (In the formula, R ¹¹ , R ¹² and R ¹³ are the same or different and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group or a nitro group. Group, n ³ represents 0 or 1 (provided that n ³ represents 0, R 3
¹¹ , R ¹² and R ¹³ do not represent hydrogen atoms at the same time)). 8. A compound represented by the general formula [II]: [In the formula, R ¹¹ , R ¹² and R ¹³ are the same or different and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group or a nitro group. Group, A is —Y ¹ —SO ₂ NR ⁹ R ¹⁰ , embedded image Embedded image [Chemical 15] Or R ¹⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or (a halogen atom, an alkyl group having 1 to 6 carbon atoms or 1 carbon atom).
A phenyl group, which may be substituted with an alkoxy group of -4, R ¹⁵ and R ¹⁶ are the same or different and each is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or (substituted by a halogen atom). may also be) alkyl group having 1 to 6 carbon atoms, R ¹⁷ is a halogen atom or -Y ² -R ^19, R ¹⁸ is {hydroxy group, a cyano group, a carboxyl group, a carbamoyl group, or an (alkoxy group having 1 to 4 carbon atoms in substituted) substituted by a carbonyl group} alkyl group having 1 to 6 carbon atoms, R ¹⁹ may be substituted with a hydrogen atom or an (alkoxy group having 1 to 4 carbon atoms) alkyl of 1 to 6 carbon atoms groups, J is -CH = or -N =, n ² is 1 or 2, n ³ is 0 or 1, Y ² is an oxygen atom, a sulfur atom or ^{-NR 14 -, R 4, R} 5, R 9, R ^10, R ^14, Y ¹ and W are as meaning and the It is shown. ] The antiviral agent containing the aryl thiadiazole derivative or its salt represented by these as an active ingredient.