JPH0156069B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel tetrazole derivative and a method for producing the same. The tetrazole derivative of the present invention has the following general formula (1):
It is expressed as [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a phenyl group, or a cycloalkyl group, A is a trimethylene group, and R ² is a phenyl lower alkyl group, a naphthyl group, a phenyl group (a halogen atom, a lower alkyl group, a lower alkoxy group) , having one or two substituents selected from a lower alkanoylamino group and a hydroxyl group), or thienyl, furyl, 1,2,
Heterocyclic group selected from 3,4-tetrahydroquinolyl, pyrrolyl, pyranyl, pyridyl group (1 or 2 selected from lower alkyl group, halogen atom, lower alkoxycarbonyl group, and oxo group)
may have as many substituents. However, the bonding position of the heterocycle is at a position other than a heteroatom.] The compound of the present invention has excellent anti-ulcer and anti-inflammatory effects, and is useful as an anti-ulcer agent and an anti-inflammatory agent. In this specification, lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,
Examples of cycloalkyl groups such as tert-butyl, pentyl, and hexyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; examples of phenyl lower alkyl groups include benzyl, β-phenethyl, α-phenethyl, and -Phenylpropyl, 4
-Phenylbutyl, 5-phenylpentyl, 6-
Lower alkoxy groups such as phenylhexyl groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy groups; lower alkanoylamino groups include formamide, acetamide, propionamide, butyramide, isobutyramide groups, and halogen atoms. Examples include fluorine, chlorine, bromine, and iodine atoms. Lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl groups, and the like. Substituted phenyl groups include phenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-bromphenyl, 3,4-dibromphenyl, 4-
Iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-methylphenyl, 3,4-dimethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-
Butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-isopropoxyphenyl,
3-butoxyphenyl, 3,4-dimethoxyphenyl, 4-acetylaminophenyl, 3-formylaminophenyl, 2-acetylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl , 3,4-dihydroxyphenyl, 2-chloro-6-methylphenyl and the like. Specific compounds of the present invention include, for example, the following. 1-Methyl-5-(2-methyl-3-benzoylpropyl)thio-1,2,3,4-tetrazole 5-[2-(4-acetylaminobenzoyl)
Ethyl]thio-1,2,3,4-tetrazole 5-[3-(2-acetylaminobenzoyl)
Propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[2-(4-acetylaminobenzoyl)ethyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3 -(4-acetylaminobenzoyl)propyl]thio-1,2,3,4-
Tetrazole 1-phenyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,3,4
-Tetrazole 1-methyl-5-[3-(4-isobutylaminobenzoyl)propyl]thio-1,2,3,4
-Tetrazole 1-methyl-5-[5-(2-acetylaminobenzoyl)pentyl]thio-1,2,3,4-
Tetrazole 1-cyclohexyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,
3,4-Titrazole 5-[3-(3,4-dimethoxybenzoyl)
Propyl]thio-1,2,3,4-tetrazole 5-[4-(3,4-dimethoxybenzoyl)
Butyl]thio-1,2,3,4-tetrazole 5-[5-(3,4-dimethoxybenzoyl)
Pentyl]thio-1,2,3,4-tetrazole 5-[6-(3,4-dimethoxybenzoyl)
hexyl]thio-1,2,3,4-tetrazole 1-methyl-5-[2-(3,4-dimethoxybenzoyl)ethyl]thio-1,2,3,4-tetrazole 1-methyl-5-[ 3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole 1-ethyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole 1-Methyl-5-[4-(3,4-dimethoxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[5-3,4-dimethoxybenzoyl)pentyl]thio -1,2,3,4-tetrazole 1-methyl-5-[6-(3,4-dimethoxybenzoyl)hexyl]thio-1,2,3,4-
Tetrazole 1-phenyl-5-[4-(3,4-dimethoxybenzoyl)butyl]thio-1,2,3,4-
Tetrazole 1-cyclohexyl-5-[4-(3,4-dimethoxybenzoyl)butyl]thio-1,2,
3,4-tetrazole 1-methyl-5-[3-(2-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3-chlorobenzoyl)propyl] Thio-1,2,3,4-tetrazole 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(2 -chlorobenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3,4-dichlorobenzoyl)propyl]thio-1,2,3,4-tetrazole 1- Methyl-5-[4-(3-chlorobenzoyl)butyl]thio-1,2,3,4-tetrazole 1-Methyl-5-[4-(4-chlorobenzoyl)butyl]thio-1,2,3 ,4-tetrazole 1-phenyl-5-[4-(4-chlorobenzoyl]butyl]thio-1,2,3,4-tetrazole 1-cyclopropyl-5-[4-(4-chlorobenzoyl)butyl] Thio-1,2,3,4-tetrazole 1-methyl-5-[3-(2-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3- methoxybenzoyl)propyl]thio1,2,3,4-tetrazole 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[ 4-(2-methoxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(3-methoxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1 -Methyl-5-[4-(4-methoxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(methoxybenzoyl)butyl]thio-1,2,3, 4-tetrazole 1-methyl-5-[5-(4-methoxybenzoyl)pentyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[4-(4-methoxybenzoyl)butyl]thio- 1,2,3,4-tetrazole 1-cyclopropyl-5-[4-(4-methoxybenzoyl)butyl]thio-1,2,3,4-
Tetrazole 1-Methyl-5-[3-(2-methylbenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3-methylbenzoyl)propyl]thio-1, 2,3,4-tetrazole 1-methyl-5-[3-(4-methylbenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(2-methylbenzoyl) Butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(3-methylbenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4- (4-Methylbenzoyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(4-ethylbenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl -5-[4-(4-ethylbenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(4-propylbenzoyl)butyl]thio-1,2,3, 4-tetrazole 1-phenyl-5-[4-(4-methylbenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3,4-dimethylbenzoyl)propyl] Thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[4-(4-methylbenzoyl)butyl]thio1,2,3,4-tetrazole 1-methyl-5-[5-(4- methylbenzoyl)pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(4-methylbenzoyl)hexyl]thio-1,2,3,4-tetrazole 1-methyl-5- [3-(2-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole 1-Methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole 1-Methyl-5-[4-(2-hydroxybenzoyl)butyl]thio-1,2 ,3,4-tetrazole 1-methyl-5-[4-(3-hydroxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(4-hydroxybenzoyl)butyl ]Thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(4-hydroxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[4-( 4-hydroxybenzoyl)butyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[4-(4-hydroxybenzoyl)butyl]thio-1,2,3,4
-Tetrazole 1-Methyl-5-[5-(4-hydroxybenzoyl)pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(4-hydroxybenzoyl)hexyl]thio-1 ,2,3,4-tetrazole 1-methyl-5-[3-(1-naphthoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(2-naphthoyl)propyl ]Thio-1,2,3,4-tetrazole 1-ethyl-5-[3-(1-naphthoyl)propyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[3-(2 -naphthoyl)propyl]thio-1,2,3,4-tetrazole 1-propyl-5-[3-(1-naphthoyl)
Propyl]thio-1,2,3,4-tetrazole 1-propyl-5-[3-2-naphthoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(1 -naphthoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(2-naphthoyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[ 4-(2-naphthoyl)butyl]thio-1,2,3,4-tetrazole 1-propyl-5-[4-2-naphthoyl)butyl]thio-1,2,3,4-tetrazole 1-methyl- 5-[5-(2-naphthoyl)pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(2-naphthoyl)hexyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[3-(2-naphthoyl)
Propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-( 2-Thenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3-tenoyl)propyl]thio-1,2,3,4-tetrazole 1-ethyl-5- [3-(2-Thenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(2-tenoyl)butyl]thio-1,2,3,4-tetrazole 1- Methyl-5-[4-(3-thenoyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(2-thenoyl)butyl]thio-1,2,3,4 -Tetrazole 1-propyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[5-(2-thenoyl)pentyl]thio-1,2 ,3,4-tetrazole 1-methyl-5-[6-(2-thenoyl)hexyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[3-(2-thenoyl)propyl]thio -1,2,3,4-tetrazole 1-cyclopropyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(2- tenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3 -(3-furoyl)propyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl- 5-[4-(2-furoyl)butyl]thio-1,2,3,4-tetrazole 1-Methyl-5-[4-(3-furoyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(2-furoyl)butyl]thio-1,2,3,4-tetrazole 1-propyl-5-[3-(2-furoyl)propyl]thio-1,2,3 ,4-tetrazole 1-methyl-5-[5-(2-furoyl]pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(2-furoyl)hexyl]thio-1 ,2,3,4-tetrazole 1-phenyl-5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(2-furoyl)propyl ]Thio-1,2,3,4-tetrazole 1-methyl-5-(3-benzylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-ethyl-5-(3-benzylcarbonylpropyl)thio -1,2,3,4-tetrazole 1-methyl-5-(4-benzylcarbonylbutyl)thio-1,2,3,4-tetrazole 1-ethyl-5-(4-benzylcarbonylbutyl)thio-1 ,2,3,4-tetrazole 1-propyl-5-(3-benzylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-methyl-5-(5-benzylcarbonylpentyl)thio-1,2 ,3,4-tetrazole 1-methyl-5-(6-benzylcarbonylhexyl)thio-1,2,3,4-tetrazole 1-phenyl-5-(3-benzylcarbonylpropyl)thio-1,2,3 ,4-tetrazole 1-cyclohexyl-5-(3-benzylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-methyl-5-(3-β-phenethylcarbonylpropyl)thio-1,2 ,3,4-tetrazole 1-ethyl-5-(3-β-phenethylcarbonylpropyl)thio1,2,3,4-tetrazole 1-methyl-5-(4-β-phenethylcarbonylbutyl) Thio-1,2,3,4-tetrazole 1-ethyl-5-(4-β-phenethylcarbonylbutyl)thio-1,2,3,4-tetrazole 1-propyl-5-(3-β- phenethylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-butyl-5-(3-β-phenethylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-methyl-5 -(3-α-phenethylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-methyl-5-[3-(4-phenylbutylcarbonyl)propyl]thio-1,2,3, 4-
Tetrazole 1-phenyl-5-(3-β-phenethylcarbonylpropyl)thio-1,2,3,4-tetrazole 1-cyclohexyl-5-(3-β-phenethylcarbonylpropyl)thio-1, 2, 3, 4-
Tetrazole 1-Methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-ethyl-5-{3-[( 3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-methyl-5-{4-[(3,4-dihydrocarbostyryl-6-yl) carbonyl]butyl}thio-1,2,3,4-tetrazole 1-ethyl-5-{4-[3,4-dihydrocarbostyryl-6-yl)carbonyl]butyl}
Thio-1,2,3,4-tetrazole 1-methyl-5-{3-[(3,4-dihydrocarbostyryl-5-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1 -Methyl-5-{4-[3,4-dihydrocarbostyryl-7-yl)carbonyl]butyl}
Thio-1,2,3,4-tetrazole 1-phenyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1 -Cyclohexyl-5-{3-(3,4-dihydrocarbostyryl-6-yl)carbonyl]
propyl}thio-1,2,3,4-tetrazole 1-methyl-5-{3-[(3,4-dihydrocarbostyryl-8-yl)carbonyl]propyl}thio-1,2,3,4- Tetrazole 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-phenyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[4-(1-methyl-3,4-dihydrocarbostyryl-6-yl) )
carbonyl]butyl}thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(1-ethyl-3,4
-dihydrocarbostyryl-6-yl)carbonyl]butyl}thio-1,2,3,4-tetrazole 1-phenyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-5-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-cyclohexyl-5-{3-[(1-methyl-3,4-dihydrocarbostyryl-5-) carbonyl]propyl}thio-1,2,3,
4-tetrazole 1-methyl-5-{3-[(1-methyl 3,4
-dihydrocarbostyryl-7-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole 1-methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2, 3,4-tetrazole 1-methyl-5-[4-(5-methyl-2-thenoyl)butyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[3-(5-methyl- 2-
tenoyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,
4-tetrazole 1-methyl-5-[3-(4-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(3-methyl-2- tenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(5-chloro-2-tenoyl)propyl]thio-1,2,3,4-tetrazole 1-phenyl- 5-[3-(5-chlor-2-
tenoyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,
4-tetrazole 1-methyl-5-[3-(4-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(5-methoxycarbonyl-2 -furoyl)propyl]thio-1,2,
3,4-tetrazole 1-methyl-5-[4-(5-methoxycarbonyl-2-furoyl)butyl]thio-1,2,
3,4-tetrazole 1-phenyl-5-[3-(5-methoxycarbonyl-2-furoyl)propyl]thio-1,
2,3,4-tetrazole 1-cyclohexyl-5-[3-(5-methoxycarbonyl-2-furoyl)propyl]thio-
1,2,3,4-tetrazole 1-methyl-5-[3-(5-ethoxycarbonyl-2-furoyl)propyl]thio-1,2,
3,4-tetrazole 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole 1-methyl-5-[4-(2,5-dimethyl-
3-furoyl)butyl]thio-1,2,3,4-
Tetrazole 1-phenyl-5-[3-(2,5-dimethyl-3-furoyl)propyl]thio-1,2,3,
4-tetrazole 1-cyclohexyl-5-[3-(2,5-dimethyl-3-furoyl)propyl]thio-1,
2,3,4-tetrazole 1-methyl-5-[3(2,5-dimethyl-3
-furoyl)propyl]thio-1,2,3,4-
Tetrazole 1-methyl-5-[3-(4,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio -1,2,3,4-tetrazole 1-methyl-5-[4-(2-pyrrolylcarbonyl)butyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[4-(2 -pyrrolylcarbonyl)butyl]thio-1,2,3,4-tetrazole 1-propyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-methyl -5-[5-(2-pyrrolylcarbonyl)pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(2-pyrrolylcarbonyl)hexyl]thio-1,2, 3,4-tetrazole 1-phenyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(2-pyrrolylcarbonyl) Propyl]thio-1,2,3,4
-Tetrazole 1-methyl-5-[3-pyrrolylcarbonyl]
Propyl]thio-1,2,3,4-tetrazole 1-ethyl-5-[3-(3-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3 -(1-methyl-2-pyrrolylcarbonyl)propyl]thio-1,2,
3,4-tetrazole 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(4-pyridylcarbonyl)propyl] Thio-1,2,3,4-tetrazole 1-methyl-5-[4-(2-pyridylcarbonyl)butyl]thio-1,2,3,4-tetrazole 1-methyl-5-[4-(3 -pyridylcarbonyl)butyl]thio-1,2,3,4-tetrazole 1-propyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-methyl-5 -[5-(2-pyridylcarbonyl)pentyl]thio-1,2,3,4-tetrazole 1-methyl-5-[6-(2-pyridylcarbonyl)hexyl]thio-1,2,3,4- Tetrazole 1-phenyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1, 2, 3, 4
-Tetrazole 1-methyl-5-[3-(1,2,3,4-tetrahydroquinolin-2-yl)carbonylpropyl]thio-1,2,3,4-tetrazole 1-phenyl-5-[3- (1, 2, 3, 4-
Tetrahydroquinolin-6-yl)carbonylpropyl]thio-1,2,3,4-tetrazole 1-cyclohexyl-5-[3-(1,2,
3,4-tetrahydroquinolin-5-yl)carbonylpropyl]thio-1,2,3,4-tetrazole 1-methyl-5-[3-(2-pyranylcarbonyl)propyl]thio-1,2,3 ,4-tetrazole 1-methyl-5-[3-(6-methyl-2-pyridylcarbonyl)propyl]thio1,2,3,
4-tetrazole 1-methyl-5-[3-(5-chloro-2-pyridylcarbonyl)propyl]thio-1,2,
3,4-Tetrazole The compound (1) of the present invention is produced, for example, by the method shown in the following Reaction Formula-1. [In the formula, R ¹ , A and R ² are the same as above. One of X ¹ and X ² is a halogen atom, and the other is a mercapto group or a group

[Formula]] That is, it is produced by reacting the tetrazole derivative (2) with the ketone (3). In the above reaction, instead of ketone (3), a method may also be employed in which a compound with a protected ketone group is used to react with compound (2), and then the protecting group of the ketone group is removed. The reaction between the tetrazole derivative (2) and the ketone (3) or a compound with a protected ketone group can be carried out advantageously using a condensing agent. Compound
The ratio of (2) and compound (3) or its ketone-protecting compound to be used is not particularly limited, but usually the former is used in an equimolar to 5-fold molar range, preferably an equimolar to 5 times the latter.
It is desirable to use twice the molar amount. Various basic compounds are used as condensing agents, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; Mention may be made of alkali metals, triethylamine, pyrylidine, organic bases such as N,N-dimethylaniline, and the like. The above reaction can be carried out without a solvent or in the presence of a solvent. When using a solvent, you can use any solvent as long as it does not participate in the reaction, but examples include alcohols such as methanol, ethanol, and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, benzene, and toluene. , aromatic hydrocarbons such as xylene and chlorobenzene, ketones such as acetone and methyl ethyl ketone, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide and hexamethyl phosphoric triamide. In the present invention, the reaction temperature is not particularly limited, but it is usually room temperature to 200°C, preferably 50 to 150°C. Further, in the above reaction, metal iodide compounds such as sodium iodide and potassium iodide can be added. As the protecting group for the ketone, any one that is stable under the conditions of the above condensation reaction can be used, such as lower alcohols such as methanol and ethanol, lower alkylene diols such as ethylene glycol and 1,3-trimethylene diol, Examples include lower alkanethiols such as methanethiol and ethanethiol, and lower alkylenedithiols such as 1,2-ethylenedithiol and 1,3-trimethylenedithiol. After the reaction, the protective group of the ketone is removed by a conventional method. For example, the ketal protected with the above-mentioned lower alcohol, lower alkylene diol, etc. can be easily converted into a carbonyl group by contacting with an acid. can. Examples of acid catalysts used in this case include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acid, acetic acid, propionic acid, p
-Organic acids such as toluenesulfonic acid may be mentioned. Examples of solvents used in this reaction include water, organic acids such as acetic acid and propionic acid, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane, dimethyl sulfoxide, dimethyl formamide, etc. Examples include aprotic polar solvents. In this case, if an organic acid is used as a solvent, no additional acid catalyst is required. This reaction is usually carried out at room temperature to 200°C, preferably at 50°C to 200°C.
It is carried out at 100℃ for about 30 minutes to 12 hours. In addition, the thioketal protected with the lower alkanethiol, lower alkylene dithiol, etc.
Reaction conditions that can convert ordinary thioketals to carbonyl groups can be adopted. For example, mercuric chloride-
It is easily removed by treatment with mercury oxide, mercuric chloride-cadmium carbonate, silver nitrate-N-chlorosuccinimide, etc. The protecting group removal reaction is carried out using a suitable solvent, for example, a mixed solvent of water and a water-soluble lower alcohol such as methanol or ethanol, or an organic solvent such as acetone or acetonitrile, at a temperature of 0 to 100°C, preferably 50 to 80°C. 1~ at °C
This is done by processing for about 5 hours. The compounds of the present invention can also be expressed by the following reaction formula:
It can also be produced by the method shown below. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above, Y ¹ represents a halogen atom] Tetrazole derivative (2) in the above reaction formula -
The same reaction conditions as for the reaction in the above reaction formula can be used for the reaction between and the nitrile (4). The reaction between compound (5) and Grignard reagent (6) is carried out in a suitable inert solvent at about -70°C to 50°C, preferably at -30°C.
This can be achieved by processing for about 1 to 6 hours at a temperature of .degree. C. to room temperature. As inert solvents, customary solvents for Grignard reactions can be used, for example ethers such as diethyl ether, dioxane, tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, saturated solvents such as pentane, hexane, heptane, cyclohexane, etc. Examples include hydrocarbons. The amount of Grignard reagent (6) to be used is at least equimolar, preferably equimolar to compound (5).
A 1.5-fold molar amount is used. The reaction product of compound (5) and compound (6) thus produced is subjected to conventional hydrolysis to obtain compound (1) of the present invention. The hydrolysis reaction is carried out in an appropriate manner in the presence of acids such as mineral acids such as hydrochloric acid and sulfuric acid, aliphatic carboxylic acids such as formic acid, acetic acid, and propionic acid, and perhalogenated acids such as perchloric acid and periodic acid. The reaction can be carried out in a suitable solvent at a temperature of about 0 to 100°C, preferably 50 to 80°C, for about 1 to 5 hours. Examples of the solvent include lower alcohols such as methanol and ethanol that are soluble in water, ethers such as tetrahydrofuran and dioxane, and mixed solvents of water and solvents such as acetone and acetonitrile. The amount of acid used is
It is used in at least an equimolar amount to (5). A method in which the reactive groups of compound (5) and Grignard reagent (6) in the above reaction formula are exchanged, that is,
The compound (1) of the present invention can also be produced by the method shown in the following reaction formula. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above, and Y ² represents a halogen atom] The reaction between the above compound (2) and compound (7) is the compound in the above reaction formula - The same reaction conditions as for the reaction between (2) and compound (3) can be used, and the obtained compound (8)
According to the reaction conditions normally used for Grignard reagent production, e.g. in a suitable solvent at room temperature to 100°C.
Compound (9) can be easily obtained by reacting with magnesium for 30 minutes to several hours.
In this case, the magnesium used is compound (8)
It is used in at least an equimolar amount, preferably an equimolar to 1.5 times the molar amount. In addition, the reaction between compound (9) and compound (10) is the reaction of compound (5) in the above reaction formula.
The same reaction conditions as for the reaction of and compound (6) are adopted. [In the formula, R ¹ , R ² , A, X ¹ and X ² are the same as above, R ³ represents a lower alkyl group] The reaction between compound (2) and compound (11) in the above reaction formula is , the same reaction conditions as for compounds (2) and (3) in the above-mentioned reaction formula can be employed. The hydrolysis reaction with compound (12) is carried out using a conventional catalyst such as a basic compound such as sodium hydroxide or potassium hydroxide, hydrochloric acid, etc. in a suitable inert solvent.
This can be advantageously carried out in the presence of a mineral acid such as sulfuric acid at 50°C to 110°C for about 30 minutes to several hours. An example of the solvent is water. The reaction between compound (13) and compound (14) is carried out in a suitable inert solvent at about -70°C to room temperature, preferably -
It can be carried out in about 1 to 6 hours at 30°C to room temperature. Examples of the solvent used include ethers such as diethyl ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and saturated hydrocarbons such as hexane, heptane, pentane, and cyclohexane.
The amount of compound (14) used in this reaction is at least twice the molar amount of compound (13), preferably 2 to 3 times the molar amount. [In the formula, R ¹ , R ² and A are the same as above, and M represents a metal atom such as zinc, cadmium or magnesium. Y ³ and Y ⁴ represent halogen atoms] The reaction between compound (13) and the halogenating agent in the above reaction formula can be carried out without a solvent or in a suitable inert solvent at room temperature to about 100°C, preferably,
It is carried out at 50 to 80°C for about 30 minutes to 6 hours.
Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide, and examples of the solvent include chloroform, methylene chloride, carbon tetrachloride, etc. Examples include halogenated hydrocarbons, dioxane, tetrahydrofuran, ethers such as diethyl ether, and the like. The amount of the halogenating agent to be used is usually a large excess of compound (13) when the reaction is carried out without a solvent, and at least an equimolar amount when the reaction is carried out in a solvent, preferably at least an equimolar amount. It is 2 to 4 times the molar amount. For the reaction between compound (15) and compound (16) or compound (17), the same reaction conditions as for the reaction between compound (13) and compound (14) in the above reaction formula can be employed. In this case, the usage amounts of compound (16) and compound (17) are as follows:
At least equimolar amount, preferably equimolar to
1.5 times the molar amount. [In the formula, R ¹ , R ² , A and Y ² are the same as above,
B represents a lower alkyl group] The reaction between compound (8) and compound (18) in the above reaction formula is the reaction between compound (15) and compound (16) or compound (17) in the above reaction formula. The same reaction conditions can be used. In addition, the reaction from compound (19) to compound (1) is expressed by the above reaction formula -
The same reaction conditions as in the reaction for converting a thioketal protected with a lower alkanethiol, lower alkylene dithiol, etc. into a carbonyl group can be adopted. Furthermore, among the compounds of the present invention, the compounds of the present invention in which R ² is a hydroxyl-substituted phenyl group are those in which the corresponding R ²
It can also be produced by subjecting a compound showing a phenyl group substituted with a lower alkoxy group to a hydrolysis reaction. The hydrolysis reaction is carried out, for example, in hydrobromic acid with 1-
This is done by refluxing for 6 hours. Furthermore, the compound (1a) of the present invention can also be produced by the method shown in the following reaction formula. [In the formula, R ¹ and A are the same as above. Y ⁵ is a halogen atom, hydroxyl group or group

[Formula], R ⁴ is a naphthyl group, a phenyl group (which may have one or two substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group, and a hydroxyl group) , or an aromatic heterocyclic group having one oxygen atom, sulfur atom, or nitrogen atom as a hetero atom (having one or two substituents selected from a lower alkyl group, a halogen atom, a lower alkoxycarbonyl group, and an oxo group) ] In the reaction formula, the reaction between compound (15) and compound (20) is the reaction between compound (20) and compound (15).
An equivalent to excess amount, preferably 1 to 3 times the molar amount, is used, and the temperature is about 0 to 150°C, preferably 0 to 150°C.
This is carried out at room temperature for about 1 to 5 hours. Examples of the solvent include nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Furthermore, the above reaction proceeds advantageously in the presence of a catalyst commonly used in Friedel-Crafts reactions, such as aluminum chloride, antimony pentachloride, ferric chloride, titanium tetrachloride, boron trifluoride, chloride, etc. Examples include stannic, zinc chloride, mercuric chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid, and phosphorus pentoxide. Among them, aluminum chloride, stannic chloride, and zinc chloride are preferably used. The amount of the catalyst to be used is equivalent to or in excess of compound (15), preferably 1 to 3 times the molar amount. In the above reaction formula, compound (2) which is a raw material
and (3) include new compounds as well as known compounds, and can also be produced, for example, by the methods shown in the reaction formulas. [In the formula, R ⁴ and A are the same as above, Y ⁶ and
Y ⁷ represents a halogen atom. B represents a protected keto group] In the reaction formula -, the reaction between compound (21) and compound (20) is the reaction of compound (20) in the above reaction formula -
The same reaction conditions as for the reaction between and compound (15) can be adopted. The reaction between compound (3a) or compound (3c) and thiourea can be carried out without a solvent or in the presence of a solvent. As the solvent, the same solvent used in the above reaction formula can be used. The ratio of compound (3a) or (3c) and thiourea to be used can be selected as appropriate, but usually the latter is used in an equimolar to 5-fold molar amount, preferably an equimolar to 2-fold molar amount of the former. The reaction temperature is not particularly limited, but is usually room temperature to 200°C, preferably 40 to 200°C.
It is carried out at 150℃. Incidentally, the reaction can be carried out in the presence of the same condensing agent as used in the above-mentioned reaction formula. The protection reaction of the keto group of compound (3a) is carried out using, for example, lower alcohols such as methanol and ethanol, lower alkylene diols such as ethylene glycol and 1,3-trimethylene diol, methanethiol, A ketone protecting reagent such as a lower alkanethiol such as ethanethiol, a lower alkylene dithiol such as 1,2-ethylenedithiol, and 1,3-trimethylenedithiol and compound (3a) are added without a solvent or in an appropriate solvent under anhydrous conditions. is carried out in the presence of a catalyst. Examples of the catalyst used include sulfonic acids such as ethanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid, and Lewis acids such as zinc chloride, aluminum chloride, and boron trifluoride. Examples of the solvent used include:
Examples include ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as chloroform and methylene chloride. The ketone protecting reagent used is used in at least an equimolar amount, usually in excess, relative to compound (3a).
The above reaction is carried out at a temperature of 0 to 80°C, preferably 0 to room temperature. [In the formula, A, B and R ² are the same as above, and Y ⁸ represents a halogen atom. One of Z ¹ and Z ² represents a cyano group, the other represents MgY ⁹ , and Y ⁹ represents a halogen atom] In the reaction formula -, the reaction between compound (22) and compound (23) is expressed in the reaction formula - Compound (5)
The same reaction conditions as for compound (6) can be adopted. For the reaction between compound (3e) or compound (3g) and thiourea, the same reaction conditions as for the reaction between compound (3a) or compound (3c) and thiourea in reaction formula - can be adopted; ) The same reaction conditions as for the keto group protection reaction of compound (3a) can be adopted. [In the formula, R ¹ is the same as above, Y ¹⁰ represents a halogen atom] The reaction of compound (2a) in reaction formula - with thiourea is the reaction of compound (3a) in reaction formula - above.
Alternatively, reaction conditions similar to those for the reaction of (3c) with thiourea can be adopted. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation, extraction, recrystallization, distillation, column chromatography, and preparative thin layer chromatography. The compounds of the present invention are useful as anti-ulcer agents and are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. class ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into suppository form,
A wide range of conventionally known carriers can be used, such as polyethylene glycol, cocoa butter, higher alcohols, ethers of higher alcohols, gelatin,
Examples include semi-synthetic glycerides.
When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and the anti-ulcer agent may also contain conventional solubilizing agents, buffers, soothing agents, etc.
Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. . There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly alone.
Administered intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the anti-ulcer agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 50 mg/kg body weight per day. It is better. Also,
The dosage unit form preferably contains 10 to 1000 mg of the active ingredient. Pharmacological Test 1 The pharmacological activity of the compound represented by the general formula (1) was tested according to the pyloric ligation method of Shei Rat, which is the most common test method for testing gastric juice secretion suppressive action. Male Wistar rats weighing approximately 170 g were used in this test. The rats were fasted for 24 hours and the compound to be tested 100 minutes before pylorus ligation.
Test compounds Nos. 1 to 3 were administered subcutaneously, and test compounds Nos. 4 to 15 were administered intraduoduolaterally at 4 mg/Kg.
After hours, gastric fluid volume, total acidity and pepsin activity were measured. Suppression rate is % with physiological saline administration group set as 0.
I asked for it. The results are shown in Table 1 below. In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 10 to less than 50% ++: 50% or more Test compound 1 1-Methyl-5-[3-(2-tenoyl)propyl]thio-1,2,3,4-tetrazole 2 1-Methyl-5- [3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole3 1-methyl-5-[3-(,4-dimethoxybenzoyl)propyl]thio-1,2,3,4
-tetrazole 4 1-methyl-5-(3-benzylcarbonylpropyl)thio-1,2,3,4-tetrazole 5 1-methyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1, 2, 3,
4-tetrazole 6 1-methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-
Tetrazole 7 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole 8 1-Methyl-5-[3-(5-methyl-2-
tenoyl)propyl]thio-1,2,3,4-
Tetrazole

[Table] Pharmacological Test 2 Male Wistar rats (weighing approximately 170 g) were fasted for 24 hours, restrained in a stress cage, and immersed up to the lower edge of the sternum in a water tank with a water temperature of 23°C. Slaughtered after 7 hours,
8 ml of 10% formalin was injected into the collected stomach and fixed. The stomach was incised from the greater curvature side, the length of each ulcer formed on the mucosa was measured, and the sum of the lengths was defined as the ulcer index (UI). The test drug was administered immediately before the rat was restrained.
Form of 0.5% CMC suspension (pharmacological concentration 1 x 10 ^-3 molar)
Orally administered. The stress ulcer inhibition rate of the test drug was calculated using the following formula. The results are shown in Table 2. Inhibition rate = UI of vehicle-administered control group - UI of test drug-administered group /
UI of vehicle-administered control group benzoyl)propyl]thio-1,2,3,4-tetrazole3 1-methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,
4-tetrazole 4 1-methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole 5 1-methyl-5-[3-(2-furoyl)propyl]thio- 1,2,3,4-tetrazole6 1-methyl-5-[3-(5-methyl-2-
tenoyl)propyl]thio-1,2,3,4-
Tetrazole

[Table] ++: 60% or more The compound of the present invention and the method for producing the same will be explained in more detail below with reference to Reference Examples and Examples. Reference example 1 1-methyl-5-mercapto-1,2,3,4
- 0.9g of tetrazole and 1.3g of 3-chloropropylethylketone ethylene ketal in acetone 50g
Dissolve in ml. To this was added 0.1 g of potassium iodide and 1.1 g of potassium carbonate, and the mixture was refluxed for a period of time. Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Elution with benzene-ether (5:1, V/V) yields 0.6 g of 1-methyl-5-(4,4-ethylenedioxyhexyl)thio-1,2,3,4-tetrazole. Colorless liquid. NMR: δ ^CDCl3 _ppn (60MHz): 0.87 (3H, t, J=7
Hz), 1.30-2.00 (6H, m), 3.32 (2H, t,
J=6Hz), 3.90 (3H, s) Reference example 2 1-methyl-5-mercapto-1,2,3,4
-Dissolve 11.6g of tetrazole in 100ml of acetone. Add to this 21.7g of 4-bromobutyric acid methyl ester
Add 15 g of potassium carbonate and reflux for 4 hours. Acetone was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing the chloroform solution with saturated saline, dry over magnesium sulfate.
Chloroform was distilled off, and the residue was purified using silica gel column chromatography (Wako Pure Chemical Industries, Ltd., Wako Gel C).
-200). Benzene-ether (5:1)
After elution, distillation under reduced pressure yields a colorless liquid 4-
(1-methyl-1,2,3,4-tetrazole-
20 g of 5-yl)thio-butyric acid methyl ester are obtained. Boiling point 175-177℃/0.88mmHg Reference example 3 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid methyl ester 17g
Add 150 ml of 20% hydrochloric acid to the solution and reflux for 2 hours.
After cooling, the reaction solution was diluted with water and extracted with chloroform. After washing the chloroform solution with saturated saline,
Dry with magnesium sulfate. After distilling off the chloroform, a colorless liquid of 4-(1-methyl-1,2,
3,4-tetrazol-5-yl)thio-butyric acid is obtained. n ²⁶ _D = 1.5133 Reference example 4 1-methyl-5-mercapto-1,2,3,4
-Dissolve 4.6 g of tetrazole and 9.4 g of 1-bromo-3-chloropropane in 100 ml of acetone. Add 6.8 g of potassium carbonate to this and reflux for 3 hours.
Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate. After chloroform was distilled off, the residue was subjected to silica gel column chromatography (Wako Gel C-200) and eluted with benzene-ether (5:1) to obtain 1-methyl-5.
-(3-chloropropyl)thio-1,2,3,4
- Obtain 8.5 g of tetrazole. Colorless liquid. NMR: δ ^CDCl3 _ppn 2.00-2.60 (2H, m), 3.40 (2H, t
，
J = 6Hz), 3.68 (2H, t, J = 6Hz),
3.93 (3H, s) Reference Example 5 In the same manner as Reference Example 4, 1-cyclohexyl-
5-(3-chloropropyl)thio-1,2,3,
4-tetrazole is obtained. Colorless liquid, n ¹⁴ _D =
1.5387 Reference example 6 1-methyl-5-mercapto-1,2,3,4
-Dissolve 2.3 g of tetrazole and 3.6 g of 4-brombutyronitrile in 50 ml of acetone. Add 3 g of potassium carbonate to this and reflux for 3 hours. After distilling off the acetone, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Wakogel C-200). Elute with benzene-ether (5:1) to obtain 4-(1-methyl-
3.5 g of 1,2,3,4-tetrazol-5-yl)thiobutyronitrile are obtained. Elemental analysis value: C ₅ H ₉ N ₅ S Calculated value (%): C, 35.07; H, 5.30; N,
40.90 Actual value (%): C, 35.26; H, 5.41; N,
40.98 Reference example 7 20g (0.15 mol) of acetanilide and carbon disulfide
37g of 4-chlorobutyric acid chloride dissolved in 110ml
(0.27 mol) is added. While stirring at room temperature, 60 g (0.45 mol) of aluminum chloride was gradually added, refluxed for 30 minutes, and then left at room temperature for 2.5 hours. Decant the carbon disulfide and pour the residue into ice-concentrated hydrochloric acid (20ml).
Pour into a tank, remove the precipitated crystals, and wash with water. Suspend the crude crystals in ethanol, and after stirring, collect the crystals and wash with water. Recrystallize from ethanol to obtain γ-chloro-4
- Obtain 10 g of acetamidobutyrophenone. Colorless granular crystals (ethanol), melting point 157-163℃ Reference example 8 16g of aluminum chloride (0.12g in 80ml of carbon tetrachloride)
20 g (0.12 mol) of 6-chlorhexanoyl chloride was added dropwise under ice-cooling. After dropping, stir for 15 minutes and add 7.8g (0.1mol) of benzene.
Add dropwise under ice-cooling. After stirring for 1 hour under ice-cooling,
Pour into hydrochloric acid and extract with carbon tetrachloride. The carbon tetrachloride extract was washed with water, saturated sodium bicarbonate solution, water, and saturated saline in this order, dried over anhydrous magnesium sulfate, and then distilled to obtain 5-chloropentyl phenyl ketone 7.3
get g. Melting point 143-150℃/0.5mmHg Reference example 9 26.7g of aluminum chloride in 20ml of nitrobenzene
Add 15.5 g of 4-chlorobutyric acid chloride under ice cooling.
drip. Gradually add 12.8 g of naphthalene under ice cooling and continue stirring at the same temperature for 30 minutes. Further at room temperature 2
After stirring for an hour, pour into ice-hydrochloric acid, extract with chloroform, wash sequentially with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dry over anhydrous sodium sulfate, and distill. A fraction with a boiling point of 187-191℃/1.6mmHg was taken, purified by silica gel column chromatography, crystallized from hexane, and then recrystallized from hexane-petroleum ether to yield 4.2g of 2-(4-chlorobutyryl)naphthalene. get. Colorless scaly crystals, melting point 43~
44℃ Reference example 10 16 g of aluminum chloride (0.12
18.6 g (0.12 mol) of 4-chlorovaleric acid chloride was added dropwise under ice-cooling, and after stirring for 15 minutes, 7.8 g (0.1 mol) of benzene was added dropwise at below 5°C, and at the same temperature Continue stirring for an hour. Pour into hydrochloric acid-ice and extract with chloroform. The chloroform layer is washed with water, saturated aqueous sodium bicarbonate, water, and saturated brine, and then dried over anhydrous magnesium sulfate. After chloroform was distilled off, the crude crystals were recrystallized from hexane to obtain 8.3 g of 4-chlorobutyl phenyl ketone. Colorless scaly crystals, melting point 49-50°C Reference Example 11 The following compound was obtained in the same manner as in the above Reference Example. γ-Chlor-3,4-dimethoxybutylphenone, pale yellow prismatic crystals (recrystallized from ligroin), melting point 90-92°C 2-(γ-chlorobutyryl)furan,
NMRδ ^CDCl3 _ppn 2.0-2.5 (2H, m), 3.00 (2H, t, J
= 7Hz), 3.62 (2H, t, J = 6Hz), 6.47 (1H,
m), 7.14 (1H, d, J=4Hz), 7.51 (1H, d,
J=2Hz) γ-Chlor-4-chlorobutyrophenone, colorless granular crystals (recrystallized from methanol-water), melting point 30℃ γ-chloro-4-ethylbutyrophenone, colorless liquid, boiling point 141-148℃/ 0.9mmHg γ-chloro-4-methoxybutyrophenone, colorless scaly crystals (recrystallized from petroleum ether-ethyl acetate), melting point 31°C 2-(γ-chlorobutyryl)pyrrole,
NMRδ ^CDCl3 _ppn 2.0-2.5 (2H, m), 2.96 (2H, t, J
= 7Hz), 3.63 (2H, t, J = 6Hz), 6.25 (1H,
m), 6.85-7.18 (2H, m), 10.2 (1H, br.1H) 2-(γ-chlorobutyryl)-5-methylthiophene, NMRδ ^CDCl3 _ppn 2.0-2.5 (2H, m), 2.52 (3H
，
s), 3.04 (2H, t, J=7Hz), 3.62 (2H, t,
J = 6Hz), 6.74 (1H, d, J = 4Hz), 7.48 (1H,
d, J = 4Hz) 3-(γ-chlorobutyryl)-2,5-dimethylfuran, NMRδ ^CDCl3 _ppn 2.0-2.5 (2H, m), 2.27
(3H, s), 2.54 (3H, s), 2.84 (2H, t, J=
7Hz), 3.16 (1H, s), 3.60 (2H, t, J = 6Hz) 2-(γ-Chlorbutyryl)-5-chlorothiophene, colorless liquid, boiling point 139-144℃/0.75mmHg 2-(γ-Chlorbutyryl) Pyridine, colorless liquid, NMRδ ^CDCl3 _ppn : 2.23 (2H, m), 3.43 (2H, t,
J=7Hz), 3.68 (2H, t, J=7Hz), 7.2-8.1
(3H, m), 8.63 (1H, d) Reference example 12 Magnesium 1.9g, n-butyl bromide
A Grignard reagent was prepared from 11.2 g and 80 ml of anhydrous ether, and under ice cooling, a solution of 7 g of 4-chlorobutyronitrile in 15 ml of ether was added dropwise, stirred at the same temperature for 2 hours, and then further stirred at room temperature for 2 hours. Slowly add 10% hydrochloric acid dropwise under ice cooling to decompose, and pH≒1
shall be. After stirring at room temperature for 1 hour, extraction with ether was performed, and the ether layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, the solvent was distilled off, and then distilled to obtain 1.6 g of 3-chloropropyl butyl ketone. . Boiling point: 104-106°C/30mmHg Reference Example 13 The following compound is obtained in the same manner as in Reference Example 12 above. 3-Chlorpropyl cyclopentyl ketone, colorless liquid, boiling point 127-137℃/22mmTg 3-chloropropyl benzyl ketone, colorless liquid, boiling point 108-119℃/0.15mmHg 3-bromopropyl cyclohexyl ketone, NMRδ ^CDCl3 _ppn 1.2-2.4 (11H , m), 2.0-2.5
(2H, m), 2.64 (2H, t, J=7Hz), 3.44 (2H,
t, J = 6 Hz) Reference example 14 Dissolve 1.5 g of 3-chloropropyl ethyl ketone in 10 ml of ethylene glycol, and add 2 g of methyl orthoformate and 0.2 g of p-toluenesulfonic acid.
and stirred at room temperature for 5 hours. After neutralizing by adding sodium hydroxide, water is added and extracted with ether. The ether solution is washed with water and saturated brine, and dried over magnesium sulfate. The ether was distilled off, and the residue was distilled under reduced pressure to obtain a colorless liquid, 3-
Chlorpropyl ethyl ketone 1.3 g of ethylene ketal is obtained. Boiling point: 98-102°C/33mmHg Reference Example 15 The following compound was obtained in the same manner as in Reference Example 14. 4-Chlorbutylophenone ethylene ketal, NMRδ ^CDCl3 _ppn 1.8-2.2 (4H, m), 3.43 (2H,
t, J=6Hz), 3.65-4.0 (4H, m), 7.1-7.5
(5H, m) 3-bromopropyl cyclohexyl ketone ethylene ketal, NMRδ ^CDCl3 _ppn 0.9-2.2 (15H,
m), 3.40 (2H, t, J=6Hz), 3.93 (4H, s) 3-chloropropyl β-phenethyl ketone, boiling point 130-139℃/0.25mmHg 2-(4-chlorobutyryl)-5-methoxycarbonylfuran , NMRδ ^CDCl3 _ppn 2.0~2.5 (2H,
m), 3.11 (2H, t, J=7Hz), 3.63 (2H, t,
J=6Hz), 3.92 (3H, s), 7.1-7.3 (2H) 6-(4-chlorobutyryl)-3,4-dihydrocarbostyryl, pale yellow needles (acetone),
Melting point 158-160℃ Example 1 1-Methyl-5-[4,4-ethylenedioxy-4-(4-ethylphenyl)butyl]thio 1,
Dissolve 0.8 g of 2,3,4-tetrazole in 5 ml of acetic acid. Add 2.5 ml of water and 0.5 ml of concentrated hydrochloric acid to this and heat on a water bath for 1 hour. Add water to the reaction solution and extract with chloroform. Chloroform solution,
Wash with water, saturated aqueous sodium bicarbonate and saturated saline, and dry over magnesium sulfate. Chloroform is distilled off, and the residue is purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Elute with benzene-ether (10:1) to obtain 0.5 ml of 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole.
get. Colorless needle crystals (recrystallized from hexane-ether), melting point 68-69℃ Elemental analysis: C ₁₄ H ₁₈ N ₄ OS Calculated value (%): C, 57.91; H, 6.25; N,
19.90 Actual value (%): C, 57.68; H, 6.20; N,
19.81 Example 2 The following compound is obtained in the same manner as in Example 1. 1-Methyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172°C 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140℃ 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 3 1-Methyl-5-[4 ,4-ethylenedioxy-4-(2-pyridyl)butyl]thio-1,2,
Dissolve 0.7 g of 3,4-tetrazole in 5 ml of acetic acid. Add 25 ml of water and 0.5 ml of concentrated hydrochloric acid to this and heat on a water bath for 1 hour. Add water to the reaction solution and extract with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Elute with benzene-ether (10:1) and recrystallize the obtained compound from hexane-ether to give 1-methyl-5.
-[3-(2-pyridylcarbonyl)propyl]
0.5 g of thio-1,2,3,4-tetrazole is obtained. Colorless needle crystals, melting point 73-75℃ Elemental analysis: C ₁₁ H ₁₃ N ₅ OS Calculated value (%): C, 50.17; H, 4.97: N,
26.60 Actual value (%): C, 50.12; H, 4.97; N,
26.90 Example 4 The following compound is obtained in the same manner as in Example 3. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 41-42°C 1-methyl-5-[3 -(5-Methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 78-80℃ 1-Methyl-5- [3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 91-92℃ 1-Methyl- 5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 94-96℃ 1-Methyl- 5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5℃ 1-Methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1 ,2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190℃ 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals ((recrystallized from hexane-ethyl acetate), melting point 110-113.5°C Example 5 Acetone 1-methyl-5-mercapto in 50ml
Add 1.2 g of 1,2,3,4-tetrazole, 2.1 g of potassium carbonate, and 3.2 g of 3-chloropropyl 4-ethylphenyl ketone, and reflux for 2 hours with stirring. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, and insoluble materials were removed. The liquid was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (manufactured by Merck & Co., Kieselgel 60, eluent benzene:ether = 10:1), recrystallized from hexane-ether, and 1-methyl-5-
[3-(4-ethylbenzoyl)propyl]thio 1,2,3,4-tetrazole (yield 49%) is obtained. Colorless needle crystals, melting point 68-69°C Elemental analysis: C ₁₄ H ₁₈ N ₄ OS Calculated value (%): C, 57.91; H, 6.25; N, 19.90 Actual value (%): C, 57.78; H, 6.23; N, 19.71 Example 6 In the same manner as in Example 5, the following compound was obtained. 1-Methyl-5-[3-(4-acetylaminobenyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172℃ 1-Methyl -5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl)thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ Example 7 1-Methyl-5-mercapto in 50ml of acetone
Add 1.2 g of 1,2,3,4-tetrazole, 2.1 g of potassium carbonate, and 2.8 g of 3-chloropropyl 2-pyridyl ketone, and reflux for 2 hours with stirring. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, and insoluble materials were removed. The liquid was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (manufactured by Merck & Co., Kieselgel 60, eluent, benzene:ether = 10:1), and hexane-
Recrystallized from ether to give 1-methyl-5-[3-
(2-pyridylcarbonyl)propyl]thio-1,
2,3,4-tetrazole (yield 50%) is obtained.
Colorless needle crystals, melting point 73-75°C Elemental analysis: C ₁₁ H ₁₃ N ₅ OS Calculated value (%): C, 50.17; H, 4.97; N, 26.60 Actual value (%): C, 50.21; H, 4.89; N, 26.72 Example 8 The following compound was obtained in the same manner as in Example 7. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 41-42°C 1-methyl-5-[3 -(5-Methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 78-80℃ 1-Methyl-5- [3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 91-92℃ 1-Methyl- 5-[3-(2-pyrrolylcarbonyl)propyl]thio 1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 94-96℃ 1-Methyl-5 -[3-(2,5-dimethyl-
3-furoyl)propyl]thio1,2,3,4-
Tetrazole, colorless plate crystals (recrystallized from hexane-ether), melting point 67-68.5°C 1-methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1 , 2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190
°C 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ethyl acetate), melting point 110-113.5℃ 1-Methyl-5 -[3-(5-methoxycarbonyl-2-furoyl)propyl]thio-1,2,
3,4-tetrazole, colorless needle crystals (hexane-
(Recrystallized from ethyl acetate), melting point 96-97℃ Example 9 1-Methyl-5-mercapto in 50 ml of acetone
Add 1.2 g of 1,2,3,4-tetrazole, 2.1 g of potassium carbonate and 3.5 g of 3-chloropropyl 2-naphthyl ketone, and reflux for 2 hours with stirring. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, and insoluble materials were removed. The liquid was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (Merck, Kieselgel 60, eluent, benzene:ether = 10:1), and recrystallized from ethanol to obtain 1-methyl-5-[3 -(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole (yield 51%) is obtained. Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120℃ Elemental analysis value: C ₁₆ H ₁₆ N ₄ OS Calculated value (%): C, 61.52; H, 5.16; N, 17.94 Actual value (%): C , 61.59; H, 5.08; N, 18.06 Example 10 1-Methyl-5-mercapto in 50 ml of acetone
Add 1.2 g of 1,2,3,4-tetrazole, 2.1 g of potassium carbonate and 2.9 g of 3-chloropropyl benzyl ketone, and reflux for 2 hours with stirring.
The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform, and insoluble materials were removed. The liquid was concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography (manufactured by Merck & Co., Kieselgel 60, eluent, benzene:ether = 10:1), and 1-methyl-
5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole (yield 50%)
get. Colorless liquid, n ²⁵ _D = 1.5610 Elemental analysis value: C ₁₃ H ₁₆ N ₄ OS Calculated value (%): C, 56.50; H, 5.84; N, 20.27 Actual value (%): C, 56.40; H, 5.83; N, 20.17 Example 11 The following compound is obtained in the same manner as in Example 10. 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl)]thio 1,2,3,4-tetrazole, colorless liquid, n ^22.5 _D = 1.5561 Example 12 Magnesium 0.25 g, 4-ethyl- 2.6 g of 1-bromobenzene and 10 g of dry tetrahydrofuran
Make (4-ethylphenyl)magnesium bromide from ml. Add 1-methyl-5 to this while stirring on ice.
-(3-cyanopropyl)thio-1,2,3,4
-Tetrazole 1.8g dry tetrahydrofuran
Add 10ml solution dropwise. After dropping, stir at room temperature for 3 hours. Add 50 ml of 1N hydrochloric acid under ice cooling and stir for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck, Kieselgel 60). Elute with benzene-ether (10:1),
0.7 g of 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 68-69°C Example 13 The following compound was obtained in the same manner as in Example 12. 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-Methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 14 Magnesium 0.25 g, 2-brome pyridine 2.1
Pyridylmagnesium bromide is prepared from g and 10 ml of dry tetrahydrofuran. To this was added dropwise a solution of 1.8 g of 1-methyl-5-(3-cyanopropyl)thio-1,2,3,4-tetrazole in 10 ml of dry tetrahydrofuran while stirring on ice. After dropping, stir at room temperature for 3 hours. 1N hydrochloric acid under ice cooling
Add 50ml and stir for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck, Kieselgel 60). Elute with benzene-ether (10:1) to obtain 1-methyl-5-[3-
(2-pyridylcarbonyl)propyl]thio-1,
0.6 g of 2,3,4-tetrazole is obtained. Colorless needle crystals (hexane-ether), melting point 73-75°C Example 15 The following compound was obtained in the same manner as in Example 14. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 41-42°C 1-methyl-5-[3 -(5-Methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 78-80℃ 1-Methyl-5- [3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 94-96°C 1-methyl-5- [3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether), melting point 67-68.5°C Example 16 0.3 g of magnesium is suspended in 5 ml of dry tetrahydrofuran. A small piece of iodine is added to this under stirring in a nitrogen stream, and then 0.3 g of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole is added. Add 0.1 ml of ethyl bromide and heat externally to start the reaction. The remaining 1-methyl-5-(3-chloropropyl)thio-1,
A solution of 1.8 g of 2,3,4-tetrazole in 15 ml of dry tetrahydrofuran is added dropwise. After dropping, reflux is performed for 1 hour. A solution of 1.1 g of 1-cyano-4-ethylbenzene in 5 ml of dry tetrahydrofuran is added dropwise to the resulting Grignard reagent under ice-cooling and stirring. Stir at room temperature for 3 hours. Add 20 ml of 1N hydrochloric acid under ice cooling and stir for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The ether is distilled off, and the residue is purified by silica gel column chromatography (Merck, Kieselgel 60). Elute with benzene-ether (10:1) to obtain 1-methyl-5-[3-
(4-ethylbenzoyl)propyl]thio-1,
0.7 g of 2,3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 68
~69°C Example 17 The following compound is obtained in the same manner as in Example 16. 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140℃ 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystal (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 18 0.3 g of magnesium was dissolved in 5 ml of dry tetrahydrofuran. Suspend in A small piece of iodine is added to this under stirring in a nitrogen stream, and then 0.3 g of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole is added. Add 0.1 ml of ethyl bromide and heat externally to start the reaction. The remaining 1-methyl-5-(3-chloropropyl)thio-1,
A solution of 1.8 g of 2,3,4-tetrazole in 15 ml of dry tetrahydrofuran is added dropwise. After dropping, reflux is performed for 1 hour. A solution of 0.9 g of 2-cyanopyridine in 5 ml of dry tetrahydrofuran was added dropwise to the resulting Grignard reagent under ice-cooling and stirring. Stir at room temperature for 3 hours. Add 20 ml of 1N hydrochloric acid under ice cooling and stir for 1 hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate.
The ether is distilled off, and the residue is purified by silica gel column chromatography (Merck, Kieselgel 60). Elution with benzene-ether (10:1) yields 0.6 g of 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole. Colorless needle crystals (hexane)
(recrystallized from ether), melting point 73-75°C Example 19 The following compound was obtained in the same manner as in Example 18. 1-Methyl-5-[3-(2-thenoyl)propyl]thio 1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point
55-56℃ 1-Methyl-5-[3-(2-furoyl)propyl]thio 1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) , melting point 78-80℃ 1-Methyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (reproduced from hexane-ethyl acetate) crystals), melting point 91-92℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (reproduced from hexane-ethyl acetate) crystal), melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether), melting point 67-68.5°C Example 20 1-Methyl-5-(3-carboxypropyl)
Dissolve 2 g of thio-1,2,3,4-tetrazole in 20 ml of anhydrous benzene. Under argon flow -70℃
While stirring, 13.3 ml of a 1.5N ether solution of 4-ethylphenyllithium was added dropwise. Stir for 3 hours while gradually raising the temperature to room temperature. The mixture was further stirred overnight at room temperature, and the reaction mixture was poured into ice water and extracted with ether. The ether solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate.
The ether is distilled off, and the residue is purified by column chromatography (Merck Kieselgel 60).
Elution with benzene-ether (10:1) yields 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole 0.7
get g. Colorless needle crystals (recrystallized from hexane-ether), melting point 68-69°C Example 21 The following compound was obtained in the same manner as in Example 20. 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 22 1-Methyl-5-( 3-carboxypropyl)
Dissolve 2 g of thio-1,2,3,4-tetrazole in 20 ml of anhydrous benzene. Under argon flow -70℃
While stirring, 13.3 ml of a 1.5N ether solution of 2-pyridyllithium was added dropwise. Stir for 3 hours while gradually raising the temperature to room temperature. The mixture was further stirred overnight at room temperature, and the reaction mixture was poured into ice water and extracted with ether. The ether solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. The ether is distilled off, and the residue is purified by column chromatography (Merck Kieselgel 60). Elution with benzene-ether (10:1) yields 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole 0.6
get g. Colorless needle crystals (recrystallized from hexane-ether), melting point 73-75°C Example 23 The following compound was obtained in the same manner as in Example 22. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 41-42°C 1-methyl-5-[3 -(5-Methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 78-80℃ 1-Methyl-5- [3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 94-96°C 1-methyl-5- [3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether), melting point 67-68.5°C Example 24 2.3 g of 2-(4-ethylphenyl)-1,3-dithiane was dissolved in 20 ml of dry tetrahydrofuran,
Cool to −78°C. To this was added dropwise 6.5 ml of a 1.6N n-butyllithium solution in n-hexane under stirring in an argon stream. Stir for 30 minutes at -78°C.
In this, 1-methyl-5-(3-chloropropyl)
A solution of 1.9 g of thio-1,2,3,4-tetrazole in 5 ml of dry tetrahydrofuran is added dropwise. −78
After stirring at ℃ for 1 hour, the mixture was stirred for 4 hours while gradually raising the temperature to 0℃. Pour the reaction solution into ice water and extract with ether. The ether solution is washed with water and saturated saline, and then dried over magnesium sulfate. The ether is distilled off and the residue is dissolved in 20 ml of acetonitrile. 7 g of silver nitrate and 4.9 g of N-chlorosuccinimide are dissolved in 40 ml of water and 100 ml of acetonitrile. The above dithiane solution was added dropwise to this while stirring at 0° C. in a nitrogen stream. After stirring at 0°C for 30 minutes, warm to room temperature and stir for an additional 30 minutes. Dilute with water and extract with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified using column chromatography (Merck, Kieselgel 60). Elute with benzene-ether (10:1) to obtain 1-methyl-5-[3-
(4-ethylbenzoyl)propyl]thio-1,
0.4 g of 2,3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 68
~69°C Example 25 The following compound is obtained in the same manner as in Example 24. 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 26 2-(2-pyridyl) -1,3-Zitian 2.0
Dissolve g in 20 ml of dry tetrahydrofuran and -78
Cool to ℃. This was then stirred under a stream of argon.
1.6N n-butyllithium n-hexane solution
Drop 6.5ml. Stir for 30 minutes at -78°C. To this was added dropwise a solution of 1.9 g of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole in 5 ml of dry tetrahydrofuran. After stirring at -78°C for 1 hour, the mixture was stirred for 4 hours while gradually raising the temperature to 0°C. Pour the reaction solution into ice water and extract with ether. The ether solution is washed with water and saturated saline, and then dried over magnesium sulfate. The ether is distilled off and the residue is dissolved in 20 ml of acetonitrile. 7g silver nitrate and N-chlorosuccinimide
Dissolve 4.9g in 40ml of water and 100ml of acetonitrile. The above dithiane solution was added dropwise to this while stirring at 0° C. in a nitrogen stream. After stirring at 0°C for 30 minutes, warm to room temperature and stir for an additional 30 minutes. Dilute with water and extract with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform is distilled off, and the residue is purified by column chromatography (Merck, Kieselgel 60). Benzene-ether (10:
1) and 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,
0.4 g of 3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 73-75°C Example 27 The following compound was obtained in the same manner as in Example 26. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether) Melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) , melting point 78-80℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate) , melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5°C Example 28 (a) 1-Methyl-5-(3-carboxypropyl)thio-1,2,3,4-tetrazole 2 g
Add 5 ml of thionyl chloride to the mixture and stir at 40-50°C for 1 hour. Excess thionyl chloride is distilled off under reduced pressure. Dry benzene is added and water is removed by azeotroping, and the resulting mixture is used as it is in the next reaction. (b) Add 571 mg of copper iodide to a sealed two-necked flask, degas it under reduced pressure, and then fill it with nitrogen. This is anhydrous ether
Inject 10ml and cool the whole to -40℃. to this
Add 5 ml of an ether solution of 1.32M4-ethylphenyllithium, stir at -40°C for 5 minutes, and then
Cool to −78°C. Add to this the 4-
5 ml of a cold solution of 230 mg of (1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid chloride in anhydrous ether is injected and stirred at -78°C for 15 minutes. 35 ml of anhydrous methanol is poured into this reaction solution, and the flask is returned to room temperature. Pour the reaction mixture into a saturated aqueous ammonium chloride solution and extract with ether. The ether solution is dried over magnesium sulfate and the ether is distilled off. The residue was purified by column chromatography (Merck Kieselgel 60) and eluted with benzene-ether (10:1) to give 1-methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1, 0.1 g of 2,3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 68-69°C Example 29 The following compound was obtained in the same manner as in Example 28. 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 30 (a) 1-Methyl-5 -(3-carboxypropyl)thio-1,2,3,4-tetrazole 2g
Add 5 ml of thionyl chloride to the mixture and stir at 40-50°C for 1 hour. Excess thionyl chloride is distilled off under reduced pressure. Dry benzene is added and water is removed by azeotroping, and the resulting mixture is used as it is in the next reaction. (b) Add 571 mg of copper iodide to a sealed two-necked flask,
After vacuum degassing, fill with nitrogen. This is anhydrous ether
Inject 10ml and cool the whole to -40℃. to this
1.32M2-Ether solution of pyridyllithium 5
ml, stirred at -40℃ for 5 minutes, and then heated to -78℃.
Cool. 5 ml of a cold anhydrous ether solution containing 230 mg of 4-(4-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid chloride obtained above was poured into this, and the mixture was stirred at -78°C for 15 minutes. do.
35 ml of anhydrous methanol is poured into this reaction solution, and the flask is returned to room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is distilled off. The residue was purified by column chromatography (Merck Kieselgel 60) and eluted with benzene-ether (10:1) to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)].
0.1 g of [propyl]thio-1,2,3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from hexane-ether), melting point 73-75°C Example 31 The following compound was obtained in the same manner as in Example 30. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether) Melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) , melting point 78-80℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole pale yellow prismatic crystals ((recrystallized from hexane-ethyl acetate)) , melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5°C Example 32 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4- Add 2 g of tetrazole to 40 ml of 47% hydrobromic acid and reflux for 5 hours. After cooling, pour into ice-water, extract with ethyl acetate, wash the organic layer with water and saturated brine, and dry over magnesium sulfate. Ethyl acetate was distilled off and silica gel column chromatography (Wacoal Gel C
-20) and purified with hexane-ethyl acetate (1:
1) and 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,
0.3 g of 3,4-tetrazole is obtained. Colorless needle crystals (recrystallized from water), melting point 128.5-129.5℃ Reference example 16 16 g of aluminum chloride was suspended in 100 ml of carbon tetrachloride, and 4-(1-methyl-1,2,
26.5 g of 3,4-tetrazol-5-yl)thio-butyric acid chloride is added dropwise. After stirring for 30 minutes, 7.8 g of benzene was added dropwise at 5°C, and stirring was continued at the same temperature for 1 hour. Pour the reaction solution into hydrochloric acid-ice and extract with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The chloroform was distilled off, the residue was purified by column chromatography (Merck Kieselgel 60, eluent: chloroform), and then recrystallized from methanol-water to give colorless needle-like crystals of 1-methyl-5-(3-
10.5 g of benzoylpropyl)thio-1,2,3,4-tetrazole are obtained. Melting point: 57.5-58°C Example 33 The following compound was obtained in the same manner as in Reference Example 16. 1-Methyl-5-[3-(4-ethylbenzoyl)propyl]thio-1,2,3,4-tetrazole Colorless needles (recrystallized from hexane-ether), melting point 68-69℃ 1-Methyl- 5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172°C 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140℃ 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C Example 34 4 g of aluminum chloride is suspended in 20 ml of carbon disulfide and 1.5 g of furan is added. Under ice cooling and stirring, 4-
(1-methyl-1,2,3,4-tetrazole-
Drop 4.4 g of 5-yl)thio-butyric acid chloride,
Stir at the same temperature for 1 hour. Pour the reaction solution into ice-hydrochloric acid and extract with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. Distill the chloroform,
The residue was subjected to column chromatography (Wakogel C-
200, eluent, chloroform) and recrystallized from hexane-ether to give colorless needle-like crystals of 1-methyl-5-[3-(2-furoyl)propyl]thio-1,2,3,4- Obtain 0.8 g of tetrazole.
Melting point: 41-42°C Example 35 The following compound is obtained in the same manner as in Example 34. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 78-80℃ 1- Methyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate), melting point 91-92°C 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 94-96°C 1-Methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5℃ 1-Methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1 ,2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190℃ 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ethyl acetate), melting point 110-113.5℃ Reference example 17 1- Dissolve 2.4 g of methyl-5-chloro-1,2,3,4-tetrazole in 30 ml of ethanol.
Add 1.5 g of thiourea to this and reflux for 2 hours. Next, add 4.7 g of 3-bromopropyl cyclohexyl ketone and a 10% aqueous sodium hydroxide solution.
Add 10 ml and reflux for 3 hours. Ethanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by column chromatography (Wako Gel C-200, eluent, chloroform) to obtain a colorless liquid of 1-methyl-5-(3-cyclohexylcarbonylpropyl)thio-1,2,3. ，
1.4 g of 4-tetrazole is obtained. n ¹² _D =1.5267 Example 36 The following compound is obtained in the same manner as in Reference Example 17. 1-Methyl-5-[3-(4-acetylaminobenzoyl]propyl]thio-1,2,3,4-
Tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172°C 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 37 S-(1-methyl- Dissolve 1.9 g of 1,2,3,4-tetrazol-5-yl)isothiourea hydrochloride in 50 ml of ethanol. To this were added 5 ml of 10% aqueous sodium hydroxide solution and 1.8 g of 3-chloropropyl 2-pyridyl ketone, and refluxed for 2 hours. Distill the ethanol, add water to the residue,
Extract with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. After distilling off the chloroform and purifying the residue by column chromatography (Wako Gel C-200, eluent: chloroform), it was recrystallized from hexane-ether to give 1-methyl-5- as colorless needle-like crystals.
0.5 g of [3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole is obtained.
Melting point: 73-75°C Example 38 The following compound was obtained in the same manner as in Example 37. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether) Melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) , melting point 78-80℃ 1-Methyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needles (reproduced from hexane-ethyl acetate) crystals), melting point 91-92℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (reproduced from hexane-ethyl acetate) crystal), melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether), melting point 67-68.5°C 1-methyl-5-[3-(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1, 2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190℃ 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ethyl acetate), melting point 110-113.5℃ Reference example 18 1- Add 1.4 g of methyl-5-chloro-1,2,3,4-tetrazole and 1.9 g of 3-mercaptopropyl cyclohexyl ketone to 50 ml of methanol.
dissolve in Add 0.8 g of potassium hydroxide to this and reflux for 5 hours. Methanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with dilute aqueous sodium hydroxide solution, water and saturated brine, and dried over sodium sulfate. Chloroform was distilled off, and the residue was purified by column chromatography (Wako Gel C-200, eluent, chloroform) to obtain 1-methyl-
5-(3-cyclohexylcarbonylpropyl)
0.6 g of thio-1,2,3,4-tetrazole is obtained. n ¹² _D =1.5267 Example 37 The following compound is obtained in the same manner as in Example 38. 1-Methyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172°C 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140°C 1-methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 40 1-Methyl-5-chlor -1,2,3,4-tetrazole 1.4g and 3-mercaptopropyl 2
-Dissolve 1.8g of pyridyl ketone in 100ml of methanol. Add 0.6 g of sodium mercury to this and reflux for 3 hours. Methanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. Add chloroform solution to dilute sodium hydroxide solution,
Wash with water and saturated saline, and dry with sodium sulfate. Chloroform was distilled off, the residue was purified by column chromatography (Wako Gel C-200, eluent chloroform), and then recrystallized from hexane-ether to give colorless needle-like crystals of 1-methyl-5-[3
-(2-pyridylcarbonyl)propyl]thio-
0.2 g of 1,2,3,4-tetrazole is obtained. Melting point: 73-75°C Example 4 The following compound was obtained in the same manner as in Example 40. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether) Melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio 1,2,3,4-tetrazole, pale yellow needles (recrystallized from hexane-ethyl acetate), Melting point 78-80℃ 1-Methyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) ), melting point 91-92℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (recrystallized from hexane-ethyl acetate) ), melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5℃ 1-Methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1 ,2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190℃ 1-methyl-5-{3-[(1-methyl-3,
4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ethyl acetate), melting point 110-113.5℃ Reference example 19 4- Chlorbutyrophenone 1.8g and thiourea 0.8g
g in 50 ml of ethanol and stirred under reflux for 2 hours. To this, 1-methyl-5-chloro-1,
Add 1.2 g of 2,3,4-tetrazole and 5 ml of 10% aqueous sodium hydroxide solution, and reflux for 3 hours. Ethanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. Chloroform solution in water,
Wash with saturated saline and dry with magnesium sulfate. The chloroform was distilled off, the residue was purified by column chromatography (Wako Gel C-200, eluent: chloroform), and then recrystallized from methanol-water to give colorless needle-like crystals of 1-methyl-5-(3-benzoylpropyl). ) 0.3 g of thio-1,2,3,4-tetrazole is obtained. Melting point: 57.5-58°C Example 42 The following compound was obtained in the same manner as in Reference Example 19. 1-Methyl-5-[3-(4-acetylaminobenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 170-172°C 1-Methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4-
Tetrazole, colorless prismatic crystals (recrystallized from hexane-ethyl acetate), melting point 86-87°C 1-methyl-5-[3-(4-chlorobenzoyl)propyl]thio-1,2,3,4-tetrazole, Colorless prismatic crystals (recrystallized from methanol-water), melting point 139-140℃ 1-Methyl-5-[3-(4-methoxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless scaly crystals (recrystallized from hexane-ethyl acetate), melting point 107-108°C 1-methyl-5-[3-(4-hydroxybenzoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals ( recrystallized from water), melting point
128.5-129.5℃ 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole,
Colorless prismatic crystals (recrystallized from ethanol), melting point 118-120°C 1-methyl-5-[3-(benzylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ²⁵ _D = 1.5610 1-Methyl-5-[3-(β-phenethylcarbonyl)propyl]thio-1,2,3,4-tetrazole, colorless liquid, n ^25.5 _D = 1.5561 Example 43 3-chloropropyl 2-pyridyl ketones
1.8 g and 0.8 g of thiourea were dissolved in 50 ml of ethanol, and stirred and refluxed for 2 hours. To this were added 1.2 g of 1-methyl-5-chloro-1,2,3,4-tetrazole and 5 ml of a 10% aqueous sodium hydroxide solution, and the mixture was refluxed for 3 hours. Ethanol was distilled off under reduced pressure, and the residue was added to water and extracted with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. After evaporating the chloroform and purifying the residue by column chromatography (Wako Gel C-200, eluent chloroform), it was recrystallized from hexane-ether to give colorless needle-like crystals of 1-methyl-5-[3-(2 0.2 g of -pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole is obtained. Melting point: 73-75°C Example 44 In the same manner as in Example 43, the following compound is obtained. 1-Methyl-5-[3-(2-thenoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether), melting point 55-56℃ 1-Methyl- 5-[3-(2-furoyl)propyl]thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ether) Melting point
41-42℃ 1-Methyl-5-[3-(5-methyl-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needle crystals (recrystallized from hexane-ethyl acetate) , melting point 78-80℃ 1-Methyl-5-[3-(5-chloro-2-thenoyl)propyl]thio-1,2,3,4-tetrazole, pale yellow needles (reproduced from hexane-ethyl acetate) crystals), melting point 91-92℃ 1-Methyl-5-[3-(2-pyrrolylcarbonyl)propyl]thio-1,2,3,4-tetrazole, pale yellow prismatic crystals (reproduced from hexane-ethyl acetate) crystal), melting point 94-96℃ 1-methyl-5-[3-(2,5-dimethyl-
3-furoyl)propyl]thio-1,2,3,4
-Tetrazole, colorless plate crystals (recrystallized from hexane-ether) Melting point 67-68.5℃ 1-Methyl-5-{3-[(3,4-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1 , 2,3,4-tetrazole, colorless needle crystals (recrystallized from ethanol), melting point 188-190℃ 1-methyl-5-{3-(1-methyl-3,4
-dihydrocarbostyryl-6-yl)carbonyl]propyl}thio-1,2,3,4-tetrazole, colorless needle crystals (recrystallized from hexane-ethyl acetate), melting point 110-113.5°C Example 45 Above Example 1 The following compound is obtained in the same manner as above. 1-Phenyl-5-(3-benzylcarbonylpropyl)thio-1,2,3,4-tetrazole, pale yellow liquid, n ^27.5 _D 1.5948 Formulation example 1 1-Methyl-5-[3-[4-ethylbenzoyl] ) Propyl]thio-1,2,3,4-tetrazole 150g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methylcellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g Compound of the present invention , Avicel, corn starch and magnesium stearate mixed and polished, then sugar coated.
Compress the tablets with an R10mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets. Formulation example 2 1-methyl-5-[3-(2-tenoyl)propyl]thio-1,2,3,4-tetrazole
150g Citric acid 1.0 Lactose 33.5g Dicalcium phosphate 70.0g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbovacs)
1500) 4.5g polyethylene glycol (Carbowax
6000) 45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol Appropriate amount Mix the compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68, and sodium lauryl sulfate. The above mixture was sieved through a No. 60 screen, and polyvinylpyrrolidone, Carbowax 1500 and 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed. Pass it through a No. 10 screen, put it in a tray and put it in an oven at 100℃ for 12 hours.
Dry for ~14 hours. The dry particles are sieved through a No. 16 screen, dried sodium lauryl sulfate and dry magnesium stearate are added and mixed, and compressed into the desired shape using a tablet machine. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish enough times for internal use. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth. Pigmented coatings are applied until the desired shade is obtained. After drying, the coated tablets are polished to a uniform gloss. Formulation example 3 1-methyl-5-[3-(3,4-dimethoxybenzoyl)propyl]thio-1,2,3,4
-Tetrazole 5g polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 10.0ml Add the above parabens, sodium metabisulfite and sodium chloride to about half the amount of distilled water above at 80°C while stirring. dissolve. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper to prepare an injection.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a phenyl group, or a cycloalkyl group, A is a trimethylene group, and R ² is a phenyl lower alkyl group, a naphthyl group, a phenyl group (a halogen atom, a lower alkyl group, a lower alkoxy group) , having one or two substituents selected from a lower alkanoylamino group and a hydroxyl group), or thienyl, furyl, 1,2,
Heterocyclic group selected from 3,4-tetrahydroquinolyl, pyrrolyl, pyranyl, pyridyl group (1 or 2 selected from lower alkyl group, halogen atom, lower alkoxycarbonyl group, and oxo group)
may have as many substituents. However, the bonding position of the heterocycle is at a position other than the heteroatom. )
] A tetrazole derivative and its salt.