KR840001570B1 - Process for preparing tetrazole derivatives - Google Patents

Abstract

Title compds. (I; R2 = H, lower alkyl, Ph, cycloalkyl; l=0-2; m=0-1; A=C alkylene; X=-CO-, -S(O)n-etc.; n=0-2; R3=lower alkyl, cycloalkyl, maphthyl, etc.), useful as antiulcer agent, were prepd. by the reaction of II(Z1=Y1 or -S(O)l-AY1; Y1=halogen, mercapto, amidinothio) and III(Z2=Y2-A-(X)m-, Y2; Y2=halogen, mercapto, amidinothio). Thus, 8g 4-acetaimidobutylate and 12g PCl5 were stirred in benzene for 1.5hr, and reacted with hydrogen azide benzene soln. to give 5.7g 4-(5-methyl-1,2,3,4,-tetrazol-l-yl)butylate.

Description

Method for preparing tetrazole derivatives

The present invention relates to a process for the preparation of novel tetrazole derivatives for use in the medical treatment of gastric and duodenal ulcers.

The compound of the present invention is a tetrazole derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

의 기(R⁵는 저급알킬임), 페닐고리에 하나의 할로겐 치환체를 가질 수 있는 페닐(저급)알킬, 할로겐, 저급알킬, 저급알콕시, 저급알카노일아미노, 하이드록시, 카르복시 및 이미노로 구성되는 군으로부터 선택한 1개 내지 3개의 치환체를 가질 수 있는 페닐, 저급알킬 및 아미노에서 선택한 치환체를 가질 수 있는 헤테로 사이클기로 치환한 저급알킬(이때 헤테로사이클기는 피리딜, 푸릴, 티아조릴 중에서 선택된다), 또는 질소, 산소, 유황 중에서 선택한 1개 내지 4개의 이종원자를 포함하는 것으로서 저급알킬, 할로겐, 카르복시, 옥소, 아미노, 저급알콕시카르보닐, 저급알콕시, 하이드록시, 니트로, 페닐, 사이클로알킬 및 저급알킬아미노로 구성되는 군에서 선택한 1 내지 2개의 치환체를 가질 수 있는 헤테로사이클기이며, 또 m이 0일 때는 R³는 구조식 -NR⁶R⁷의 기일 수도 있으며, 이때 R⁶가 수소, 저급알킬 또는 페닐(저급) 알킬이며, 또 R⁷가 수소, 저급알킬 또는 -CZ-NHR⁸의 기(Z는 유황 또는 저급알킬로 치환할 수 있는 아미노이고, 또 R⁸은 저급알킬 또는 아미노임), 저급알킬 치환체를 가질 수 있는 테트라조릴, -CO-R⁹의 기(R⁹는 저급알킬, 1개 내지 3개의 저급알콕시 치환체를 가질 수 있는 페닐, 사이클로알킬, 또는 질소 및 산소중에서 선택한 하나의 이종원자를 포함하는 5원 또는 6원의 불포화 헤테로사이클 기임)이거나 또는 그 R⁶및 R⁷가 그들이 결합되게 되어있는 질소원자와 같이 결합하여

기를 형성할 수 있고; 전기 구조식 -B-CO-R⁴에서 B는 저급알킬렌이고 또 R⁴는 하이드록시, 저급알콕시, 또는 구조식 -NR¹⁰R¹¹의 기이며, 이때 R¹⁰및 R¹¹은 같거나 다를 수가 있으며, 그 각기는 수소 또는(하이드록시, 푸릴, 피리딜, 페닐 및 1개 내지 2개와 저급알콕시 치환체를 갖는 페닐로 구성된 군에서 선택한 하나의 치환체를 가질 수 있는) 저급알킬, (하이드록시 또는 저급알콕시로 구성되는 군으로부터 선택한 하나의 치환체를 가질 수 있는) 사이크알킬, (저급알킬, 저급알콕시, 할로겐, 니트로, 카르복시 및 저급알킬아미노로 구성되는 군으로부터 선택한 1개 내지 2개의 치환체를 가질 수 있는) 페닐 또는 디아조릴이거나 또는 이 R¹⁰및 R¹¹가 사이클고리상에 질소 또는 산소의 중간원소가 포함되거나 포함되지 않음에 상관없이 이들이 결합하게 되어 있는 질소원자와 함께 결합하여 저급알킬치환체를 가질 수 있는 5원 또는 6원의 포화헤테로사이클기를 형성할 수도 있고, 단, m이 0일 때는 R³는 비치환페닐(저급)알킬이나 또는 비치환 페닐이 아니다.In formula (I), R ¹ is lower alkyl or phenyl or a group of the formula -S (O) L-A- (X) _m -R ₃ , and R ¹ is -S (O) L-A- (X) when _m -R ³ , R ² is hydrogen, lower alkyl, phenyl or cycloalkyl or when R ¹ is lower alkyl or phenyl R ² is a group of formula -B-CO-R ⁴ ; In the structural formula-S (O) ℓ-A- (X) _m -R ³ , X is -CO- or S- (O) _n- , ℓ and n are each 0, 1 or 2, and l is 0 Or 1, A is alkylene having 1 to 8 carbon atoms, and R ³ is lower alkyl, cycloalkyl, naphthyl,

Group of R ⁵ is lower alkyl, consisting of phenyl (lower) alkyl, halogen, lower alkyl, lower alkoxy, lower alkanoylamino, hydroxy, carboxy and imino which may have one halogen substituent in the phenyl ring Lower alkyl substituted with a heterocycle group which may have a substituent selected from phenyl, loweralkyl and amino which may have 1 to 3 substituents selected from the group, wherein the heterocycle group is selected from pyridyl, furyl, thiazolyl, Or lower alkyl, halogen, carboxy, oxo, amino, lower alkoxycarbonyl, lower alkoxy, hydroxy, nitro, phenyl, cycloalkyl and lower alkylamino, containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocycle group which may have 1 to 2 substituents selected from the group consisting of, and when m is 0, R ³ is a structural formula Or a group of —NR ⁶ R ⁷ , wherein R ⁶ is hydrogen, lower alkyl or phenyl (lower) alkyl, and R ⁷ is hydrogen, lower alkyl or a group of —CZ—NHR ⁸ (Z is sulfur or lower alkyl); Substitutable amino and R ⁸ is lower alkyl or amino), tetrazolyl which may have lower alkyl substituents, a group of -CO-R ⁹ (R ⁹ is lower alkyl, 1 to 3 lower alkoxy substituents) Phenyl, cycloalkyl, or a 5 or 6 membered unsaturated heterocycle group containing one heteroatom selected from nitrogen and oxygen, or R ⁶ and R ⁷ are the nitrogen atoms to which they are bound In combination

Can form groups; In the electrical formula -B-CO-R ⁴ , B is lower alkylene and R ⁴ is hydroxy, lower alkoxy, or a group of the formula -NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ¹¹ can be the same or different, Each of which is hydrogen or lower alkyl (which may have one substituent selected from the group consisting of hydroxy, furyl, pyridyl, phenyl and phenyl having 1 to 2 and lower alkoxy substituents), (hydroxy or lower alkoxy) Phenyl (which may have one substituent selected from the group consisting of), phenyl (which may have 1 to 2 substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, nitro, carboxy and lower alkylamino) Dia or quinolyl and quinoxalyl or or R ¹⁰ and R ¹¹ is a nitrogen atom to which they are attached to no matter not included or without a middle element of nitrogen or oxygen in the ring cycle, and R ³ is not an unsubstituted phenyl (lower) alkyl or or unsubstituted phenyl and may form a saturated heterocyclic 5- or 6-membered, which may have a lower alkyl substituent, provided that, m this case is zero coupling to the.

The compounds of the present invention have a prophylactic or medical action against gastric ulcers and / or duodenal ulcers, and are useful as medical drugs for gastric ulcers and / or duodenal ulcers in humans and other animals.

As used herein, the term "lower alkyl" includes straight or branched chain alkyl groups having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl and the like. It is included.

The term “cycloalkyl” denotes a cycloalkyl having from 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclhexyl, cyclooctyl and the like.

The term "lower alkoxy" denotes alkoxy having 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy and the like. do.

The term “lower alkylene” denotes alkylene having 1 to 6 carbon atoms, for example methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, tetra Methylene, pentamethylene, hexamethylene and the like.

The term “alkylene having from 1 to 8 carbon atoms” includes heptamethylene, 4-methylheptamethylene and octamethylene in addition to the lower alkylene described above.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

The term “lower alkanoylamino” denotes an alkanoylamino having 1 to 6 carbon atoms in the alkanoyl moiety, for example formamido, acetamido, propionamido, butylamido, isobutylamido , Pentylamido, hexylamide, and the like.

The term "lower alkoxycarbonyl" denotes alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butyric Oxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The term “lower alkylamino” denotes a monoalkyl- or dialkylamino having 1 to 6 carbon atoms in the alkyl moiety, for example methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butyl Amino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dibutylamino, dihexylamino.

“Phenyl (lower) alkyl” refers to benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl, -2-phenylethyl, 5-phenylpentyl, 6-phenyl Hexyl and 2-methyl-3-phenylpropyl. “Petyl (lower) alkyl-” with halogen substituents in the phenyl ring is 4-chlorobenzyl, 3-bromobenzyl, 2-fluorobenzyl, 2- (2-bromophenyl) ethyl, 2- (3-chloro Phenyl) ethyl, 2- (4-iodephenyl) ethyl, 1- (2-iodophenyl) ethyl, 1- (3-chlorophenyl) ethyl, 1- (4-bromophenyl) ethyl, 3- (2 -Fluorophenyl) propyl, 3- (3-chlorophenyl) propyl, 3- (4-bromophenyl) propyl, 4- (2-chlorophenyl) butyl, 4- (3-bromophenyl) butyl, 4 -(4-iodophenyl) butyl, 1,1-dimethyl-2- (4-chlorophenyl) ethyl, 5- (4-bromophenyl) pentyl, 5- (2-chlorophenyl) pentyl, 5- ( 3-fluorophenyl) pentyl, 6- (2-chlorophenyl) hexyl, 6- (3-iodophenyl) hexyl, 6- (4-bromophenyl) hexyl and 2-methyl-3- (4-chloro Phenyl) propyl.

“Lower alkyl with one substituent selected from the group consisting of hydroxy, furyl, pyridyl, phenyl and phenyl having 1 to 2 lower alkoxy substituents” is hydroxymethyl, 3-hydroxypropyl, 5- Hydroxypentyl, 2-phenylethyl, 3-phenylpropyl, 4-methoxybenzyl, 2- (3,4-diethoxyphenyl) ethyl, 4- (3-ethoxyphenyl) butyl, 2- (2-furyl ) Ethyl, 3- (2-furyl) propyl, 2- (3-furyl) ethyl, 5- (2-furyl) pentyl2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 3 -(3-pyridyl) propyl, 4- (2-pyridyl) butyl, 6- (2-pyridyl) hexyl and the like.

“Cycloalkyl with one substituent selected from hydroxy and lower alkoxy” includes 2-methoxycyclopropyl, 2-ethoxycyclopropyl, 3-methoxycyclopentyl, 2-methoxycyclopropyl, 2-ethoxycyclohexyl, 4-methoxycyclohexyl, 2-ethoxycyclohexyl, 4-butoxycyclohexyl, 5-methoxycyclooctyl, 2-hydroxycyclopropyl, 3- Hydroxycyclobutyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 5-hydroxycyclooctyl and the like.

"Imminos that can be substituted with one lower alkyl" include imino, methylimino, ethylimino, propylimino, isopropylimino, butylimino, pentylimino, hexylimino and the like.

“Phenyl which may have 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkanoylamino, hydroxy, carboxy and amino” is phenyl, 2-chlorophenyl, 3-chlorophenyl , 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4- Iodophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichloro Phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2, 5-dimethylphenyl, 3,4,5-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3, 4-diethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,5-dimethoxyphenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 4-formami Dophenyl, 2-propionamidophenyl, 3-butylamidophenyl, 4-hexyl amidophenyl, 3,4-diacetamidophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxy Phenyl, 3,4-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,4-dicarboxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2,4-diaminophenyl, 3-methyl-4-chlorophenyl, 2-chloro-6-methylphenyl, 2-methoxy-3-chlorophenyl and 3,5-di Tert-butyl-4-hydroxyphenyl and the like.

"Phenyl which may have 1 to 3 lower alkoxy substituents" includes the alkoxy-substituted phenyl groups described above.

“Phenyl which may have 1 to 2 substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, nitro, carboxy and lower alkylamino” includes the aforementioned substituted phenyl groups, as well as 2-nitrophenyl, 3- Nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2- (dimethylamino) phenyl, 3- (diethylaminophenyl), 4- (methylethylaminophenyl), 3,4-di (dimethylamino ) Phenyl and the like.

“Heterocycle group-substituted lower alkyl which may have one substituent selected from lower alkyl and amino on the heterocycle ring” as defined for the R ³ group is 2-pyridylmethyl, 3-pyridylmethyl, 4- Pyridylmethyl, 1- (2-pyridyl) ethyl, 2- (2-pyridyl) ethyl, 3- (4-pyridyl) propyl, 4- (2-pyridyl) butyl, 5- (3-pyrid Dill) pentyl, 6- (2-pyridyl) hexyl, 1,1-dimethyl-2- (2-pyridyl) ethyl. (2-methyl-6-pyridyl) methyl, (4-methyl-2-pyridyl) methyl, 2-furylmethyl, 3-furylmethyl, 1- (2-furyl) ethyl, 2- (2-furyl) Ethyl, 5- (3-furyl) pentyl, 6- (2-furyl) hexyl, 4- (2-furyl) butyl, 3- (2-furyl) propyl, (5-ethyl-2-furyl), methyl ( 3-methyl-2-furyl) methyl, (2-methyl-3-furyl) methyl, 2-thiazolylmethyl, 4-thiazolylmethyl, (2-methyl-4-thiazolyl) methyl, 2- (2- Ethyl-4-thiazolyl) ethyl, 3- (2-thiazolyl) propyl, 4- (2-methyl-5-thiazolyl) butyl, 6- (2-butyl-4-thiazolyl) hexyl, 1,1 -Dimethyl-2- (2-methyl-4-thiazolyl) ethyl, 2-amino-6-pyridylmethyl, 4-amino-2-pyridylmethyl, 2- (6-amino-2-pyridyl) ethyl , 5-amino-2-furylmethyl, 3-amino-2-furylmethyl, 4- (2-amino-3-furyl) propyl, (4-amino-2-thiazolylmethyl, 2- (2-amino- 4-thiazolyl) ethyl and 1,1, -dimethyl-2- (2-methyl-4-thiazolyl) ethyl and the like.

As defined for the R ³ group “It contains from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur and is lower alkyl, halogen, carboxy, oxo, amino, lower alkoxycarbonyl, lower alkoxy, hydroxy, nitro, Heterocycle groups which may have 1 to 2 substituents selected from the group consisting of phenyl, cycloalkyl and lower alkylamino, for example, thienyl, furyl, phyllyl, pyridyl, pyranyl, pilimidyl , Quinolyl, 1,2,3,4-tetrahydroquinolyl, imideazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1H-1,2,4- Triazolyl, 4H-1,2,4-triazolyl, thiazolyl, 1,2,3,4-tetrozolyl, benzimidazolyl, quinazolyl, 2,4-dihydroquinazolyl, 3H-, 4H Heterocycle groups such as -1,3,4-benzotriazinyl; There is also a heterocycle group having 1 to 2 substituents on the ring. Suitable examples of these heterocycle groups include 2-thienyl, 3-thienyl, 4-methyl-2-thienyl, 5-ethyl-2-thienyl, 5-hexyl-2-thienyl, 3-chloro-2- Thienyl, 2-chloro-3-thienyl, 5-bromo-3-thienyl, 5-fluoro-2-thienyl, 4,5-diethyl-2-thienyl, 5-amino-2- Thienyl, 4-nitro-2-thienyl, 5-carboxy-2-thienyl, 4-methoxy-2-thienyl, 2-furyl, 3-furyl, 4-methyl-2-furyl, 5-ethyl -2-furyl, 2,5-dimethyl-3-furyl, 4-ethoxy-2-furyl, 5-butoxy-2-furyl, 5-amino-2-furyl, 4-chloro-2-furyl, 5 Bromo-3-furyl, 5-carboxy-2-furyl, 5-propoxycarbonyl-2-furyl, 2-phyllyl, 3-phyllyl, 4-methyl-2-phyllyl, 1-methyl -2-phyllyl, 5-tert-butyl-2-phyllyl, 5-chloro-2-phyllyl, 4-iodo-3-phyllyl, 2-pyridyl, 3-pyridyl, 4-pyri Dyl, 3-methyl-2-pyridyl, 3-hydroxy-2-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 2,3, -dimethyl-6-pyri Dill, 5-nitro-2-pyridyl, 5-chloro-2-pyridyl, 4- Hydroxy-5-pyridyl, 6-ethyl-2-pyridyl, 5-hydroxy-2-pyridyl, 4-ethoxy-2-pyridyl, 5-hexyloxy-2-pyridyl, 6- Ethyl-2-pyridyl, 3-nitro-2-pyridyl, 4-nitro-2-pyridyl, 4-bromo-2-pyridyl, 6-fluoro-2-pyridyl, 4-amino-2 -Pyridyl, 3-chloro-2-pyridyl, 3-carboxy-2-pyridyl, 6-carboxy-2-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 4-methyl- 2-pyranyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 4-methyl-2-pyrimidyl, 5-hexyl-2-pyrimidyl, 6-propyl-2-pyr Imidyl, 5-methyl-2-pyrimidyl, 4-pentyl-2-pyrimidyl, 2-amino-4-methyl-6-pyrimidyl, 4-hydroxy-2-pyrimidyl, 4- Amino-2-pyrimidyl, 4-nitro-2-pyrimidyl, 4-carboxy-2-pyrimidyl, 4-methoxy-2-pyrimidyl, 2-quinoryl, 3-methyl-2- Quinolyl, 4-methoxy-2-quinolyl, 5-nitro-2-quinolyl, 3-chloro-2-quinolyl, 3-hydroxy-2-quinolyl, 5-amino-2-quinolyl, 4-quinolyl, 2-hydroxy-5-quinolyl, 2-hydroxy-6-quinolyl, 2-hydroxy-7-quinolyl, 2-hydroxy-8-quinolyl, 2-methoxy -7-quinolyl, 2-imideazolyl, 4-imideazolyl, 1-methyl-2-imideazolyl, 4-chloro-2-imideazolyl, 5-methoxy-2-imide Deazolyl, 5-hydroxy-2-imideazolyl, 4-amino-2-imideazolyl, 1-nitro-2-imideazolyl, 4H-1,2,4-triazole-5 -Yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-3-yl, 4-methyl-1,2,4-triazol-3-yl, 3,4-dimethyl-1,2,4-triazol-5-yl, 3-methoxy-1,2,4-triazol-5-yl, 3-amino-1,2,4-triazole- 5-yl, 3-nitro-1,2,4-triazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 4-methyl-2-thiazolyl, 4-methoxy- 2-thiazolyl, 2-amino-4-thiazolyl, 4-nitro-2-thiazolyl, 5-hydroxy-2-thiazolyl, 2-benzimidazolyl, 4-methyl-2-benzimidazolyl , 5-methoxy-2-benzimidazolyl, 6-amino-2- Zidemidazolyl, 7-nitro-2-benzimidazolyl, 4-hydroxy-2-benzimidazolyl, 1,2,3,4-tetrozol-1-yl, 1,2,3, 4-tetrazol-5-yl, 1-methyl-1,2,3,4-tetrazol-5-yl, 1-hexyl-1,1,3,4-tetrazol, -5-yl, 1- Propyl-1,2,3,4-tetrazol-5-yl, 1-butyl-1,2,3,4-tetrazol-5-yl, 1-pentyl-1,2,3,4-tetrazole -5-yl, 1-hexyl-1,2,3,4-tetrazol-5-yl, 1-cyclohexyl-1,2,3,4-tetrazol-5-yl, 1-cyclopropyl -1,2,3,4-tetrazol-5-yl, 1-cyclobutyl-1,2,3,4-tetrazol-5-yl, 1-cyclopentyl-1,2,3,4 -Tetrazol-5-yl, 1-cycloheptyl-1,2,3,4-tetrazol-5-yl, 1-cyclooctyl, -1,1,3,4-tetrazol-5-yl , 1-phenyl-1,2,3,4-tetrazol-5-yl, 5-methyl-1,2,3,4-tetrazol-5-yl, methylamino-1,2,3,4- Tetrazol-1-yl, 5-butylamino-1,2,3,4-tetrazol-1-yl, 3,4-dihydroxyquinazolin-4-one-2-yl (4-hydroxyquina Zonin-2-yl), quinazolin-2-yl, quinazolin-4-yl, 3-methyl-3,4-di Idroquinazolin-4-one-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-amino-1,3,4-oxadiazol-2-yl, 5- Methoxy-1,3,4-oxadiazol-2-yl, 5-nitro-1,3,4-oxadiazol-2-yl, 5-hydroxy-1,3,4--oxadiazole 2-yl, 5-chloro-1,3,4-oxadiazol-2-yl, 5-carboxy-1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazole -2-yl, 5-amino-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-methoxy-1,3, 4-thiadiazol-2-yl, 5-chloro-1,3,4-thiadiazol-2-yl, 5-hydroxy-1,3,4-thiadiazol-2-yl, 5-nitro -1,3,4-thiadiazol-2-yl, 3,4-dihydrocarbostyryl-6-yl, 1-methyl-3,4-dihydrocarbostyryl-6-yl, 1-propyl -3,4-dihydrocarbostyryl-6-yl, 3H, 4H-1,3,4-benzotriazin-5-one-2-yl and 3-methyl-3H, 4H-1,3,4 -Benzotriazin-5-one-2-yl and the like.

Formula -NR ⁶ R ⁷ R ⁷ "tetra that may have a lower alkyl substituent quinolyl and quinoxalyl" as previously defined with respect to the way of example, 1,2,3,4-tetrazol-5-yl, 1-methyl-1 in , 2,3,4-tetrazol-5-yl, 1-ethyl-1,2,3,4-tetrazol-5-yl, 1-propyn-1,2,3,4-tetrazol-5 -Yl, 1-butyl-1,2,3,4-tetrazol-5-yl, 1-pentyl-1,2,3,4-tetrazol-5-yl and 1-hexyl-1,2,3 , 4-tetrazol-5-yl and the like.

Formula -CO-R ⁹ "groups and nitrogen of 5 or 6 members, which contain a single heteroatom selected from oxygen, unsaturated heterocycle" in the R ⁹ as defined with respect to, for example, pyridyl, pyranyl, pireu Loryl, furyl especially 2-pyridyl, 3-pyridyl, 4-pyridyl, 2H-pyran-2-yl, 2H-pyran-3-yl, 4H-pyran-2-yl, 3,4-dihydro -2H-pyran-2-yl, 3,4-dihydro-2H-pyran-4-yl, 2-pyrroline, 3-pyrroline, 2-furyl, 3-furyl.

“Thiazolyl” and 2-thiazolyl, 4-thiazolyl and 5-thiazolyl as defined for R ¹⁰ and R ¹¹ in formula —NR ¹⁰ R ¹¹ .

In formula -R ¹⁰ R ¹¹ , R ¹⁰ and R ¹¹ are bonded together with the nitrogen atom to which they are bound, regardless of whether or not intermediate elements of nitrogen or oxygen are included on the cycle ring. A 5- or 6-membered saturated heterocycle group ”which may be used as an example, such as filoridino, morpholino, 1-pyredidyl1-piperazinyl, 4-methyl-1-piperazinyl, 4-methyl -1-piperazinyl, 4-propyl-1-piperazinyl, 4-tert-butyl-1-piperazinyl, 4-hexyl-1-piperazinyl and the like.

The compounds of the present invention can be prepared by various methods. For example, a compound in which R ² in the structural formula (I) is a -B-CO-R ⁴ group can be prepared according to the following Scheme-I.

Reactivity-I

In Reaction-I above, R ¹⁰ , R ¹¹ , B are as described above and R ¹ ′ is lower alkyl or phenyl, R ¹² is lower alkyl and Y is halogen.

The reaction of aminocarboxylic acid (2) and lower alcohol (3) in the above Reaction Scheme -I is carried out under the conditions generally used in conventional esterification reaction and is usually carried out under a catalyst. The catalyst can be used any conventionally used in conventional esterification reactions.

Suitable examples of the catalyst include inorganic acids (e.g. hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, poric acid, borontrifluoride perchloric acid), organic acids (e.g. trifluoroacetic acid, trifluoromethanesulphonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid , Benzenesulfonic acid, ethanesulfonic acid), trifluorometansulfonic anhydride, thionyl chloride, acetone dimethylacetal or the like. Acidic ion exchange resins are also used as catalysts. The amount of these catalysts is not critical but may be any amount in the range used in conventional esterification reactions.

The above-mentioned esterification reaction may be performed in a suitable solvent or without using a solvent. Any solvent used in conventional esterification may be used. Suitable examples of the solvent include aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride), ethers (e.g. diethyl ether, tetrahydrofuran, di Oxane, ethylene glycol monomethyl ether), or analogs thereof.

Compounds (2) and (3) can be used in a wide range of ratios, but when the solvent is not used to prepare the desired compound in high yield, the latter is used in excess of the former, and when the solvent is used The latter is used in an amount of 1-5 mol, preferably 1-2 mol, with respect to 1 mol of the former.

Preferably, the reaction proceeds while the water produced in the reaction system is removed using an appropriate drying agent such as anhydrous calcium chloride, anhydrous calcium sulfate or phosphorus pentoxide to increase the yield of the product.

The reaction temperature is not critical but is preferably in the range of about -20 to 200 ° C, more preferably about 0 to 150 ° C. The reaction period may vary depending on the type of initiator and the reaction conditions, but usually the reaction is completed within about 10 minutes to 20 hours. The aminocarboxylic acid ester (4) obtained by the above esterification reaction is then reacted with the carboxyhalide (5) in the presence of a dehydrogenating-halogenating agent.

Basic compounds are usually used as the dehydrogenation-halogenating agent. Suitable examples of base compounds include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or inorganic bases such as carbonate and alcoholates such as sodium methylate and sodium ethylate and triethylamine, pyridine, N , N-dimethylaniline, N-methylmorphinine, 4-dimethylaminopyridine, 1,6-diazabicyclo [4.3.0] nonene-5 (DBN), 1,5-diazabicyclo [5 . 4.0] organic bases such as undecene-5 (DBU) and 1,5-diazabicyclo [2.2.2] octane (DABCO). The aminocarboxylic acid ester (4) may substitute a solvent by using it in excess instead of using any specific solvent.

The above reaction can be carried out in a suitable solvent or without using any solvent. Any inert solvent which has no side effects in the reaction can be used. Suitable examples of the solvent include halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride), ethers (e.g. diethyl ether, tetrahydroputane, dioxane), aromatic hydrocarbons (e.g. benzene, toluene, chiselene ), Esters (eg methyl acetate, ethyl acetate), aprotic solvents (eg N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide), or analogs thereof.

Although the amount of compound (4) and compound (5) is not fixed, when using a solvent, the latter is normally used in the same amount with respect to 1 mol of former electrons, or 1 to 2 mol preferably. The reaction temperature and the duration of the reaction are not critical but usually the reaction is carried out for 30 minutes to 12 hours at a temperature of -30 to 100 ° C, preferably 0 to 50 ° C.

Compound (6) thus obtained is reacted with PCl ₅ in a suitable solvent. Any inert solvent which has no side effects in the reaction can be used. Suitable examples of the solvent include aromatic hydrocarbons (e.g. benzene, xylene, toluene), halogenated aromatic hydrocarbons (e.g. chlorobenzene, bromobenzene), ethers (e.g. diethyl ether, dioxane), aliphatic hydrocarbons (Eg, n-hexane, n-heptane) and analogs thereof. PCl ₃ is usually used in an amount of about 1 to 2 mol, preferably 1 to 1.2 mol, based on 1 mol of compound (6). The reaction is usually carried out for a period of about 30 minutes to 5 hours at a temperature of -20 to 50 ° C, preferably 0 to 25 ° C. The desired imine derivative is then reacted with HN ₃ without separation from the reaction mixture to afford the desired compound (1a).

Hydrogentriazide (HN ₃ ) is usually used in the form of a solution dissolved in benzene, xylene, diethyl ether or n-hexane. The amount of such a derivative and NH ₃ is usually used in an amount in the range of about 1 to 5 mol, preferably 1 to 3 mol, with respect to 1 mol of the former. Reaction is performed for 3 hours-2 days at the temperature of 0-150 degreeC.

Compound (1a) can be hydrolyzed and converted to another compound (1b) of the present invention. Hydrolysis usually proceeds under a catalyst. Any catalyst commonly used in conventional hydrolysis can be used. Suitable examples of catalysts are basic compounds such as sodium hydroxide, potassium hydroxide and barium hydroxide and inorganic acids such as sulfuric acid, hydrochloric acid and nitric acid. The amount of catalyst is not critical. The hydrolysis proceeds in a conventional manner, preferably in a suitable solvent such as water or lower alcohols (eg methanol, ethanol, isopropanol). The reaction temperature is also not critical but usually ranges from room temperature to about 150 ° C., preferably from 50 to 110 ° C. The reaction usually completes in about 30 minutes-10 hours. The carboxylic acid derivative (1b) can be converted to another compound (1c) of the present invention by carrying out a conventional amido bond-forming reaction with the amine (7).

In this reaction, a compound having an active carboxyl group may be used instead of compound (1b), and a compound having an activated amino group may be used instead of amine (7). The amido bond-forming reaction can be carried out under the conditions used in the conventional amido bond-forming reaction. For example, this reaction consists of a mixed anhydride method, i.e., a reaction of carboxylic acid (1b) with an alkyl halocarboxylate to make a mixed acid anhydride, and reaction of the resulting mixed acid anhydride with an amine (7). ; (Ii) converting the active ester method, that is, the carboxylic acid (1b) to an active ester such as p-nitrophenylester or N-hydrooxysucciamide ester or 1-hydroxybenzotriazole ester and the activity thereof A method consisting of reacting the ester with the amine 7 again; (Iii) a carbodiimide method, i.e., a process consisting of condensing carboxylic acid (1b) with an amine in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonylimidazole, (iii) carboxylic acid halide Method, i.e., consisting of converting carboxylic acid (1b) to its halide compound and reacting the halide compound with amine (7), (i) other methods, such as carboxylic acid (1b) Treatment with a dehydrating agent such as to convert it to an acid anhydride compound and then react the acid anhydride compound with an amine (7) or to convert the carboxylic acid (1b) to an ester as a lower alcohol; The obtained ester can then proceed in a way consisting of reacting with the amine 7 at high pressure and high temperature. It is preferable to use the mixed anhydride method and the carboxylic acid halide method among these methods.

Alkyl halocarboxylates used in the mixed anhydride process include, for example, methylchloroformate, ethyl bromoformate, ethylchloroformate, ethyl bromoformate, isobutylchloroformate and other analogues.

Mixed anhydrides can be prepared by known Shoten-Bauman reactions and can be used in subsequent reactions with amines (7) to prepare compounds of the invention (1c) without separation from the reaction mixture. The Shoten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any compound commonly used in the Shoten-Baumann reaction, for example triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] nonene Organic bases and carbonic acids such as -5 (DBN), 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) Inorganic base compounds such as potassium, sodium carbonate, potassium bicarbonate and sodium bicarbonate. The reaction usually proceeds for about 5 to 10 hours at a temperature of -20 to 110 ° C, preferably 0 to 50 ° C. Mixed acid anhydride processes are usually run in a suitable solvent. Solvents include all solvents normally used in conventional mixed anhydride methods. Suitable examples of solvents include halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane), aromatic hydrocarbons (e.g. benzene, toluene, xylene), ethers (e.g. diethyl ether, tetrahydrofuran, dimethoxyethane) , Esters (eg methylacetate, ethyl acetate), aprotic polar solvents (eg dimethylformamide, dimethylsulfoxide, hexamethylphosphorictriamide), or analogs thereof.

Carboxylic acid (1b), alkyl halocarboxylate and amine (7) are usually used in the same molar amount, but alkyl halocarboxylate and amine (7) are 1 to 1.5 moles based on moles of carboxylic acid (1b). Can also be used as

Carboxylic acid halide crimes are prepared by reacting carboxylic acid (1b) with a halogenating agent to produce a halide compound of carboxylic acid (1b), and then separating or purifying the resulting carboxylic acid halide from the reaction mixture or not. It proceeds by making compound (1c) of this invention react with amine (7) in the absence. The reaction of the carboxylic acid (1b) with the halogenating agent proceeds in the presence or absence of a solvent. The solvent includes all solvents which have no side effects in the reaction, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride), ether (Eg, dioxane, tetratidefuran, diethyl ether), dimethylformamide, dimethyl sulfoxide and the like.

Halogenating agents include all conventional halogenating agents capable of converting the hydroxy group of the carboxyl group to halogen, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide and the like There is an analog.

The ratio of the amount of the carboxylic acid (1b) and the halogenating agent used is not important, but when the reaction is carried out without solvent, the latter is used in a large amount, and when the reaction is carried out in a solvent, the latter is one mole of the former, More preferably, it is used in the amount of 1-4 mol. The reaction temperature and reaction time are not critical, but usually the reaction proceeds from room temperature to about 100 ° C. for about 30 minutes to 6 hours at temperatures from 50 to 80 ° C. preferably. The carboxylic acid halide thus obtained is reacted with amine (7) under the same conditions as used in the reaction of compound (4) and compound (5). The compounds of the present invention can also be prepared by the method as shown in the following Scheme-II.

[Reactivity-II]

R ¹ ′, R ⁴ , B and Y in the reaction scheme (II) are as described above. The reaction of Compound (8) and Compound (9) in the above Scheme-II proceeds to the conditions normally used in conventional dehydrogenation-halogenation reactions. This reaction is preferably carried out using a dehydrogenation-halogenating agent in the presence of an alkali metal iodine such as sodium iodide or potassium iodide. The amount of the compound (9) is not critical, but is usually at least the same molar amount per mole of the compound (8), preferably 1 to 2 moles.

The dehydrogenating-halogenating agent used in the above reaction includes various basic compounds, examples of which include inorganic bases (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate), alkali metals (e.g. sodium , Potassium), tertiary amines (e.g., triethylamine, pyridine, N, N-methylaniline) and analogs thereof.

This reaction can be carried out in the presence or absence of a solvent. This solvent includes all solvents without adverse reactions to the reaction, for example, lower alcohols (e.g. methanol, ethanol, propanol), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, ethylin glycol mono) Methylethyl), aromatic hydrocarbons (eg benzene, toluene, xylene), ketones (eg acetone, methylethylketone), dimethylformamide, dimethylsulfoxamide, hexamethylphosphorictriamide or the like.

The reaction is usually carried out at room temperature to 200 ° C., preferably at 50 to 150 ° C. and at a temperature of about 30 minutes to 6 hours. Compounds in which R ¹ is —S (O) 1 -A- (X) _m -R ³ in the formula (1) and ℓ is 0 can be prepared by the method as shown in the following scheme-III, for example. Can be.

[Reactivity-III]

In Reaction Scheme-III, R ³ , X, A, m and the like are as described above, R ′ ² is hydrogen, lower alkyl, phenyl or cycloalkyl, any one of Y ¹ and Y ² is halogen The other is a mercapto or amidinothio group.

The condensation reaction of the compound (10) and the compound (10) in the above Reaction Scheme-III proceeds under the same conditions as those used in the reaction of the compound (8) and the compound (9) as in the above Reaction Scheme-II.

When the starting compound (11) is a compound having-(X) _m -device -CO-, the keto group may be protected by a conventional keto protecting group by a conventional method, and after the condensation reaction with the compound (10), the keto protecting group Is removed in the conventional way. This keto protecting group includes all groups that are stable under the condensation reaction conditions described above, for example, lower alcohols (e.g. methanol, ethanol), lower alkylenedithiols (e.g. ethylene glycol, 1,3-trimethylenediol), Lower alkanethiols (eg, methanethiol, ethanethiol), lower alkylenedithiols (eg, 1,2-ethylenedithiol, 1,3-trimethylenedithiol) and analogs thereof.

Removal of keto protecting groups can proceed according to conventional methods. For example, ketal groups formed as lower alcohols or lower alkylenediols are acid catalysts such as inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid) and organic acids (e.g. acetic acid, propionic acid, p-toluenesulphonic acid). It can be converted easily to the corresponding carbonyl group by contact with.

The reaction can be carried out in a suitable solvent such as alcohol (e.g. methanol, ethanol), ketone (e.g. acetone, methyl ethyl ketone), ether (e.g. dioxane), aprotic polar solvents (e.g. dimethyl sulfoxide, dimethylform Amides) and analogs thereof.

When using an organic solvent, no specific acid catalyst is required. This reaction is usually carried out at room temperature up to 200 ° C., preferably at a temperature of 50-100 ° C. for about 30 minutes to 12 hours. In addition, when the keto group is protected in the form of a thioketal formed by treatment with a lower alkeninthiol or a lower alkylenedithiol, the thioketal can be converted to the corresponding carbonyl group by a conventional method.

For example, thioketal protecting groups can be easily removed by treating it with water temperature-hydrogen chloride, mercury chloride-cadmium carbide, silver nitrate-N-chlorosuccinimide, or the like. Removal of the protecting group is carried out at a temperature of from 0 to 100 ° C., preferably from 50 to 80 ° C., in a suitable solvent such as a water soluble lower alcohol (eg methanol, ethanol) or a mixture of water and an organic solvent such as acetone, acetonitrile or the like. You can proceed during the time.

Some of the starting compounds (10) and (11) used in the above-mentioned reaction degree-III include known compounds, but also some of the novel compounds that can be produced by the methods as shown in the following reactions-IV to VIII.

[Reactivity-IV]

In Scheme-IV, R ³ , A, Y ² are as described above, one of Y ³ and Y ⁴ is halogen and the other is mercapto or amidinothio group. The reaction of compound (12) and compound (13) in Scheme -IV proceeds under the same conditions as those used for the reaction of compound (8) and compound (9) in Scheme -II.

The oxidation reaction for converting compound (11a) to compound (11b) is usually carried out using an oxidizing agent in a suitable solvent. All solvents can be used in any of the conventional solvents, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid), alcohols (e.g. methanol, ethanol), halogens and hydrocarbons (e.g. chloroform , Dichloromethane), or analogs thereof.

The oxidizing agent may also be any conventional oxidizing agent effective for oxidizing mercapto groups to sulfoxide or sulfone groups, for example peracids (performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o Carbonyl and benzoic acid), hydrogen peroxide, dichromic acid, dichromate (eg sodium dichloromate, potassium dichloromate), permanganic acid, permanganate (eg sodium permanganate, potassium permanganate) or analogs thereof.

This oxidant is usually used in an amount of 1 mole or more, preferably 1 to 1.5 moles, per 1 mole of the compound (11a).

The reaction is usually carried out at about 0 to 40 ° C., preferably at about room temperature for about 20 to 50 hours.

Oxidation for converting compound (11a) to the corresponding sulfonic acid derivative (11c) also proceeds under the same conditions as used to oxidize compound (11a) to compound (11b), provided that the oxidizing agent is added to 1 mole of compound (11a) 2 mol or more, preferably 2 to 4 mol, and the reaction time is in the range of about 3 to 8 hours.

The oxidation reaction for converting compound (11b) to compound (11c) is also carried out under the same conditions as used for oxidizing compound (11a) to compound (11b). In addition, the compound in which Y ² is an amidinothio group in the above Reaction Scheme-IV is subjected to thiolation of the halogenated compound under the same conditions as those used for reacting the compound (11d) or (11e) with urea as shown in Reaction Scheme-V shown below. It can be prepared by reacting with urea.

Reactivity-V

In Reactivity-V, A and Y are as described above, R ³ ′ is an aromatic group among the groups defined for R ³ , Y ⁵ is halogen and D is a keto group protected with a suitable keto protecting group.

The reaction between the compound (14) and the compound (15) is such that the compound (14) is used in the same molar amount or excess, preferably 1 to 3 moles, with respect to 1 mole of the compound (15), and the reaction temperature is about 0 to 150 degreeC, Preferably it is in the range of 0-room temperature, and reaction time advances in a suitable solvent on the conditions which become the range of about 1-5 hours. Suitable examples of solvents are nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, 1,2-dichloroethane or the like. This reaction is preferably carried out in the presence of a catalyst usually used in Friedel-Crafts reactions. Suitable examples of catalysts include ammonium chloride, antimony pentachloride, ferric chloride, titanium tetrachloride, borontrifluoride, ditin chloride, zinc chloride, water temperature of chloride, hydrogen fluoride, sulfuric acid, polylinic acid, phosphorpentachloride or the like. Among them, aluminum chloride, tin tin chloride or zinc chloride is particularly suitable. It is used in the same molar amount or excess amount with respect to 1 mol of catalyst compounds (15), Preferably it is 1-3 mol amount.

The reaction of the compound (11d) or (11e) with thiourea is carried out in the presence or absence of a solvent.

The solvent may be the same as that used in the reaction of the compounds (8) and (9) in Reactivity-II. The ratio of the amount of the compound (11d) or (11e) and thiourea is not important, but the latter is usually used in an amount of 1 to 5 moles, preferably 1 to 2 moles, per 1 mole of the former. The reaction temperature is also not critical but usually ranges from room temperature to 200 ° C., preferably 40 to 150 ° C. This reaction can also be carried out in the presence of a dehydrogenation-halogenating agent as used in the reactions of compounds (8) and (9) of Scheme-II.

The protection of the keto group of compound (11d) is effected in the same manner as described in Reactivity-III above, i.e., compound (11d) is lower alcohol (e.g. methanol) in the presence of a suitable solvent in anhydrous conditions or in the absence of a solvent and in the presence of a catalyst. , Ethanol), lower alkylenediol (e.g. ethylene glycol, 1,3-trimethylenediol), lower alkanediol (e.g. methanethiol, ethanethiol), lower alkylenedithiol (e.g. 1,2-ethylene By treating with a suitable keto protecting agent such as dithiol, 1,3-trimethyledinthiol). Suitable examples of catalysts include sulfonic acids (e.g. ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid), Lewis acids (e.g. zinc chloride, aluminum chloride, borontrifluoride) or analogues thereof, and suitable examples of solvents are ethers (e.g. , Dioxane, tetrahydrofuran), aromatic hydrocarbons (eg benzene, toluene), halogenated hydrocarbons (eg chloroform, methyl chloride). There is an analogue. Ketone protecting agents are usually used in excess in amounts of at least the same molar amount relative to compound (11d). This reaction is carried out at a temperature from 0 to room temperature, preferably to 0 to 80 ° C.

[Reactivity-VI]

In Reaction Scheme-VI, A, D, Y, R ³ and the like are as described above, and one of E ¹ and E ² is cyano and another is MgY ⁶ group, and Y ⁶ is halogen.

The reaction of compound (16) and compound (17) is carried out in a suitable solvent at -70 to 50 ° C, preferably at -30 ° C to room temperature for about 1 to 6 hours.

The solvent may be any inert solvent commonly used in the Grignard reaction, for example ether (e.g. diethylethyl, dioxane, tetrahydrofuran), aromatic hydrocarbon (e.g. benzene, toluene), saturated hydro Carbon (eg, pentane, hexane, heptane, cyclohexal), or analogs thereof.

Compound (17) is used in an amount of at least the same molar amount, preferably 1 to 1.5 moles, per 1 mole of compound (16). The reaction of compound (11h) or (11i) with thiourea is carried out under the same conditions as those used for reacting compound (11d) or (11e) with thiourea in Scheme-V. In addition, the keto group protection of compound (11h) is also made in the same manner as in the keto group protection of compound (11d).

Reactivity-VII

In Reactivity-X, R ² ′ and Y are as described above.

The reaction of compound (10a) with thiourea is also carried out under the same conditions as used in the reaction of compound (11d) or (11e) with thiourea in Reactivity-V. The compound (1) of the present invention in which the group R ¹ is a -SA-CO-R ³ group can also be prepared by the method as shown in the following schemes -XII-XII.

[Reactivity-VIII]

R ² ′, R ³ , Y, Y ¹ , Y ² , A and L in the above reaction degree-V are as described above.

The reaction of the tetrazole derivative (10) with the nitrile (18) is carried out under the same conditions as those used for the reaction of the compounds (8) and (9) in Reactivity-II. Oxidation of compound (19) is also carried out in the same manner as in Scheme-IV. The reaction of the compound (19 ') with the Grignard reagent (20) is also carried out under the conditions as used in the reaction of the compounds (16) and (17) of Reactivity-VI. In this reaction, the reactor of compound 19 'and the Grignard reagent may be exchanged.

Reactivity-IX

R ² ′, R ³ , Y, Y ¹ , Y ² , A and L in the above degree-response are as described above. Reaction of compound (10) and compound (21) is performed on conditions and with what was used by reaction of compound (8) and (9) of Reaction degree-II.

The oxidized reaction of compound (22) is also carried out in the same manner as in IV. Compound 22 'may be prepared by conventional methods for preparing Grignard reagents, for example, by treating the compound 22' with Mg in a suitable solvent for 30 minutes to several hours at a temperature from room temperature to 100 캜. It is easily converted to compound (23) by treating in the same manner.

In this reaction, Mg (magnesium) is used in an amount of at least the same molar amount, preferably 1 to 1.5 moles, per 1 mole of the compound (22 ').

In addition, the reaction of the compound (23) with the compound (24) is carried out under the same conditions as those used for the reaction of the compounds (16) and (17) in Reactivity-IV.

[Reactivity-X]

R ² ′, R ³ , Y ¹ , Y ² , A and L are the same as described above and R ¹³ is lower alkyl.

The reaction of the compound (10) and the compound (25) is carried out under the same conditions as those used for the reaction of the compounds (8) and (9) in Reactivity-II.

Hydrolysis of the compound (26) is carried out in the same manner as in the hydrolysis of the compound (1a) of Reactivity -I. Oxidation of compound (27) is also carried out in the same manner as in Scheme-IV. The reaction of compound (27 ') with compound (28) is carried out in a suitable inert solvent for about 1 to 6 hours at a temperature of -70 ° C to room temperature, preferably -30 ° C to room temperature. Reasonable examples of inert solvents include ethers (e.g. diethyl ether, dioxane, tetrahydrofuran), aromatic hydrocarbons (e.g. benzene, toluene), saturated hydrocarbons (e.g. hexane, hefran, pentane, cyclohexane) Or an analog thereof.

Compound (28) is used in an amount of at least 2 mol, preferably 2-3 mol, based on 1 mol of compound (27 ').

Reactivity-XI

In Reactivity-XI, R ² ′, R ³ , Y, A and 1 are as described above, Y ⁷ is halogen and M is a metal such as zinc, cadmium or magnesium.

The reaction of the compound (27 ') with the halogenating agent is carried out in the same manner as in the reaction of the compound (1b) and the halogenating agent in Reactivity-I. The reaction of Compound (29) with Compound (30) or (31) is carried out under the same conditions as those used for the reaction of Compound (28) of Compound (27 ') in Reactivity -X.

In this reaction, compound (30) or (31) is used in an amount of at least the same molar amount, preferably 1 to 1.5 moles, per 1 mole of compound (29).

[Reactivity-XII]

In Reactivity-XII, R ² ′, R ³ , Y, A and L are as described above and F is lower alkylene.

The reaction of the compound (32) and the compound (33) is carried out under the same conditions as those used in the reaction between the compound (27 ') and the compound (28) of Reactivity -X. Conversion of compound (34) to compound (1f) is carried out in the same manner as in the conversion of thioketal (where the keto group is protected with lower alkadiol or lower alkylenedithiol) to the corresponding carbonyl group in Reaction-III. can do.

Group is phenyl, the compound of the present invention (1) is a group R ³ can also be prepared by the hydrolysis of the compounds to be phenyl having lower alkoxy substituent, and the hydrolysis is R ³ that has a hydroxy substituent, for example, that The compound can be carried out by refluxing in hydrobromic acid for 1-6 hours.

The compounds of the present invention may also be prepared by the method as shown in the following Reactivity Scheme -X.

[Reactivity-XIII]

In the above Reactivity-X, R ² ′, R ³ ′, A and 1 are as described above, and Y ⁸ is halogen or hydroxy or a group of the following structural formula.

The reaction of the compound (35) and the compound (14) is carried out under the same conditions as those used for the reaction of the compound (14) and the compound (15) in Reactivity -V. Furthermore, the compound (1) of the present invention, wherein R ¹ is -S (O) L-AS (O) nR ³ , can be prepared by the method as shown in the following Reactivity-XIV.

Reactivity-XIV

In Reactivity-XIV, R ² ′, R ³ ′, A, Y ¹ , Y ² and 1 are as described above.

The reaction of compound (36) and compound (37) is carried out under the same conditions as those used for reaction of compound (8) and compound (9) in Reactivity-II. The starting compound 36 used in the above Reactivity-IV can be prepared, for example, by the same method as shown in the following Reactions-XV to XVII.

[Reactivity-XV]

In Reactivity-XV, R ² ′, A and Y are as described above, R ⁹ is a mercapto or amidinothio group and Y ¹⁰ is halogen.

The reaction of the compounds (38) and (39) is carried out under the same conditions as those used for the reactions of the compounds (8) and (9) in Reactivity-II. Compound (38) of the present invention having the following structural formula when using compound (38) twice or more in the reaction, that is, 2 moles or more, preferably 2 to 4 moles, per 1 mole of compound (39) You can create your own.

In the above formula (1i), R ² ′ and A are as described above.

[Reactivity-XVI]

In Reactivity-XVI, R ² ′, A and Y are as described above and RY ¹¹ and Y ¹² are each a mercapto or amidinothio group. The reaction of the compounds (40) and (41) is also carried out under the same conditions as those used for the reactions of the compounds (8) and (9) in Reactivity-II. In addition, when the compound (40) is used in an amount of 2 times or more with respect to 1 mole of the compound (41), preferably in an amount of 2 to 4 moles, the compound (1i) of the present invention is directly I can make it.

Reactivity-XVII

In Reactivity-X, R ² ′ and A are as described above and Y ¹³ is a halogen or mercapto or amidinothio group. The oxidation reaction for converting compound (36c) to compound (36d) and the oxidation reaction for converting compound (36d) to compound (36e) are the same as those used for the oxidation of compound (11a) to (11b) in Reaction-IV. Carry out on condition. In addition, the oxidation reaction for converting compound (36c) to compound (36e) is carried out under the same conditions as used in the oxidation reaction for converting compound (11a) to compound (11c) in Reaction-IV.

기인 본 발명 화합물(1)은 다음의 반응도-ⅩⅧ에 도시한 바와 같은 방법으로 제조할 수 있다.Group R ³

The compound (1) of the present invention can be produced by the method as shown in the following Reactivity-X.

[Reactivity-XVIII]

In the above Reactivity-X, R ² ′, R ⁵ , A, Y and 1 are as described above. The reaction between the compound 361 and the compound 42 is carried out under the same conditions as those used for reacting the compound 11d or 11e with thiourea in Reaction-V. The sulfoxide or sulfone derivative (1 L) in the compound of the present invention can be prepared by the method as shown in the following Reactivity-X.

[Reactivity-XIX]

In the above Reactivity-X, R ² ′, R ³ , A and m are as described above, X ′ is a group S (O) n or —CO—, and X ″ is a group S (O) n ″ or —CO And ℓ ′, ℓ ″ n ′ and n ″ are 0 or 1 or 2, respectively, provided that these symbols ℓ ′, ℓ ″, n ′ and n ″ are (ℓ ″ + n ″)-(ℓ ′ + n ') is in the range of ≥ 1. The oxidation reaction for converting compound (1k) to compound (1l) can be carried out in the same manner as the oxidation reaction of Reactivity-IV, and the number of oxygen introduced can be adjusted by controlling the amount of oxidizing agent.

For example, when introducing one oxygen into compound (1k), the oxidizing agent is used in an amount of 1 mole or more, preferably 1 to 1.5 moles, with respect to 1 mole of compound (1k); In the case of introducing two oxygens, the oxidizing agent is used in an amount of 2 mol or more, preferably 2 to 2.5 mol, with respect to 1 mol of the compound (1k); In the case of introducing three oxygens, the oxidizing agent is used in an amount of 3 moles or more, preferably 3 to 3.5 moles, with respect to 1 mole of the compound (1k). 4 mol or more per 1 mol, preferably 4 to 6 mol.

Furthermore, the compound (1) of the present invention can also be prepared by the method as shown in the following reactivity diagrams-XV.

[Reactivity-XX]

R ² ′, R ⁶ , R ⁹ , A, Y and 1 in the above reaction degree-V are as described above. The reaction of Compound (1r) and Compound (43) is carried out under the same conditions as those used for the reaction of Compounds (8) and (9) in Reactivity-II.

[Reactivity-XXI]

In Reactivity-XI, R ² ′, R ⁶ , A, Y and L are as described above and R ¹⁴ is tetrazolyl which may have hydrogen, lower alkyl or lower alkyl substituent. The reaction of the compound (36f) and the compound (45) is also carried out under the same conditions as those used for the reaction of the compounds (8) and (9) of Reactivity-II.

[Reactivity-XXII]

In Reactivity-XII, R ² , A, Y and 1 are as described above. The reaction of the compound (36f) and the compound (46) is also carried out under the same conditions as those used for the reaction of the compounds (8) and (9) in Reactivity-II. Hydrolysis of compound (1u) is carried out in the same manner as in (1a) hydrolysis of compound of Scheme-I.

[Reactivity-XXIII]

In Reactivity-XIII, R ² ′, R ⁷ , A and L are as described above, and R ¹⁵ is lower alkyl or phenyl (lower) alkyl. The reaction of compound (1w) and compound (47) was carried out using a suitable solvent under a basic compound for about 30 minutes to 12 hours at a temperature ranging from -30 to 100 ° C., preferably from room temperature to 70 ° C., without using any solvent. Conduct. Suitable examples of base compounds are alkali metal hydrides (eg sodium hydride, potassium hydride), alkali metals (eg sodium potassium), alkali metal amides (eg sodium amide, potassium amide) or analogs thereof.

Suitable examples of solvents are ethers (e.g. dioxane, tetrahydrofuran), aromatic hydrocarbons (e.g. benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphorictriamide, or the like . Compound (47) is used in an amount of at least 1 mol, preferably 1-2 mol, based on 1 mol of compound (1w).

[Reactivity-XXIV]

In Reactivity-XIV, R ² ′, A and L are as described above and R ¹⁶ and R ¹⁷ are each lower alkyl. The reaction of compound (1v) and compound (48) is appropriate inert solvents such as water, alcohols (e.g. methanol, ethanol, isopropanol), fatty acid esters (e.g. methyl acetate, ethyl acetate), dimethylformamide, dimethyl sulfoxide Among them, it is preferably carried out in water or alcohol at room temperature to 150 DEG C, preferably at 50 to 100 DEG C for 1 to 5 hours.

The amount of compound (1v) and compound (48) is not important, but the latter is usually used in at least the same molar amount, preferably 1 to 1.5 molar amount, per 1 mole of the former.

[Reactivity-XXV]

In Reactivity-XV, R ² ′, A and 1 are as described above and each of R ¹⁸ and R ¹⁹ is lower alkyl. The reaction of compound (1v) and compound (49) is water, alcohol (eg methanol, ethanol, isopropanol), aromatic hydrocarbons (eg benzene, toluene), halogenated hydrocarbons (eg chloroform, dichloromethane, chlorobenzene) , Solvents such as acetone, tetrahydrofuran- and the like, preferably in the presence or absence of an alcohol solvent. Compound (49) is usually used in an amount of at least equal moles, preferably 1 to 1.5 moles, per 1 mole of compound (1v).

The reaction is carried out at room temperature to 150 DEG C, preferably at room temperature to 100 DEG C for about 1 to 5 hours. S-alkylation of compound (1z) is carried out under the same conditions as in the reaction of compounds (1v) and (49). In addition, the reaction of Compound (50) and Compound (51) is also carried out under the same conditions as in the reaction of Compounds (1v) and (48) of Reactivity-IV.

Compound (1) having an acidic group can be converted into these salts using a pharmaceutically acceptable basic compound. These basic compounds include metal hydroxides such as sodium hydroxide or potassium hydroxide and alkali metal alcoholates such as sodium methylate or potassium ethylate. Compound (1) having a basic group can also be converted into these salts using pharmaceutically acceptable acids. Pharmacologically acceptable acids include inorganic acids such as sulfuric acid, nitric acid hydrochloric acid or bromic acid and organic acids such as acetic acid, P-toluenesulfonic acid, ethanesulfonic acid, hydroxyl, maleic acid, succinic acid or benzoic acid. The compound obtained in the above-mentioned preparation can be eluted from the reaction mixture and purified by conventional methods. For example, this separation can be carried out by distillation, recrystallization, column chromatography, extraction and the like.

Compound (1) of the present invention or pharmacologically acceptable salts thereof exhibits excellent inhibitory effects on neurological ulcers and indomethacin induced ulcers with little side effects such as central nervous system action, anticotin action and gastric emptying rate change. It is also useful as a medicine for gastric ulcer and duodenal ulcer.

Compound (1) of the present invention or salts thereof is usually used in conventional pharmaceutical form. Pharmaceuticals may be prepared using conventional diluents and conventional carriers such as fillers, swelling agents, binders, wetting agents, disintegrants, surfactants, lubricants or the like. The preparations can be in various forms, ie in the form of tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) or analogs thereof. Tablets can be made using conventional weighting agents as follows. That is, excipients (e.g. lactose, sucrose, sodium chloride, glucose, urea.starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, aqueous glucose solution, starch) Aqueous solution, aqueous gelatin solution, carboxymethylcellulose, cellac, methylcellulose, potassium phosphate, polyvinyl fluoridone, etc., disintegrant (e.g., dried starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, polycarbonate) Oxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceryl stearate, star arch, lactose, etc., disintegration inhibitors (e.g. sucrose, stearin, cacao butter, hydrogenated oil, etc.), absorption accelerators (e.g. 4 Tertiary ammonium salts, sodium lauryl sulfate, etc.), moisturizers (e.g. glycerin, starch, etc.), absorbents (e.g., starch, lactose, kaolin bentonite, colloidal silica, etc.), lubricants (e.g. , Stearic acid salts, boric acid powders, polystyrene glycols, and the like. This tablet may be in the form of dragee, gelatin coated tablets, enteric coated tablets, film coated tablets, dual or multiplicity, and the like.

Pills include excipients (e.g. glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragarant only, gelatin, ethanol, etc.), disintegrants (e.g. Conventional carriers such as kelp, agar, and the like) can be prepared. Suppositories can be prepared using conventional carriers such as polystyrene glycols, cacao butters, esters of higher alcohols or alcohols thereof, gelatin, semi-synthetic glycerides, or the like. When the active compound is prepared in injectable form, the solution or suspension containing the active compound is sterilized and isotonic in blood. Injections in the form of solutions, emulsions or suspensions may be prepared by conventional methods such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxy-isostearyl alcohol, polyoxyethylene sorbitan fatty esters, or the like. It can be prepared using a diluent.

Injectables can be made isotonic by adding a sufficient amount of sodium chloride, glucose, glycerin, or the like to it and optionally mixed with other agents such as conventional solubilizers, buffers, analgesics, colorants, preservatives, flavorings, seasonings, sweeteners and the like. have.

The therapeutic agent for ulcers of the present invention may contain a wide range of the active compound, and usually contains about 1 to 70% by weight of the active compound of the present invention, preferably 5 to 50% by weight, based on the total weight of the preparation. do.

The condensation of the ulcer therapeutic agent of the present invention is not limited and the proper route of administration is determined by the type of agent and the age, sex and other conditions of the patient to be treated, the severity of the disease and the like. Tablets, pills, solutions, suspensions, emulsions, granules and capsules, usually orally. Injectables may be administered alone or optionally by intravenous route, such as by appropriate adjuvant such as glucose or amino acids, or alone by intramuscular or intradermal or subcutaneous or intraperitoneal route.

The dosage of the active compound of the present invention may vary depending on the use, age, sex and other conditions of the patient to be treated, the severity or the like of the disease, but is usually set in the range of 0.6 to 5 mg / kg body weight per day. The active compound of the present invention is preferably to be included in the ulcer preparations in 10-1000mg dosage unit.

Pharmacological examination

The pharmacological action of compound (1) of the present invention was tested by the conventional method described later in connection with the following compounds.

[Pharmacological test 1.]

The pharmacological action of compound (1) was tested by Shae's rat pyloric binding method (cf. H. Shay et al., Gastroenterol., Vol. 5, 43, 1945), the best known method of inhibiting gastric fluid separation inhibition. . This test was performed using Wistar male rats weighing approximately 170 g and fasting 24 hours.

At doses of 100 mg / kg subcutaneous for test compounds 37,38,50,51 and 52, at doses of 200 mg / kg for subcutaneous routes for test compounds 105 and 106 and duodenum for other test compounds. The route was administered at a dose of 100 mg / kg 30 minutes prior to pyloric binding and the volume and total acidity of gastric juice and pepsin action were measured 4 hours after binding. As a control, saline was administered in place of the test compound. The inhibition rate of these test compounds (%) was calculated as the case of seeing the inhibitory action of the control group as zero (0). The results are listed in Table 1 below.

Inhibition rate (%) in the table was evaluated as follows.

+: 10-50% or less

++: 50% or more

The test compound of (*) was evaluated as follows.

+: 30 ~ 60% or less

++: 60% or more

TABLE 1

[Pharmacological examination 2]

[Neural ulcer]

After fasting about 170 grams of Wistard male rats for 24 hours, the rats were confined in a stress cage and soaked in a water bath at a temperature of 23 ° C. to cool to their chests. After 7 hours, the mice were killed and their stomachs were separated. 10% formalin (8 ml) was poured into the isolated stomach and stabilized. The stomach was incised at the large curvature and the length of each ulcer in the membrane was measured. The sum of the lengths of all ulcers is expressed as the ulcer index (UI). Before confinement of the test compound to the stress cage, the test compounds 3, 4, 6, 15 and 27 are in the form of 0.5% CMC suspension and other test compounds. In this case, the mice were orally administered at a dose of 30 mg / kg at a concentration of 1 × 10 ⁻³ mol. Also as a control only solvent (CMC solution) was administered in the same way. The inhibition rate of the neurological ulcer of this test compound was calculated by the following formula.

The results are listed in Table 2. Inhibition ratio (%) in the table was evaluated as follows.

+: 30 to 60% or less

++: 60% or more

TABLE 2

[Pharmacological examination 3]

Indomethacin induced ulcer

20 mg / kg in the form of a suspension in which about 160 g of Wistar male rats are fasted for 24 hours, followed by mixing indomethacin with 0.5% CMC and a small dose of Ino 80 (i.e., polyoxyethylene sorbitan morrooleate) Doses were administered subcutaneously to rats. After 5 hours the rats were killed to separate the stomachs. 10% formalin (8 ml) was injected and stabilized on this separated product. The stomach was incised in a large part to measure the length of the angular ulcer in the membrane. Based on the results, the inhibition rate of the test compound against indomethacin-induced ulcer was calculated in the same manner as in Pharmacological Test 2. This test compound was orally administered to rats at a dose of 100 mg / kg in the form of a 0.5% CMC suspension 30 minutes prior to indomethacin administration. The results are listed in Table 3. In this table, the percent inhibition was evaluated as follows.

+: 30 to 60% or less

++: 60% or more

TABLE 3

[Acute Toxicity]

Test compounds were orally administered to Wistar male rats and 1/2 lethal dose (LD ₅₀ ) was measured. The results are listed in Table 4.

TABLE 4

The following reference examples and examples illustrate the invention in more detail.

Reference Example 1

1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1-bromo-3-chloropropane (9.4 g) were dissolved in acetone (100 ml). Potassium carbonate (6.8 g) was added to this solution and the mixture was refluxed for 3 hours. Acetone was distilled off and water was added to the residue.

The mixture was extracted with chloroform and the chloroform solution was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography (Wakogel C-200 manufactured by Wako Junyaku Co., Ltd.). The column was eluted with linzen-ether (5: 1, V / V) to give 1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (8.5 g) as a colorless liquid (n _D ¹⁴ = 1.5396).

Reference Example 2

The following compounds were prepared in the same manner as described in Reference Example 1.

1-cyclohexyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole, colorless liquid, n _D ¹⁴ = 1.5387

1-methyl-5- (4-bromobutyl) thio-1,2,3,4-tetrazole, colorless liquid, n _D ¹⁹ = 1.55 30

Reference Example 3

2-mercapropyridine (5.6 g) and 1-bromo-3-chloropropane (11.7 g) were dissolved in acetone (100 ml) and calcium carbonate (6.9 g) was added to this solution. This mixture was refluxed for 5 hours.

After distilling off the acetone, water was added to the residue, and the mixture was extracted with chloroform. This chloroform solution was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (Kieselgel 60, available from Merck). The column was eluted with chloroform-methanol and the eluate was distilled off to give 2- (3-chloropropyl) thiopyridine (8.2 g) in the form of red oil.

Reference Example 4

In the same manner as in Reference Example 3, the following compound was prepared.

5-amino-2- (3-chloropropyl) thio-1,2,3-thiadiazole pale yellow needle, melting point 121-121.5 ° C. (ethanol-water)

5-methyl-2- (4-bromobutyl) thio-1,3,4-oxadiazole brown liquid,

Reference Example 5

1-Methyl-5- (4-bromobutyl) thio-1,2,3,4-tetrazole prepared in Reference Example 2 was dissolved in Ui-San (50 ml). This 30% aqueous hydrogen peroxide solution (2.3 g) was added at room temperature with stirring and the compound was stored at room temperature for 2 nights. The mixture was diluted with water and extracted with chloroform. The chloroform solution was washed with water and saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution and dried over magnesium sulfate.

Chloroform was distilled off to prepare 1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutylsulfoxide (5.5 g) as a colorless liquid.

Reference Example 6

1-Methyl-5- (4-bromobutyl) thio-1,2,3,4-tetrazole prepared in Reference Example 2 was dissolved in Uisan (50 ml). A 30% aqueous solution of hydrogen peroxide (6.9 g) was added to this solution and the mixture was stirred for 6 hours. Sodium hydrogen sulfite was added to this ice-cooled mixture to destroy excess acid. Water was added to this mixture and the mixture was extracted with chloroform.

The chloroform solution was washed with water and saturated aqueous sodium bicarbonate solution and dried over magnesiumsulfite. Chloroform was distilled off and the residue was recrystallized in ethanol to give 1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutylsulfone (2.9 g) as a colorless flake (melting point 83.5-85.5 ° C.) Obtained as

Reference Example 7

2- (3-Chloropropyl) thiopyridine (4.4 g) prepared in Reference Example 3 was dissolved in Uric acid (40 ml). 30% aqueous hydrogen peroxide solution (2.7 g) was added to this solution and the mixture was stirred at room temperature for 3 hours.

The mixture was left at room temperature overnight, diluted with water and extracted with chloroform. The chloroform solution was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfide. Chloroform was distilled off and the residue was purified by column chromatography (Kieselgel 60). This column was eluted with chloroform-methanol (50: 1) to give 2-pyridyl 3-chloropropyl sulfoxide (2.7 g) as a colorless liquid.

Reference Example 8

2- (3-Chloropropyl) thiopyridyl (3.7 g) prepared in Reference Example 3 was dissolved in Euisan (30 ml). A 30% aqueous hydrogen peroxide solution (6.9 g) was added to this solution and the mixture was stirred for 4 hours at room temperature. After dilution with water, sodium hydrogensulfite was added to this ice-cooled mixture to destroy excess acid. The mixture was extracted with chloroform and the extract was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfide. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60).

The column was eluted with chloroform-methanol 50: 1 to give 2-pyridyl 3-chloropropyl sulfone (4 g) as a colorless liquid.

Reference Example 9

The following compounds were prepared in the same manner as described in Reference Example 8.

1-methyl-5- (2-chloroethyl) thio-1,2,3,4-tetrazole, colorless prism (ether), melting point 48-49.5 ° C

5-methyl-2- (3-chloropropyl) thio-1,3,4-oxadiazole, colorless liquid n _D ²⁶ = 1. 5147

5-methyl-2- (3-chloropropyl) sulfinyl-1,3,4-oxadiazole, colorless liquid, n _D ²⁶ = 1. 5279

Reference Example 10

Dissolve 1-methyl-5-mercapto-1,2,3,4-tetrazole (0.9 g) and 3-chloropropyl ethyl ketone ethylen ketal (1.3 g) with acetone (50 ml). Potassium iodide (0.1 g) and potassium carbonate (1.1 g) are added to this solution and the mixture is refluxed for 6 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue is purified by silica gel column chromatography (Kiesel gel 60). This column is eluted with benzene-ether (5: 1) to give 1-methyl-5- (4.4-ethylenedeoxyhexine) thio-1,2,3,4-tetrazole (0.6 g) as a colorless liquid. .

Reference Example 11

1-Methyl-5-mercapto-1,2,3,4-tetrazole (11.6 g) is dissolved in acetone (100 ml). Methyl 4-bromobutytate (21.7 g) and potassium carbonate (15 g) are added to this solution and the mixture is refluxed for 4 hours. Acetone is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off and the residue is subjected to silica gel column chromatography (Wakogel C-200) separation. The column was eluted with benzene-ether (5: 1) and the eluate was distilled off under reduced pressure to give methyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrate (20 g) as colorless. Obtained as a liquid.

Boiling Point 175-177 ℃ / 0.80mmHg

Reference Example 12

20% hydrochloric acid (150 ml) is added to methyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrate (17 g) and the mixture is refluxed for 2 hours. After cooling the reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to obtain 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyl acid as colorless liquid n _D ²⁶ = 1.5133.

Reference Example 13

1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.3 g) and 4-bromobutyronitrile (3.6 g) are dissolved in acetone (50 ml). Potassium carbonate (3 g) is added to this solution and the mixture is refluxed for 3 hours. Acetone is distilled off and water is added to the residue. The aqueous mixture is extracted with chloroform and the chloroform solution is washed with saturated sodium chloride water and dried over magnesium sulfate.

Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200). The column is eluted with benzene-ether (5: 1) to afford 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyronitrile (3.5 g).

Elemental Analysis for C ₅ H ₉ N ₅ S

Calculation (%): C, 35.07; H, 5.30; N, 40.90

Confirm (%): C, 35,26; H, 5.41; N, 40,98

Reference Example 14

Acetoanilide (20 g, 0.15 ml) was dissolved in carbon disulfide (110 ml) and 4-chlorobutyl acid chloride (37 g, 0.27 mol) was added to this solution. Aluminum chloride (60 g, 0.45 mol) was slowly added to this mixture with stirring at room temperature. The resulting mixture is refluxed for 30 minutes and left at room temperature for 2.5 hours at room temperature.

The carbon disulfide is decanted and the residue is poured into ice hydrochloric acid (20 ml). The precipitated crystals are collected by filtration and washed with water. The crude crystal thus obtained is suspended in ethanol. After stirring, the crystals were collected by filtration, washed with water and recrystallized in ethanol to give γ-chloro-4-acetamidobutyrophenone (10 g) as colorless granules (ethanol) having a melting point of 157-163 ° C.

Reference Example 15

Aluminum chloride (16 g, 0.12 mol) was suspended in carbon tetrachloride (80 ml) and 6-chlorohexanoyl chloride (20 g, 0.12 mol) was added dropwise to this suspension under ice cooling.

After the addition was completed the phosphorus mixture was stirred for 15 minutes and benzene (7.8 g 0.1 mol) was added dropwise to this mixture under ice cooling. After stirring under ice cooling for 1 hour, the mixture was poured into ice hydrochloric acid and extracted with carbon tetrachloride. The carbon tetrachloride extract was washed with water and saturated sodium bicarbonate and then saturated sodium chloride water and dried over anhydrous magnesium sulfate. The dry solution is distilled to give 5-chloropentylphenyl ketone (7.3 g) having a boiling point of 143-150 ° C./0.5 mmHg.

Reference Example 16

Aluminum chloride (26.7 g) was added to nitrobenzene (20 ml) and 4-chlorobutyl acid chloride (15.5 g) was added dropwise to this mixture during ice cooling. Naphthalin (12.8 g) is slowly added to this mixture under ice cooling and stirring is continued for 30 minutes at the same temperature. After two more hours of stirring at room temperature, the reaction mixture is poured into ice hydrochloric acid and extracted with chloroform. The chloroform extract is washed with water, saturated sodium bicarbonate water, water followed by saturated sodium chloride water and dried over anhydrous sodium sulfate. The dry solution is distilled off.

Fractions having a boiling point of 187-191 ° C./1.6 mm Hg were separated and purified by silica gel column-chromatography. The product thus obtained is crystallized from hexane and again recrystallized in hexane-petroleum ether to give 2- (4-chlorobutyryl) naphthalin (4.2 g) as colorless flake (melting point 43-44 ° C).

Reference Example 17

Aluminum chloride chlorite (16 g, 0.12 mol) is suspended in carbon tetra chloride (80 ml). 4-chlorobatter acid chloride (18.6 g, 0.12 mol) of this suspension was added dropwise under ice cooling. The mixture is stirred for 15 minutes and benzene (7.8 g, 0.1 mol) is added dropwise to the mixture at 5 占 폚 or lower.

Stirring is continued for 1 hour at the same temperature. The mixture is poured into ice hydrochloric acid and extracted with chloroform. The chloroform layer is washed sequentially with water and saturated sodium bicarbonate water, followed by saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate.

Chloroform was distilled off and the crude crystal obtained was recrystallized from hexane to give 4-chlorobutylphenyl ketone (8.3 g) having a melting point of 49-50 ° C. as a colorless flake.

Reference Example 18

The following compounds are prepared in the same manner as described in the Reference Example above.

Reference Example 19

A Grignard reagent was prepared from magnesium (1.9 g) and n-butylbutromide (11.2 g) and anhydrous ether (80 ml), and 4-chlorobutyronitrile (7 g) was added to ether (15 ml) in this reagent under ice cooling. The dissolved solution is added dropwise.

The mixture is stirred at the same temperature for 2 hours and further stirred at room temperature for 2 hours. 10% hydrochloric acid is added dropwise to this mixture under ice cooling to decompose the product and acidify the mixture to about 1 pH. After stirring for 1 hour at room temperature, the mixture is extracted with ether. The ether charge is washed with saturated sodium bicarbonate and saturated sodium chloride water and dried over magnesium sulfate. The solvent was distilled off and the residue was distilled to obtain 3-chloropropylbutyl ketone (1.9 g) having a boiling point of 104-106 ° C / 36 mmHg.

Reference Example 20

The following compounds were prepared in the same manner as described in Reference Example 12.

3-chloroporophyll cyclopentyl ketone, colorless liquid, boiling point, 127-137 ° C./22 mmHg

3-Chloropropyl benzyl ketone, colorless liquid, boiling point 108-119 ° C / 0.15mmHg

3-bromopropyl cyclohexyl ketone,

Reference Example 21

3-chloropropyl ethyl ketone (1.5 g) was dissolved in ethylene glycol (10 ml) and methylorthoformate (2 g) and p-toluenesulfonic acid (0.2 g) were added to this solution. The mixture was stirred at room temperature for 5 hours. After neutralization with sodium hydroxide, water was added to this mixture and the mixture was extracted with ether. The ether solution is washed with water and saturated sodium chloride water and dried over magnesium sulfate.

The ether was distilled off and the residue was distilled under reduced pressure to prepare 3-chloropropyl ethyl ketone ethylene ketal (1.3 g) having a boiling point of 98-102 ° C./mmHg.

Reference Example 22

The following compounds were prepared in the same manner as described in Reference Example 21.

4-chlorobupilope is ethylene ketal,

3-bromopropyl cyclohexyl ketone ethylene ketal,

3-chloropropyl β-phenethyl ketone, boiling point 130-130 ° C./0.25 mmHg, 2- (4-chlorobutyl) -5-methoxycarbonylfuran,

(2H) 6- (4-chlorobutyl) -3,4-dihydrocarbostyryl pale yellow needle (acetone), melting point 158-160 ° C

Reference Example 23

γ-aminobutyl acid (15.5 g) was suspended in methanol (200 ml) and thionyl chloride (53.6 g) was added dropwise to this stirring suspension under ice cooling. The mixture is left overnight and methanol and thionyl chloride are distilled off. Benzene is added and the mixture is concentrated under reduced pressure.

The obtained residue (25 g) is dissolved in acetone (200 ml) and water (50 ml). Potassium carbonate (22.8 g) is added to this solution and then acetyl chloride (13 g) is added dropwise to this stirring compound under ice cooling. Stirring is continued for 1 hour under ice cooling and then further stirred for 2 hours at room temperature. Acetone is distilled off and water is added to the residue. This mixture is extracted with chloroform.

The chloroform solution is washed with saturated sodium chloride water and dried over magnesium sulfate. Chloroform is distilled off and the residue is distilled under reduced pressure to prepare methyl-4-acetamido butytate (1.6 g) as a colorless liquid. Boiling point 130-132 ℃ / mmHg

Example 1A

Methyl 4-acetamidobutylate (8 g) is dissolved in benzene (80 ml). Phosphorose pentachloride (12 g, 0.055 mol) is added to this stirring solution under ice cooling. The mixture is stirred at room temperature for 1.5 hours and then concentrated to about 3 minutes / volume under reduced pressure.

To the obtained iminochloride solution was added dropwise a hydrogen azide benzene solution (0.0173 mol / 10 ml, 57.8 ml) with stirring under ice cooling. The mixture is stirred for 1 hour at room temperature and allowed to stand overnight to reflux slowly for 2 hours. The reaction mixture is concentrated and ice water is added to it. This mixture is extracted with chloroform.

The chloroform solution is washed with water and sodium hydroxide dilution water followed by water and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Wakogel C-200). The column is eluted with chloroform-methanol (50: 1) to prepare methyl 4- (5-methyl-1,2,3,4-tetrazol-1-yl) butylate (5.7 g) as a colorless liquid.

Example 1B

In the same manner as in Example 1A, the following compound was prepared.

Methyl 4- (5-phenyl-1,2,3,4-tetrazol-1-yl) butylate, colorless prism (ether), melting point 52-54 ° C

Methyl 4- (5-butyl-1,2,3,4-tetrazol-1-yl) butylate, pale yellow liquid,

Methyl 5- (5-methyl-1,2,3,4-tetrazol-1-yl) valetate, pale yellow liquid,

Example 2A

20% hydrochloric acid (30 ml) is added to methyl 4- (5-methyl-1,2,3,4-tetrazol-1-yl) butylate (5.5 g) and the mixture is refluxed for 2 hours. The mixture is concentrated to dryness under reduced pressure. Acetone and benzene were added to this residue, and water was removed by azeotropic distillation to prepare 4- (5-methyl-1,2,3,4-tetrazol-1-yl) butyric acid (4.7 g) as a colorless liquid. do.

Elemental analysis for C ₆ H ₁₀ N ₄ O ₂ ,

Calculation (%): C, 42.35; H, 5.92; N, 32.93

Found (%): C, 42.18: H, 5.72; N, 33.24

The liquid product thus obtained is left to crystallize for 1 week, and the crystal product is further recrystallized in ether-acetone to prepare a colorless needle (melting point 71-72.5 ° C.).

Example 2B

In the same manner as in Example 2A, the following compounds were prepared.

4- (5-phenyl-1,2,3,4-tetrazol-1-yl) butyric acid, colorless prism material (ether), melting point 134-137 ° C

4- (5-butyl-1,2,3,4-tetrazol-1-yl) butyric acid, colorless prismatic material (acetone-ether), melting point 77-79 ° C

5- (5-methyl-1,2,3,4-tetrazol-1-yl) valeric acid, colorless acicular substance (acetone), melting point 109.5-113 ° C

Example 3

4- (5-methyl-1,2,3,4-tetrazol-1-yl) butyric acid (1.7 g) was dissolved in dimethylformamide (50 ml) and triethylamine (1.1 g) was added to the solution. Add. Isobutylchloroformate (1.5 g) is added dropwise to this stirring mixture under ice cooling and the mixture is stirred for 30 minutes at room temperature.

Diethylamine (0.9 g) is added dropwise to this mixture with stirring at room temperature. The mixture is stirred for 3 hours. Dimethylformamide is distilled off and the residue is purified by silica gel column chromatography (silica gel from Melk). The column was eluted with chloroform-methanol (50: 1), boiling point 190-200 ° C. (bath temperature) /0.04 mmHg, n _D ²⁵ = 1.4908

N, N-diethyl-4- (5-methyl-1,2,3,4-tetrazol-1-yl) butyric acid amide (1.4 g) is prepared.

Elemental Analysis for C ₁₀ H ₁₉ N ₅ O

Calculated (%): C, 53.31; H, 8. 50; N, 31.09

Found (%): C, 53.46; H, 8.61; N, 31.21

Example 4

In the same manner as in Example 3, the following compounds were prepared.

Example 5

Thionichloride (10 ml) is added to 4- (5-methyl-1,2,3,4-tetrazol-1-yl) butyric acid (2 g) and the mixture is refluxed for 1 hour. Excess thionyl chloride is distilled off under reduced pressure, and anhydrous benzene is added to the residue to remove azeotropic distillation of the mixed amount of thionyl chloride. The residue is dissolved in anhydrous benzene (50 ml).

4-methoxyaniline (3 g) is added dropwise to this stirring solution under ice cooling and the mixture is stirred at room temperature for 1 hour. Benzene is added to the reaction mixture and the mixture is washed sequentially with dilute hydrochloric acid and saturated sodium bicarbonate and then saturated sodium chloride water and dried over sodium sulfate.

Benzene was distilled off and the residue was recrystallized in ethanol to give N- (4-methoxyphenyl) -4- (5-methyl-1,2,3,4-tetrazole of colorless prismatic material having a melting point of 132-134 ° C. -1-yl) Butyl amide (2.4 g) is prepared.

Example 6

In the same manner as in Example 5, the following compounds were prepared.

Example 7

Dissolve 1-methyl-4- (4-chlorobutyl) piperazine (6.2 g) in anhydrous benzene (50 ml). To this solution is added 5-methyl-1,2,3,4-tetrazole (2.6 g) and potassium carbonate (4.5 g) and sodium iodide (0.2 g) and the mixture is refluxed for 5 hours.

The reaction mixture is diluted with benzene, washed sequentially with water and saturated sodium bicarbonate water and then saturated sodium chloride water and dried over sodium sulfate.

Benzene is distilled off and the residue is purified by column chromatography (Wakogel C-200). The column was eluted with benzene-chloroform (4: 1) to give 5-methyl-1- [3- (4-methyl-1-piperazinyl) carbonyl) propyl-1,2 with n _D ²⁰ = 1.5085 as a brown liquid. Prepare, 3.4-tetrazole (4.2 g).

Example 8

In the same manner as in Example 7, the following compound was prepared.

Example 9

1-Methyl-5-mercapro-1,2,3,4-tetrazole (1.2 g) was dissolved in acetone (50 ml), and 3-bromopropyl phenyl sulfide (2.5 g) and potassium carbonate ( 1.5 g) is added to reflux the mixture for 4 hours. Acetone is distilled off and water is added to the residue.

This mixture is extracted with chloroform. The chloroform solution is washed with saturated sodium chloride water and dried over magnesium sulfate.

Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column was eluted with benzene-chloroform (3: 2) to give 1-methyl-5- (3-phenyl thiopropyl) thio-1,2,3,4-tetrazole (1.8 g) colorless with n _D ¹⁸ = 1.6008. Prepared as a liquid.

Elemental Analysis for C ₁₁ H ₁₄ N ₄ S ₂

Calculated (%): C, 49.60; H, 5. 30; N, 21.03

Found (%): C, 49.70; H, 5. 13; N, 20.94

Example 10

In the same manner as in Example 9, the following compound was prepared.

Example 11

1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.29) was dissolved in acetone (50 ml), and 2- (2-chloroethyl) thiopyridine (2.0 g) and carbonic acid were dissolved in this solution. Potassium (1.5 g) is added and the mixture is refluxed for 4 hours.

Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated sodium chloride water and dried over magnesium sulfate.

Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column was eluted with chloroform-methanol and the product was recrystallized in ethanol to yield 1-methyl-5 [2- (2-pyridyl) thioethyl) thio-1,2,3,4-dec at a melting point of 77-79.5 ° C. Trasol (1.5 g) is made of a colorless prismatic material.

Elemental analysis for C ₉ H ₁₁ N ₅ S ₂ ,

Calculated (%): C, 42.67; H, 4.38; N. 27.64

Found (%): C, 42.43; H, 4. 30; N, 27.53

Example 12

In the same manner as in Example 11, the following compound was prepared.

Example 13

Dissolve 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) in acetone (50 ml) and in this solution 1-methyl-5- (8-chlorooctyl) thio-1 , 2,3,4-tetrazole (4.1 g) and potassium carbonate (1.5 g) are added and the mixture is refluxed for 4 hours.

Acetone is distilled off and water is added to this residue. This mixture is extracted with chloroform. The chloroform solution is washed with saturated sodium chloride water and dried over magnesium sulfate, the chloroform is distilled off and the residue is recrystallized in ethyl acetate-hexane to give 1-methyl-5- [8- (1-methyl) at a melting point of 52-54 ° C. -1,2,3,4-tetrazol-5-yl) thiooctyl] thio-1,2,3,4-tetrazol (2.0 g) is obtained as a colorless needle.

Example 14

In the same manner as in Example 13, the following compound was prepared.

Example 15

1-methyl-5-chloro-1,2,3,4-tetrazole (1.18 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml) and the solution is refluxed for 3 hours. After cooling, the precipitated crystals are separated by filtration and dried.

This crystal is dissolved in ethanol (50 ml) and 2- (2- (chloroethyl) thiopyridine (1.7 g) and 10% aqueous sodium hydroxide solution are added to this solution.

The mixture is refluxed for 3 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform and the extract is washed with saturated sodium chloride water and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60, eluent; chloroform).

The product was recrystallized in ethanol to give 1-methyl-5- [2- (2-pyridyl) thioethyl] thio-1,2,3,4-tetrazole (0.7 g) at a melting point of 77-79.5 DEG C as a colorless prism. Obtained as material.

Elemental Analysis for C ₉ H ₁₁ N ₅ S ₂

Calculated (%): C, 42.67; H, 4.38; N, 27.64

Found (%): C, 42.53; H, 4. 29; N, 27.38

Example 16

In the same manner as in Example 15, the following compound was prepared.

Example 17

2-pyridyl-3-chloropropyl sulfone (2.2 g) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) are dissolved in acetone (50 ml). Potassium carbonate (1.4 g) is added to this solution and the mixture is refluxed for 5 hours. Acetone is distilled off and added to the residue.

This mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60).

The column was eluted with chloroform-methanol and the product was recrystallized in ethanol to give 3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropyl2-pyridyl at a melting point of 98.5-101 ° C. Sulfon (1 g) is obtained as a colorless prismatic material.

Elemental Analysis for C ₁₀ H ₁₃ N ₅ S ₂ O ₂

Calculation (%): C, 40.12; H, 4.38; N, 23.39

Found (%): C, 40.02; H, 4. 46; N, 23.29

Example 18

In the same manner as in Example 17, the following compound was prepared. 3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropyl 2-pyridylsulfoxide, colorless prismatic material (ethanol), melting point 88.5-90.5 ° C.

Example 19

1-Methyl-5- (4,4-ethylenedioxyhexyl) thio-1,2,3,4-tetrazole (0.6 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and concentrated hydrochloric acid (0.5 ml) are added to this solution and the mixture is heated with a water bath for 1 hour. Water is added to the reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water, saturated sodium bicarbonate water and then saturated sodium chloride water and dried over magnesium sulfate.

Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column was eluted with benzene-ether (10: 1) to give 1 _D- methyl-5- (3-propionylpropyl) thio-1,2,3,4-tetrazole (0.4 g) with n _D ²⁵ = 1.5042. Prepared as a colorless liquid.

Elemental analysis for C ₈ H ₁₄ N ₄ OS,

Calculated (%): C, 44.84; H, 6. 59; N, 26.15

Found (%): C, 44.89; H, 6.63; N, 26.23

Example 20

In the same manner as in Example 19, the following compounds were prepared:

Example 21

Dissolve 1-methyl-5- [4,4-ethylenedioxy-4- (4-ethylphenyl)] butyl] thio-1,2,3,4-tetrazole (0.8 g) in acetic acid (5 ml). . Water (2.5 ml) and concentrated hydrochloric acid (0.5 ml) are added to this solution and the mixture is heated with a water bath for 1 hour.

Water is added to this reaction mixture and the mixture is extracted with chloroform.

Chloroform is washed sequentially with water, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column was eluted with benzene-ether (10: 1) to yield 1-methyl-5- [3- (4-ethylbenzoyl) propyl] thio-1,2,3,4-tetrazole (68-69 ° C.). 0.5 g) (recrystallized from hexane-ether) is obtained as a colorless needle.

Elemental Analysis for C ₁₄ H ₁₈ N ₄ OS

Calculated (%): C, 57.91; H, 6. 25; N, 19.90

Found (%): C, 57.68; H, 6. 20; N, 19.81

Example 22

In the same manner as in Example 21, the following compound was prepared.

Example 23

1-Methyl-5- [4,4-ethylenedioxy-4- (2-pyridyl) butyl] thio-1,2,3,4-tetrazole (0.7 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and concentrated hydrochloric acid (0.5 ml) are added to this solution and the mixture is heated with a water bath for 1 hour.

Water is added to this reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed sequentially with water, saturated sodium bicarbonate water and saturated sodium chloride water and dried over magnesium sulfate.

Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kiesel gel 60).

The column was eluted with benzene-ether (10: 1) and the product was recrystallized in hexane-ether to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl] thio-1,2,3,4 -Tetrazole (0.5 g) is prepared as a colorless acicular material with a melting point of 73-75 ° C.

Elemental Analysis for C ₁₁ H ₁₃ N ₅ OS

Calculation (%): C, 50.17; H, 4.97; N, 26.60

Found (%): C, 50.12; H, 4.97; N, 26.90

Example 24

In the same manner as in Example 23, the following compound was prepared.

Example 25A

1-methyl-5-mercapto-1,2,3,4-tetrazole (0.01 mol) and potassium carbonate (0.015 mol) and α-chloroacetone (0.015 mol) were added to acetone (50 ml) and The mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. The insolubles were filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [(Ciesylgel 60) eluent: benzene-ether (10: 1)] and the product was recrystallized in methanol-ether. 1-methyl-5-acetylmethylthio-1,2,3,4-tetrazole (yield 48%) was obtained to give a colorless needle-like material having a melting point of 31 ° C.

Elemental Analysis for C ₅ H ₈ N ₄ OS

Calculated (%): C, 34.87; H, 4.68; N, 32.54

Found (%): C, 34.43; H, 4.5 4; N, 38.83

Example 25

5-mercapto-1,2,3,4-tetrazole (1 g) and potassium carbonate (2 g) and α-chloroacetone (1.4 g) are added to acetone (50 ml) and the solution is stirred for 2 hours. While refluxing.

The reaction mixture is concentrated and concentrated under reduced pressure, and the residue is dissolved in chloroform. The insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography [Kieselgel 60, eluent: benzene-ether (10: 1)] to give 5-acetylmethylthio-1.2,3,4-tetazole (0.4 g) as a colorless liquid.

Elemental Analysis for C ₄ H ₆ ON ₄ S

Calculation (%): C, 30.37; H, 3. 82; N, 35.42

Found (%): C, 30.35; H, 3.81; N, 35.50

Example 26

In the same manner as in Example 25A, the following compounds were prepared.

Example 27

1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) and potassium carbonate (1.2 g) and 3-chloropropine 4-ethylphenylketone (3.2 g) were added to acetone (50 ml). ) And the mixture is refluxed with stirring for 2 hours.

The reaction mixture is concentrated under reduced pressure to solidify, and the residue is dissolved in chloroform. Insoluble matter is filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [Kiesel gel 60, eluent: benzene-ether (10: 1)], and the product was recrystallized in hexane-ether to give 1- at a melting point of 68-69 占 폚. Methyl-5- (3-4-ethylbenzoyl) propyl thio-1,2,3,4--tetrazole (yield 49%) is prepared as a colorless needle.

Elemental Analysis for C ₁₄ H ₁₈ N ₄ OS

Calculated (%): C, 57.91; H, 6. 25; N, 19.90

Found (%): C, 57.78; H, 6. 23; N, 19. 71

Example 28

In the same manner as in Example 27, the following compound was prepared.

Example 29

1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 2-pyridyl ketone (2.8 g) were added to acetone (50 ml). And the mixture was stirred at reflux for 2 hours.

The reaction mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform. Insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure.

The residue was purified by silica gel column chromatography [Kiesel gel 60, eluent: bezel-ether (10: 1), and the product was recrystallized in hexane-ether to give 1-methyl-5- [3- (2 at a melting point of 73-75 ° C. -Pyridylcarbonyl) propyl] thio-1,2,3,4-tetrazole (yield, 50%) is obtained as a colorless needle.

Elemental Analysis for C ₁₁ H ₁₂ N ₅ OS

Calculation (%): C, 50.17; H, 4.97; N, 26.60

Found (%): C, 50.21; H, 4.89; N, 26.72

Example 30

In the same manner as in Example 29, the following compound was prepared.

Example 31

Acetone with 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) potassium carbonate (2.1 g) and 3-chloropropyl 4-methyl-5-thiazolyl ketone (3.1 g) (50 ml), and the mixture is refluxed with stirring for 2 hours.

The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chlorofull. Insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Kiesel gel 60, eluent: benzene-ether (10: 1)), and the product was recrystallized in hexane-ether to give 1-methyl-5- [3- (4-Methyl-5-thiazolylcarbonyl) propyl] thio-1,2,3,4-tetrazole (2.6 g) is prepared as a colorless needle.

Example 32

In the same manner as in Example 31, 1-methyl-5- [3- (5-carboxy-2-furolyl propyl) thio 1,2,3,4-tetrazole having a melting point of 154-157 ° C. was used as a colorless prismatic material. Obtained as (hexane-ethyl acetate).

Example 33

1-Methyl-5-mercapto-1.2,3,4-tetrazole (1.2 g) potassium carbonate (2.1 g) and 3-chloropropyl-2-naphthyl ketone (3.5 g) were added to acetone (50 ml) And reflux with stirring for 2 hours.

The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insoluble matters were separated by filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (Kieselgel 60, eluent: benzene-ether (10: 1)) and the product was recrystallized in ethanol to give a melting point of 118-120. C. 1-Methyl-5- [3- (2-naphthoyl) propyl) thio-1,2,3,4-tetrazole (yield 51%) is prepared as a colorless prismatic material.

Elemental Analysis for C ₁₆ H ₁₆ N ₄ OS

Calculated (%): C, 61.52; H, 5. 16; N, 17.94

Found (%): C, 61.59; H, 5.0 8; N, 18.06

Example 34

1-methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) potassium carbonate (2.1 g) and 3-chloropropyl benzyl ketone (2.9 g) were added to acetone (50 ml) and The mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insoluble matters are filtered off and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography [Gieselcell 60, eluent: benzene-ether (10: 1)) to give 1-methyl-5- [3- (benzylcarbonyl) propyl] thio with n _D ²⁵ = l.5610. -1,2,3,4-tetrazole (50% yield) is prepared as a colorless liquid.

Elemental Analysis for C ₁₃ H ₁₆ N ₄ OS

Calculation (%): C, 56.50; H, 5. 84; N, 20.27

Found (%): C, 56.40; H, 5.83; N, 20.17

Example 35

In the same manner as in Example 34, 1-methyl-5- [3- (β-phenethylcarbonyl) propyl] thio-1,2,3,4-tetrazole having n _D ^22.5 = 1.5561 is obtained as a colorless liquid.

Example 36

1-Methyl-5-chloro-1,2,3,4-tetrazole (2.4 g) is dissolved in ethanol (30 ml).

Thiourea (1.5 g) is added to this solution and the mixture is refluxed for 2 hours. 1-Bromopropyl cyclohexyl ketone (4.7 g) and 10% aqueous sodium hydroxide solution (10 ml) are added to this mixture and refluxed for another 3 hours. Ethanol is distilled off and water is added to the residue. This mixture is extracted with chloroform. The chloroform solution is washed sequentially with water, followed by saturated aqueous sodium chloride solution and dried over magnesium sulfate.

Chloroform was distilled off and the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform) to give 1-methyl-5- (3-cyclohexylcarbonylpropyl) thio-1 with n _D ¹² = 1.5267. , 2,3,4-tetrazole (1.4 g) is obtained as a liquid free.

Example 37

In the same manner as in Example 36, the following compound was prepared.

Example 38

S- (1-methyl-1,2,3,4-tetrazol-5-yl) isothiourea hydroxide chloride (1.9 g) is dissolved in ethanol (50 ml). To this solution is added 10% aqueous sodium hydroxide solution (5 ml) and 3-chloropropyl 2-pyridyl ketone (1.8 g) and the mixture is refluxed for 2 hours. Ethanol is distilled off and water is added to the residue. This mixture is extracted with chloroform. The chloroform solution is washed sequentially with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform) and the product was recrystallized in hexane-ether to give 1-methyl-5- [3- ( 2-pyridylcarbonyl) propyl] thio-1,2,3,4-tetrazole (0.5 g) is prepared as a colorless needle.

Example 39

In the same manner as in Example 38, the following compound was prepared.

Example 40

Dissolve 1-methyl-5-chloro-1,2,3,4-tetrazole (1.4 g) and 3-tercaptopropyl cyclohexyl ketone (1.9 g) in methanol (50 ml) and the solution Potassium (0.8 g) is added. This mixture is refluxed for 5 hours. Methanol is distilled off and water is added to this residue. This mixture is extracted with chloroform. The chloroform solution is washed sequentially with dilute aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform is distilled off and again the residue was purified by column chromatography (Wako gel C-200, eluant: chloroform) to give the n _D ¹² = 1.5267 1- methyl-5- (cyclohexyl-carbonyl 3-propyl sayikeu) of thio -1 , 2,3,4-tetrazole (0.6 g) is obtained as a colorless liquid.

Example 41

In the same manner as in Example 40, the following compound was prepared.

Example 42

1-Methyl-5-chloro-1,2,3,4-tetrazole (1.4 g) and 3-mercaptopropyl 2-pyridyl ketone (1.8 g) are dissolved in methanol (100 ml). Sodium hydroxide (0.6 g) is added to this solution and the mixture is refluxed for 3 hours.

Methanol is distilled off and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed sequentially with dilute aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform was distilled off, and the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform), and the product was recrystallized in hexane-ether to give 1-methyl-5- [3- ( 2-pyridylcarbonyl) propyl] thio-1,2,3,4-tetrazole (0.2 g) is obtained as a colorless needle.

Example 43

In the same manner as in Example 42, the following compound was prepared:

Example 44

4-Chlorobutylophenone (1.8 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml) and the solution is refluxed for 2 hours. To this mixture is added 1-methyl-5-chloro-1,2,3,4-tetrazole (1.2 g) and 10% aqueous sodium hydroxide solution (5 ml) and the mixture is refluxed again for 3 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate.

Chloroform was distilled off and the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform) and the product was recrystallized in methanol-water to give 1-methyl-5- (3-benzoylpropyl) thio-1. , 2,3,4-tetrazole (0.3 g) is obtained as a colorless acicular material with a melting point of 57.5-58 ° C.

Example 45

In the same manner as in Example 44, the following compounds were prepared:

Example 46

3-chloropropyl 2-pyridyl ketone (1.8 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml) and the solution is refluxed with stirring for 2 hours.

To this mixture is added 1-methyl-5-chloro-1,2,3,4-tetrazole (1.2 g) and 10% aqueous sodium hydroxide solution (5 ml) and the mixture is refluxed for 3 hours.

After evaporation of ethanol under reduced pressure, water is added to the residue. The mixture is extracted with chloroform and the extract is washed with water and saturated sodium chloride water and dried over magnesium sulfate. After distilling off the chloroform, the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform) and subsequently recrystallized in hexane ether to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl. ] Thio-1,2,3,4-tetrazole (0.2 g) is obtained as colorless crystals with a melting point of 73-75 ° C.

Example 47

In the same manner as in Example 46, the following compounds were prepared.

Example 48

1-Methyl-5-mercapto-1,2,3,4--tetrazole (2.4 g) and N-ethyl-N-propionyl-3-chloropropylamine (3.6 g) were added to acetone (50 ml). Dissolve.

To this mixture is added potassium carbonate (2.8 g) and potassium iodide (0.1 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and the residue is added to water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The chloroform was distilled off and the residue was purified by column chromatography (neutral alumina made by Merc) and eluted with n-hexane to give 1-methyl-5- [3- (N-ethyl-N-propionylamino) propylthio]. Obtained as a pale yellow liquid of -1,2,3,4-tetrazole (1.2 g) N n _D ^21.5 = 1.5220.

Example 49

In the same manner as in Example 48, the following compound was prepared.

Example 50

1-Methyl-5-mercapno-1,2,3,4-tetrazole (2.4 g) and N, N-diethyl-3-chloropropyl amine (3.0 g) are dissolved in acetone (50 ml).

Potassium carbonate (2.8 g) and potassium iodide (0.1 g) are added to the mixture and the mixture is refluxed for 4 hours. Acetone is added to the residue and water is added to the residue, followed by extraction with chloroform. This chloroform solution is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (neutral alumina made by Merck), and easily purified with n-hexane to give 1-methyl-5- [3- (N, N-diethylamino) -propylthio). -1,2,3,4-tetrazole (1.09 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5040.

Example 51

In the same manner as in Example 50, the following compound was prepared.

Example 52

1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.4 g) and 2-chloromethylpyridine (2.6 g) are dissolved in acetone (50 ml). Potassium carbonate (2.8 g) and potassium iodide (0.1 g) are added to the mixture and the mixture is refluxed for 4 hours. Acetone is distilled off, water is added to the residue, and extracted with chloroform.

The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After distilling off chloroform, the residue was purified by column chromatography (neutral alumina made by Merck), and eluted with n-hexane to give 1-methyl-5 (2-pyridyl) methylthio-1,2,3,4. -Tetrazole (1.0 g) is obtained as a colorless prism (ethanol) with a melting point of 78-81 ° C.

Example 53

In the same manner as in Example 52, the following compound was prepared.

Example 54

Ethyl magnesium bromide is prepared from magnesium (0.25 g) and ethyl bromide (1.2 g) and anhydrous tetrahydrofuran (10 ml). A 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyronitrile (1.8 g) solution dissolved in anhydrous tetrahydrofuran (10 ml) in this product was stirred with ice cooling. Add it down.

After adding this solution, the mixture is stirred at room temperature for 3 hours. 1N-HCl (50 ml) is added to this mixture under ice cooling and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- (3-propionylpropyl) thio-1,2, 3,4-tetrazol (0.5 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5042.

Example 55

In the same manner as in Example 54, the following compound was prepared.

Example 56

4-Ethylphenylmagnesium bromide was prepared from magnesium (0.25 g) and 4-ethyl-1-bromobenzene (2.6 g) and anhydrous tetrahydrofuran (10 ml), and this product was added to anhydrous tetrahydrofuran (10 ml). The dissolved 1-methyl-5- (3-cyanopropyl) thio-1,2,3,4-tetrazol (1.8 g) solution was added dropwise under ice cooling stirring.

After addition of this solution the mixture is stirred for 3 hours at room temperature. 1N-HCl (50 ml) is added to the mixture under ice cooling, and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform was distilled off and the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (4-ethylbenzoyl) propyl] thio-1. , 2,3,4-tetrazole (70.g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 68-69 ° C.

Example 57

In the same manner as in Example 56, the following compound was prepared.

Example 58

Pyridylmagnesium bromide was prepared from magnesium (0.2 g) and 2-bromopyridyl (2.1 g) and anhydrous tetrahydrofuran (10 ml) and dissolved in anhydrous tetrahydrofuran (10 ml) in the product. -(3-cyanopropyl) thio-1,2,3,4-tetrazole (1.8 g) is added dropwise under ice cooling stirring.

After addition of this solution, the mixture is stirred at room temperature for 3 hours. 1N-HCl (50 ml) is added to the mixture under ice cooling, and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. This chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. After distilling off the chloroform, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (2-pyridyl carbonyl) propyl) thio. -1,2,3,4-tetrazole (0.6 g) is obtained as a colorless needle (hexane ether) having a melting point of 73-75 占 폚.

Example 59

In the same manner as in Example 58, the following compounds were prepared.

Example 60

Magnesium (0.3 g) was suspended in anhydrous tetrahydrofuran (5 ml) and the suspension was stirred under a stream of nitrogen gas while the flakes were added with iodine and 1-methyl-5- (3-chloropropyl) thio-1, Add 2,3,4-tetrazole (0.3 g). Ethyl bromide (0.1 ml) is added to this mixture, and the reaction is started by heating the mixture from the outside.

A solution of 1-methyl-5- (3-chloropropyl) -thio-1,2,3,4-tetrazole (1.8 g) dissolved in anhydrous tetrahydrofuran (15 ml) was further added dropwise to this mixture.

After addition of this solution, the mixture is refluxed for 1 hour. To the obtained Grignard reagent, a propionitrile (0.5 g) solution dissolved in anhydrous tetrahydrofuran (5 ml) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 3 hours. 1N-HCl (20 ml) is added to this mixture under cooling, and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform.

This chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. The chloroform was distilled off and the residue was purified by silica gel column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) in 1-methyl-5- (3-progioylpropyl) thio-1,2. , 3,4-tetrazole (0.5 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5042.

Example 61

In the same manner as in Example 60, the following compound was prepared.

Example 62

Magnesium (0.3 g) is suspended in anhydrous tetrahydrofuran (5 ml), and a small amount of iodine is added to the suspension when the mixture is stirred under nitrogen gas inlet, and then 1-methyl-5- (3-chloropropyl) thio-1,2 Add 3,4-tetrazole (0.3 g). Ethyl bromide (0.1 ml) is added to the mixture and from outside the mixture is heated to initiate the reaction.

A solution of 1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.8 g) dissolved in anhydrous tetrahydrofuran (15 ml) was further added dropwise to the mixture.

After addition of this solution, the mixture is refluxed for 1 hour. To the obtained Grignard reagent, a solution of 1-cyano-4-ethylbenzene (1.1 g) dissolved in anhydrous tetrahydrofuran (5 ml) was added dropwise while stirring under ice cooling, and the mixture was stirred at room temperature for 3 hours. .

To this mixture is added 1N-HCl (20 ml) under ice cooling and the mixture is stirred for 1 hour. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. The chloroform was distilled off and the residue was purified by silica gel column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5-3- (4-ethylbenzoyl) propyl] thio-1. , 2,3,4-tetrazole (0.7 g) is obtained as a colorless needle (recrystallized from hexane-ether) with a melting point of 68-69 占 폚.

Example 63

In Example 62 and in the same manner to prepare the following compound.

Example 64

Suspend magnesium (0.3 g) in anhydrous tetrahydrofuran (5 ml) and add small iodine to the suspension with stirring under nitrogen gas inlet and again add 1-methyl-5- (3-chloropropyl) thio-1, Add 2,3,4-tetrazole (0.3 g). Ethyl bromide (0.1 ml) is added to this mixture, and the mixture is heated from the outside to initiate the reaction.

A 1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.8 g) solution dissolved in anhydrous tetrahydrofuran (15 ml) was further added dropwise to this mixture. After this solution is added, the mixture is refluxed for 1 hour. To the obtained Grignard reagent, a 2-cyanopyridine (0.9 g) solution dissolved in anhydrous tetrahydrofuran (5 ml) was added dropwise while stirring under ice cooling, and the mixture was stirred at room temperature for 3 hours. To this mixture was added dropwise 1N-HCl (20 ml) under ice cooling and the mixture was stirred for 1 hour.

The reaction mixture is diluted with water and extracted with pochloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl]. Thio-1,2,3,4-tetrazole (0.6 g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 73-75 ° C.

Example 65

In the same manner as in Example 64, the following compounds were prepared.

Example 66

4- (1-Methyl-1,2,3,4-tetrazol-5-yl) thio-butyl acid (2 g) is dissolved in anhydrous benzene (20 ml).

1.5N ethyllithium-ether solution (13.3 ml) was added dropwise to the mixture with stirring at −70 ° C. under argon gas inflow. The mixture is stirred for 3 hours to slowly heat to room temperature. The reaction mixture is then stirred at room temperature for 1 hour, poured into ice water and extracted with ether. The ether solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the ether, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- (3-propionyl as a colorless liquid of n _D ²⁵ = 1.5042. Propyl) thio-1,2,3,4-tetrazole (0.5 g) is obtained.

Example 67

In the same manner as in Example 66, the following compound was prepared.

Example 68

Dissolve 1-methyl-5- (3-carboxypropyl) thio-1,2,3,4-tetrazole (2 g) in anhydrous benzene (2 0 ml) and add 1.5 N ethyllithium-ether solution (13.3) to this mixture. ml) is added dropwise with stirring at -70 ° C under inflow of argon gas. The mixture is stirred for 3 hours while slowly heating at room temperature. The reaction mixture is then stirred at room temperature for 1 hour and poured into ice water and extracted with ether. The ether solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the ether, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (4-ethylbenzoyl) propyl) thio-1. , 2,3,4-tetrazole (0.7 g) is obtained as a colorless needle (recrystallized in hexane-ether) having a melting point of 68-69 ℃.

Example 69

In the same manner as in Example 68, the following compound was prepared.

Example 70

1-Methyl-5- (3-carboxypropyl) thio-1,2,3,4-tetrazole (2 g) was dissolved in anhydrous benzene (20 ml) and added to this mixture with stirring at -70 ° C under inflow of argon gas. Add dropwise to 1.5 N ethyllithium-ether solution (13.3 ml). The mixture is stirred for 3 hours while slowly heating to room temperature. The reaction mixture is then stirred at room temperature for 3 hours, poured into ice water and extracted with ether.

This ether solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the ether, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl] thio. -1,2,3,4-tetrazole (0.g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 73-75 ° C.

Example 71

In the same manner as in Example 70, the following compound was prepared.

Example 72

2-ethyl-1,3-dithiane (1.5 g) is dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -78 deg. To this mixture is added 1.6N n-butyllithium-n-hexane solution (6.5 ml) dropwise with stirring under argon gas inlet. The mixture is stirred at -78 ° C for 30 minutes. To this mixture was added dropwise a solution of 1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.9 g) dissolved in anhydrous tetrahydrofuran (5 ml). After stirring at −78 ° C. for 1 hour, the mixture is stirred for 4 hours while gradually warming to 0 ° C. The reaction mixture is poured into ice water and extracted with ether.

The ether solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the ether, the residue is dissolved in acetonitrile (20 ml). Silver nitrate (7 g) and N-chlorosuccinimide (4.9 g) are dissolved in a mixture of water (40 ml) and acetonitrile (100 ml).

The dithiane solution as described above was added dropwise to this mixture with stirring at 0 ° C. under nitrogen gas inlet, and stirred at 0 ° C. for 30 minutes, and then the mixture was heated to room temperature and further stirred for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform.

The chloroform solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- (3-propiodylpropyl) thio-1,2,3, 4-tetrazole (0.3 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5042.

Example 73

In the same manner as in Example 72, the following compound was prepared.

Example 74

2- (4-ethylphenyl) -1,3-dithiane (2.3 g) is dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -78 deg. 1.6N n-butyllithium-n-hexane solution (6.5 ml) was added dropwise to the mixture with stirring under argon gas inflow. The mixture is stirred at -78 ° C for 30 minutes.

To this mixture was added dropwise a solution of 1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.9 g) dissolved in anhydrous tetrahydrofuran (5 ml). After stirring at −78 ° C. for 1 hour, the mixture is stirred for 4 hours while gradually warming to 0 ° C. The reaction mixture is poured into ice water and extracted with ether.

The ether solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the ether, the residue is dissolved in acetonitrile (20 ml). Silver nitrate (7 g) and N-chlorosuccinimide (4.9 g) are dissolved in a mixture of water (40 ml) and acetonitrile (100 ml). To this mixture is added dropwise a dithiane solution as described above with stirring at 0 ° C. under nitrogen gas inlet.

After stirring for 30 minutes at 0 ° C., the mixture is heated to room temperature and further stirred for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (4-ethylbenzoyl) propyl) thio-1. , 2,3,4-tetrazole (0.4 g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 68-69 占 폚.

Example 75

In the same manner as in Example 74, the following compound was prepared.

Example 76

2- (2-pyridyl) -1,3-dithiane (2.0 g) is dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -78 deg. 1.6N n-butyllithium-n-hexane-solution (6.5 ml) was added dropwise to the mixture with stirring under argon gas inflow.

The mixture is stirred for 30 minutes at -78 ° C. To this mixture was added dropwise a solution of 1-methyl-5- [3-chloropropyl] thio-1,2,3,4-tetrazole (1.9 g) dissolved in anhydrous tetrahydrofuran (5 ml). After stirring at −78 ° C. for 1 hour, the mixture is stirred for 4 hours to slowly warm up to 0 ° C. The reaction mixture is poured into ice water and extracted with ether. This ether solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate.

After distilling off the ether, the residue is dissolved in acetonitrile (20 ml). Silver nitrate (7 g) and N-chlorosuccinimide (4.9 g) are dissolved in a mixture of water (40 ml) and acetonitrile (100 ml). To this mixture is added dropwise a dithiane solution as described above with stirring at 0 ° C. under nitrogen gas inlet.

After 30 minutes of stirring at 0 ° C., the mixture is heated to room temperature and further stirred for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate.

After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl] thio. -1,2,3,4-tetrazole (0.4 g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 73-75 ° C.

Example 77

In the same manner as in Example 76, the following compound was prepared.

Example 78

(A) Thionylchloride (5 ml) is added to 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyl acid (2 g) and the mixture is 40-50 ° C. Stir for 1 h. Excess amount of thionyl chloride is distilled off under reduced pressure, anhydrous benzene is added to this mixture, water is distilled off by azeotropic distillation, and the obtained mixture is directly supplied to the next reaction.

(B) Copper iodide (571 mg) is added to two sealed distillation flasks. After degassing under reduced pressure, the flask is filled with nitrogen gas. Anhydrous ether (10 ml) is poured into this flask and the whole is cooled to -40 ° C. Into this flask, a 1.32 M ethyllithium-ether solution (5 ml) was injected. After stirring at −40 ° C. for 5 minutes, the mixture is cooled to −78 ° C. In this mixture, 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyrylchloride (230 mg) obtained in step (A) described above was dissolved in anhydrous ether (5 ml). Pour the cooling solution and stir the mixture at -70 ° C for 15 minutes. Anhydrous methanol (35 ml) is poured into this mixture and the flask temperature is reduced to room temperature. The reaction mixture is poured into saturated aqueous ammonium chloride solution and extracted with ether. After drying the ether solution with magnesium sulfate, the ether is distilled off. The residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3-propionylpropyl) thio-1,2,3,4-tetrazole. (0.1 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5042.

Example 79

In the same manner as in Example 78, the following compound was prepared.

Example 80

(A) Thionylchloride (5 ml) is added to 1-methyl-5- (3-carboxypropyl) thio-1,2,3,4-tetrazole (2 g) and the mixture is 1 at 40-50 ° C. Stir for hours. Excess amount of thionyl chloride is distilled off under reduced pressure. Anhydrous benzene is added to this mixture, water is distilled off by azeotropic distillation, and the obtained mixture is directly supplied to the next reaction.

(B) Copper iodide (571 mg) is injected into two sealed distillation flasks, and after degassing under reduced pressure, the flask is filled with nitrogen gas. Anhydrous ether (10 ml) is poured into the flask and the whole is cooled to -40 ° C.

To this flask is added 1.32 M 4-ethylphenyllithium-ether solution (5 ml). After stirring at −40 ° C. for 5 minutes, the mixture is cooled to −78 ° C. To this mixture was dissolved 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyrylchloride (230 mg) obtained in step (A) described above in anhydrous ether (5 ml). The cooled solution was poured and the mixture was stirred at -78 ° C for 15 minutes. Incidental ethanol (35 ml) is injected into this mixture and the flask is reduced to room temperature. The reaction mixture is poured into saturated ammonium chloride water 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 (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (4-ethylbenzoyl) propyl] thio-1,2,3, 4-tetrazole (0.1 g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 68-69 ° C.

Example 81

In the same manner as in Example 80, the following compound was prepared.

Example 82

(A) Thionyl chloride (5 ml) was added to 1-methyl-5- (3-carboxypropine) thio-1,2,3,4-tetrazole (2 g) and the mixture was stirred at 40-50 ° C. do.

Excess thionyl chloride is distilled off under reduced pressure. Anhydrous benzene is added to this mixture, water is distilled off by azeotropic distillation, and the obtained mixture is directly supplied to the next reaction.

(B) Copper iodide (571 mg) is injected into two sealed distillation flasks and degassed under reduced pressure, and the flask is filled with nitrogen gas. Anhydrous ether (10 ml) is poured into this flask and the whole is cooled to -40 ° C.

To this flask is added 1.32M 2-pyridylithium-ether solution (5 ml). After stirring at −40 ° C. for 5 minutes, the mixture is cooled to −78 ° C. To this mixture was dissolved 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyryl chloride (230 mg) obtained in step (A) described above in anhydrous ether (5 ml). The cooled solution is poured and the mixture is stirred at -78 ° C for 15 minutes.

Anhydrous ethanol (35 ml) 60) is poured into this mixture and the flask temperature is reduced to room temperature. The reaction mixture is poured into a saturated aqueous ammonium chloride solution and extracted with ether. After drying the ether solution with magnesium sulfate, the ether is distilled off. The residue was purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10: 1) to give 1-methyl-5- [3- (2-pyridylcarbonyl) propyl) thio-1,2, 3,4-Tetazole (0.1 g) is obtained as a colorless needle (recrystallized in hexane-ether) with a melting point of 73-75 ° C.

Example 83

In the same manner as in Example 82, the following compound was prepared.

Example 84

1-methyl-5- [3- (4--methoxybenzoyl) propyl) thio-1,2,3,4-tetrazole (2 g) was added to 47% hydrobromic acid (40 ml) and the mixture was added. Reflux for 5 hours.

After cooling, the mixture is poured into iced water and extracted with ethyl acetate. The organic fillings are washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off ethyl acetate, the residue was purified by silica gel column chromatography (Wakogel C-200) and eluted with hexane-ethyl acetate (1: 1) to give 1-methyl-5- [3- (4-hydroxy Benzoyl) propyl] thio-1,2,3,4-tetrazole (0.3 g) is obtained as a colorless needle (recrystallized from water) with a melting point of 128.5-129.5 ° C.

Example 85

Aluminum chloride (16 g) was suspended in carbon tetrachloride (100 ml) and 4- (1-methyl-1,2,3,4-tetrazol-5yl) thio-butytylchloride (26.5 g) under ice cooling Add dropwise to this suspension. After stirring the mixture for 30 minutes, benzene (7.8 g) is added dropwise to the mixture at 5 DEG C or lower and the mixture is stirred at the same temperature for 1 hour.

The reaction mixture is poured into hydrochloric acid-ice and extracted with chloroform. The chloroform solution is washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue is purified by column chromatography (Kieselgel 60, eluent: chloroform). The eluate obtained is recrystallized as methanol-water to give 1-methyl-5- (3-benzoylpropyl) thio-1,2,3,4-tetrazole (10.5 g) as a colorless needle having a melting point of 57.5-58 ° C. .

Example 86

In the same manner as in Example 85, the following compound is prepared.

Example 87

Aluminum chloride (4 g) is suspended in carbon disulfide (20 ml) and furan (1.5 g) is added to this suspension.

4- [1-methyl-1,2,3,4-tetrazol-5-yl) thio-butytyl chlorite (4.4 g) is added dropwise to this mixture with stirring under ice cooling and the mixture is brought to the same temperature. Stir for 1 hour. The reaction mixture is poured into ice-hydrochloric acid and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over magnesiumsulfite.

Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluent: chloroform). The eluate was recrystallized in hexane-ether to give 1-methyl-5- [3- (2-futoyl) propyl) thio-1,2,3,4 tetrazole (0.8 g) colorless with a melting point of 41-42 ° C. Obtained as a needle material.

Example 88

In the same manner as in Example 87, the following compound was prepared.

Example 89

1-Methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.9 g) and thiophenol (1.1 g) are dissolved in acetone (50 ml). Potassium carbonate (1.5 g) and potassium iodide (0.1 g) are added to the mixture and the mixture is refluxed for 3 hours.

After distilling off the acetone, water is added to the residue and the mixture is extracted with ether. The ether solution is washed with dilute sodium hydroxide and saturated aqueous sodium chloride solution and dried over sodium sulfate. After distilling off the ether, the residue was purified by silica gel column chromatography (Kiesel gel) and then eluted with benzene-chloroform (3: 2) to give 1-methyl-5- [3-phenyl-thiopropyl) thio-1, 2,3,4-tetrazole (2.5 g) is obtained as a colorless liquid with n _D ¹⁸ = 1,6008.

Elemental Analysis for C ₁₁ H ₁₄ N ₄ S ₂

Calculation (%): C, 49, 60; H, 5. 30; N, 21.03

Found (%): C, 49.34; H, 5. 12; N, 20.85

Example 90

In the same manner as in Example 89, the following compound is prepared.

Example 91

1-methyl-5- (3-chloropropyl) thio-1,2,3,4-tetrazole (1.9 g) and 3-hydroxy-2-mercapto pyridine (1.3 g) were added to acetone (50 ml). Dissolve.

Potassium carbonate (1.4 g) and potassium iodide (0.1 g) are added to the mixture and the mixture is refluxed for 5 hours. After distilling off the acetone, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with aqueous sodium chloride solution and dried over magnesium sulfate.

After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60), eluted with chloroform-methanol and recrystallized in ethyl acetate-n-hexane to give 1-methyl-5- [3- (3-hydroxy 2-pyridyl) thiopropyl) thio-1,2,3,4-tetrazole (1.2 g) is obtained as a pale yellow particle with a melting point of 87.5-88.5 ° C.

Elemental Analysis for C ₁₆ H ₁₃ N ₅ OS ₂

Calculated (%): C, 42.40; H, 4.59; N, 24.73

Found (%): C, 42.29; H, 4.70; N, 24.66

Example 92

In the same manner as in Example 91, the following compound is prepared.

Example 93

1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1,3-dibromopropane (4 g) are dissolved in acetone (50 ml). Potassium carbonate (5.5 g) is added to the mixture and the mixture is refluxed for 3 hours. After distilling off acetone, water is added to the residue, and the precipitated crystals are separated by filtration and recrystallized in ethanol to obtain a colorless prism having a melting point of 141.5-143.5 占 폚.

Elemental Analysis for C ₇ H ₁₂ N ₈ S ₂

Calculation (%): C, 30.87; H, 4. 44; N, 41.14

Found (%): C, 30.68; H, 4. 37; N, 41.32

Example 94

In the same manner as in Example 93, the following compound was prepared.

Example 95

1-methyl-5- (3-mercaptopropyl) thio-1,2,3,4-tetrazole (1.9 g) was dissolved in 1N aqueous sodium hydroxide solution (30 ml) and acetone was added thereto while stirring under ice cooling. To 20 ml was added dropwise a solution of cyclohexyl bromide (2.0 g). After addition, the mixture is stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue, then the mixture is extracted with ether.

The ether solution is washed with dilute aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. After distilling off the ether, the residue was purified by column chromatography (Kieselgel 60), and then dissolved in n-hexane-ether (4: 1) to dissolve 1-methyl-5- (3-cyclohexylthiopropyl) thio-. 1,2,3,4-tetrazole (1.5 g) is obtained as a colorless liquid with n _D ¹⁸ = 1.5433.

Elemental Analysis for C ₁₁ H ₂₀ N ₄ S ₂

Calculated (%): C, 48.53; H, 7. 35; N, 20.59

Found (%): C, 48.40; H, 7. 58; N, 20.41

Example 96

In the same manner as in Example 95, 1-cyclohexyl-5 (3-ethylthiopropyl) thio-1,2,3,4-tetrazole is prepared as a colorless liquid with n _D ¹⁴ = 1.5433.

Example 97

1-Methyl-5- (3-mercaptopropyl) thio-1,2,3,4-tetrazole (1.9 g) was dissolved in 1N aqueous sodium hydroxide solution (30 ml) and dissolved in acetone (20 ml). A solution of 5-nitro-2-chloropyridine (1.9 g) was added dropwise under ice cooling. After addition the mixture was stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue.

The mixture is extracted with ether and the ether solution is washed with dilute aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. After ether was distilled off, the residue was purified by column chromatography (Kiesel 60) and subsequently eluted with n-hexane-ether (4: 1) to 1-methyl-5- [3- (5-nitro-2-pyridine. Dilthiopropyl) thio-1,2,3,4-tetrazole (1.4 g) is obtained as a light brown liquid with n _D ²⁹ = 1.6289.

Elemental Analysis for C ₁₀ H ₁₂ N ₆ O ₂

Calculated (%): C, 38.46; H, 3.85; N, 26.92

Found (%): C, 38.46; H, 3.68; N, 27.01

Example 98

In the same manner as in Example 97, the following compound was prepared.

Example 99A

2-mercaptopyridine (1.3 g) and 1-methyl-5- (4-bromobutyl) thio-1,2,3,4-tetrazole (2 g) are dissolved in acetone (50 ml). Potassium carbonate (1.4 g) is added to the mixture and the mixture is refluxed for 2 hours. The distilled off acetone was added to the residue, and the precipitated crystals were filtered and separated and recrystallized as ethanol-water to give 1-methyl-5- [4- (2-pyridyl) thiobutyl] thio-1,2 , 3,4-tetrazole (1.7 g) is obtained as a pale yellow prism with a melting point of 49-51.5 占 폚.

Elemental Analysis for C ₁₁ H ₁₅ N ₅ S ₂

Calculated (%): C, 46.98; H, 5. 34; N, 24.91

Found (%): C, 46.67; H, 5. 27; N, 24.94

Example 99B

Mercaptobenzel (1.3 g) and 5- (3-bromopropyl) thio-1,2,3,4- tetrazole (1.8 g) are dissolved in acetone (50 ml) and potassium carbonate (1.4 g) ) And the mixture is refluxed for 2 hours. Acetone is distilled off and added to the water residue and the mixture is extracted with chloroform. The chloroform layer is washed with 5% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform) to give 5- (3-phenylthiopropyl) thio-1,2,3,4-tetrazole (1.5 g). Is obtained as a colorless liquid.

Elemental Analysis for C ₁₀ H ₁₂ N ₄ S ₂

Calculated (%): C, 47.59; H, 4.79; N, 22.20

Found (%): C, 47.62; H, 4. 80; N, 22.15

Example 100

In the same manner as in Example 99A, the following compounds were prepared.

Example 101

1-methyl-5- (4-chlorobutyl) thio-1,2,3,4-tetrazole (2.00 g) and 2-mercapto-3H, 4H-benzotriazin-5-one (2.2 g) Is dissolved in methanol (50 ml), and sodium hydroxide (4.8 g) is added thereto, and the mixture is refluxed for 2.5 hours. After distilling off the solvent, the residue is added with water and the mixture is extracted with chloroform.

The chloroform layer is washed with 5% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off and the residue is recrystallized in methanol to obtain a colorless prism having a melting point of 94-95 ° C.

Elemental Analysis for C ₁₄ H ₁₇ N ₇ OS ₂

Calculated (%): C, 46.29; H, 4.68; N, 27.00

Found (%): C, 46.14; H, 4. 45; N, 26.89

Example 102

In the same manner as in Example 101, the following compound was prepared.

Example 103

Dissolve 1-methyl-5-[(3-iodopropyl) thio] -1,2,3,4-tetrazole (2.8 g) and thiourea (0.8 g) in ethanol (5 ml) and mix the mixture. Reflux for 2 hours. After cooling, the precipitated crystals are collected by filtration, dried, and dissolved in ethanol (50 ml). To this mixture is added cyclopentylbromide (1.3 g) and 10% aqueous sodium hydroxide solution (5 ml) and the mixture is refluxed for 3 hours. Ethanol is distilled off and water is added to the residue. This mixture is extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Wakogel C-200. Eluent: chloroform) to give 1-methyl-5- (3-cyclopentylthiopropyl) thio-1,2,3,4- Tetrazole (1.8 g) is obtained as a pale yellow liquid with n _D ²⁹ = 1.5469.

Elemental Analysis for C ₁₀ H ₁₈ N ₄ S ₂

Calculated (%): C, 46.48; H, 7.02; N, 21.68

Found (%): C, 46.43; H, 7. 10; N, 21.58

Example 104

In the same manner as in Example 103, the following compound is prepared.

Example 105

Dissolve 1-methyl-5-((3-iodopropyl) thio) -1,2,3,4-tetrazole (2.5 g) and N-methylthiourea (0.9 g) in ethanol (50 ml) and This mixture is refluxed for 2 hours. After cooling, the precipitated crystals are collected by filtration and dried. The crystals are dissolved in ethanol (50 ml) and 2-pyridylmethylchloride (1.14 g) and 10% aqueous sodium hydroxide solution (10 ml) are added thereto and the mixture is refluxed for 1.5 hours. Ethanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Wakogel C-200, eluent: chloroform-methanol (50: 1)) to give 1-methyl-5- [3- (2-pyridylmethyl) thiopropyl. ] Thio-1,2,3, 4-tetrazole (2.7 g) is obtained as a brown liquid with n _D ²⁹ = 1.5820.

Elemental Analysis for C ₁₁ H ₁₅ N ₅ S ₂

Calculated (%): C, 46.95; H, 5. 37; N, 24.89

Found (%): C, 46.81; H, 5. 41; N, 24.78

Example 106

In the same manner as in Example 105, the following compound is prepared.

Example 107

2-amino-4-methyl-6-chloropyrimidine (1.43 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml) and the mixture is refluxed for 2 hours. After cooling, the precipitated crystals are collected by filtration and dried. The crystals were dissolved in ethanol (50 ml) and added 1-methyl-5-[(3-chloropropyl) thio] -1,2,3,4-tetrazole (1.73 g) and 10% aqueous sodium hydroxide solution. (5 ml) is added and the mixture is refluxed for 4 hours. After distilling off the ethanol, water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography: Wacogel C-200, eluent chloroform-methanol (50: 1)) and then recrystallized in methanol to give 1-methyl-5- [3- (2-amino -4-methyl-6-pyrimidyl) thiopropyl] Thio-1,2,3,4-tetrazole (0.7 g) is obtained as colorless powder crystals having a melting point of 119-120 ° C.

Elemental Analysis for C ₁₀ H ₁₅ N ₇ S ₂

Calculation (%): C, 40.40; H, 5.05; N, 32.99

Found (%): C, 40.28; H, 4.87; N, 33.10

Example 108

In the same manner as in Example 107, the following compound is prepared.

Example 109

1-methyl-1,2,3,4-tetrazol-5-yl 4-bromobutylsulfoxide (2.7 g) and 1-methyl-5-mercapto-1,2,3,4--tetra The sol (1.4 g) is dissolved in acetone (50 ml) and potassium carbonate (1.4 g) is added thereto and the mixture is refluxed for 2 hours. After distilling off the acetone, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60) and eluted with chloroform-methanol (100: 1) to 1-methyl-1,2,3,4-tetrazol-5-yl 4- ( 1-methyl-1,2,3,4-tetrazol-5-yl) thiobutylsulfoxide (1.5 g) is obtained as a colorless liquid with n _D ¹⁹ = 1.5660.

Elemental Analysis for C ₈ H ₁₄ N ₈ S ₂ O

Calculated (%): C, 31.78; H, 4.67; N, 37.06

Found (%): C, 31.65; H, 4.72; N, 37.12

Example 110

In the same manner as in Example 109, the following compound is prepared.

Example 111

2-chloropyridyl (1.13 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml) and the mixture is refluxed for 1 hour. After cooling, the precipitated crystals are collected by filtration and dried. The crystals were dissolved in ethanol (50 ml) and added 1-methyl-1,2,3,4-tetrazol-5-yl-4-bromobutylsulfoxide (2.4 g) and 10% aqueous sodium hydroxide solution ( 10 ml) is added and the mixture is refluxed for 4 hours. After ethanol is distilled off, water is added to the residue, and the mixture is extracted with chloroform.

The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 50, eluent: chloroform) to give 4- (2-pyridyl) thiobutyl 1-methyl-1,2,3,4-tetrazole-5- One sulfoxide is obtained as a pale yellow liquid of n _D ^23.5 = 1.5893.

Elemental Analysis for C ₁₁ H ₁₅ N ₅ S ₂ O

Calculated (%): C, 44.42; H, 5.0 8; N, 23.55

Found (%): C, 44.32; H, 5. 12; H, 23.39

Example 112

In the same manner as in Example 111, the following compound is prepared.

Example 113

Dissolve 1-methyl-5- [3- (2-pyridyl) thiopropyl) thio-1,2,3,4-tetrazole (2.2 g) in formic acid (20 ml) and add 30% hydrogen peroxide (2.2). g) is added while stirring at room temperature. The mixture is stirred for 5 hours at room temperature and sodium hydrogen sulfite is added under ice cooling to decompose excess perforic acid.

To this mixture is added water and extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography (Kieselgel 60, eluent: chloroform-methylol (50: 1), and 3- (1-methyl-1,2,3,4-tetrazol-5-). I) sulfinylpropyl 2-pyridylsulfoxide (0.5 g) is obtained as a colorless liquid with n _D ^28.5 = 1.3795.

Elemental Analysis for C ₁₀ H ₁₃ N ₅ S ₂ O ₂

Calculation (%): C, 40.12; H, 4.38; N, 23.39

Found (%): C, 40.01; H, 4. 48; N, 23.28

Example 114

When the compound of the formula (I) having the sum of l and m is 0 as a starting material and 30% hydrogen peroxide is introduced with one oxygen, an equivalent amount of water is introduced, or two moles when two oxygens are introduced. The following compounds were prepared in the same manner as described in Example 113 except that 3 moles of oxygen and 4 moles of oxygen were used in an amount of 4 moles.

Example 115

Dissolve 3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropyl 2-pyridylsulfoxide (2.8 g) in formic acid (20 ml) and add 30% hydrogen peroxide (1.3 g) is added with stirring at room temperature and the mixture is stirred for 5 hours. To this mixture is added sodium hydrogen sulfite under ice cooling to break down excess excess form. To the obtained mixture is added water and extracted with chloroform.

The chloroform solution is washed with water and saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. After distilling off chloroform, the residue was purified by column chromatography [Wakogel C-200, eluent: chloroform-methanol (50: 1) to give 3- (1-methyl-1,2,3,4-tetrazole-5). -Yl) sulfinylpropyl 2-pyridylsulfoxide (0.8 g) is obtained as a colorless liquid with n _D ^28.5 = 1.5795.

Elemental Analysis on C ₁₀ H ₁₃ N ₂ S ₂ O ₂

Calculation (%): C, 40.12; H, 4.38; N, 23.39

Found (%): C, 40.31; H, 4. 24; N, 23.26

Example 116

A compound of the general formula (I), in which the sum of the starting materials l and m is 1, and 2 moles or 3 oxygens when 30% hydrogen peroxide is introduced in the same molar amount when two oxygens are introduced. When introduced, the following compounds were prepared in the same manner as in Example 115 except that the amount was used in an amount of 3 mol.

Example 117

4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyl 1-methyl-1,2,3,4-tetrazol-5-sulfone (1 g) in formic acid (10 ml ), And 30% hydrogen peroxide (0.4 g) is added thereto while stirring at room temperature, and the mixture is stirred for 3 hours. Water was added to the mixture, and the precipitated crystals were collected by filtration and recrystallized in ethanol-chloroform to give 4- (1-methyl-1,2,3,4-tetrazol-5-yl) sulfonylbutyl 1-methyl-1 , 2.3,4-tetrazol-5-yl sulfone (0.4 g) is obtained as a colorless acicular material with a melting point of 147-149 ° C.

Elemental Analysis for C ₈ H ₁₄ N ₈ S ₂ O ₃

Calculated (%): C, 28.74; H, 4. 22; N, 33.51

Found (%): C, 28.62; H, 4.31; N, 33.41

Example 118

The starting material is a compound of general formula (I) in which the sum of l and m is 2 and one of them is 0, and 30% hydrogen peroxide is introduced in the same molar amount when two oxygens are introduced and two oxygens are introduced. The following compound is prepared in the same manner as described in Example 117, except that it is used in an amount of 2 moles.

Example 119

3- (1-methyl-1,2,3,4-tetrazol-5-yl) sulfinylpropyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfoxide (3.0 g) It is dissolved in formic acid (30 ml), and 30% hydrogen peroxide (3.4 g) is added thereto while stirring at room temperature, and the mixture is stirred for 4 hours. Sodium hydrogen sulfite is added to this mixture under ice cooling to decompose excess perforic acid. Water was added to this mixture, and the precipitated crystals were collected by filtration and recrystallized in dimethylformamide to give 4- (1-methyl-1,2,3,4-tetrazol-5-yl) sulfonylbutyl 1-methyl-1, 2,3,4-tetrazol-5-yl sulfone (1.8 g) is obtained as a colorless prism with a melting point of 192-194 ° C.

Elemental Analysis for C ₈ H ₁₄ N ₈ S ₂ O ₄

Calculated (%): C, 27.42; H, 4.03; N, 31.98

Found (%): C, 27.22; H, 4. 12; N, 32.12

Example 120

Using the compound of general formula (I) in which the sum of l and m is 1 as a starting material, and 30% hydrogen peroxide in the same molar amount when introducing one oxygen, or in the amount of 2 mol when two oxygens are introduced. Except for the use, the following compounds were prepared in the same manner as in Example 119.

Example 121

4- (1-methyl-1,2,3,4-tetrazol-5-yl) sulfinylbutyl 1-methyl-1,2,3,4-tetrazol-5-yl sulfone (3.2 g) formic acid (30 ml) and add 30% hydrogen peroxide (2.3 g) with stirring at room temperature and stir the mixture for 5 hours. Sodium hydrogen sulfite is added to this mixture under ice cooling to decompose excess performic acid. Water was added to the mixture, and the precipitated peak was collected by filtration and recrystallized in N, N-dimethylformamide to give 4- (1-methyl-1,2,3.4-tetrazol-5-yl) sulfonylbutyl 1-methyl- 1,2,3,4-tetrazol-5-yl sulfone (2.1 g) is obtained as a colorless prism with a melting point of 192-194 ° C.

Elemental Analysis for C ₆ H ₁₄ N ₈ S ₂ O ₄

Calculated (%): C, 27.42; H, 4.03; N, 31.98

Found (%): C, 27.50; H, 3.78; N, 31.95

Example 122

Dissolve 1-methyl-5- (2-pyridyl) methyl thio-1,2,3,4-tetrazole (2.0 g) in formic acid (20 ml) and add 30% hydrogen peroxide (1.3 g) at room temperature. It is added with stirring and the mixture is stirred for 5 hours. To this mixture is added sodium hydrogen sulfite under ice cooling to decompose excess performic acid. Water is added to this mixture and it is extracted with chloroform. The chloroform solution is washed with water and aqueous sodium bicarbonate solution and dried over magnesium sulfate. After distilling off the chloroform, the residue was purified by column chromatography (wacogel C-200, eluent: chloroform-methanol (50: 1) to give 1-methyl-1,2,3,4-tetrazol-5-yl 2). -Pyridylmethylsulfoxide is obtained as a brown liquid with n _D ^26.5 = 1.5810.

Example 123

1-phenyl-5- [3- (N-benzoylamino) propylthio1-1,2,3,4-tetrazole (1.7 g) is dissolved in dimethyl formamide (30 ml). To this mixture is added 50% oily sodium hydride (0.3 g) with stirring at room temperature. After foaming the mixture is stirred at 60-70 ° C. for 1 hour. After cooling to room temperature, ethyl bromide (0.8 g) was added dropwise to the resulting mixture, which was then stirred at 60-70 ° C. for 8 hours. After distilling off dimethylformamide, the residue was purified by column chromatography (Wakogel C-200) and then eluted with chloroform to give 1-phenyl-5- [3- (N-ethyl-N-benzoylamino) propylthio]-. 1,2,3,4-tetrazole (1.2 g) is obtained as a colorless liquid with n _D ²⁴ = 1.5898.

Example 124

In the same manner as in Example 123, the following compound is prepared.

Example 125

1-methyl-5- [3- (N-ethylamino) propylthio] -1,2,3,4-tetrazole (1 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). Potassium carbonate (0.7 g) is added to this mixture, and cyclohexanecarboxylic acid chloride (0.9 g) is added dropwise with stirring under ice cooling. Stirring is continued for 2 hours under ice cooling. After distilling off the acetone, water is added to the obtained residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. Chloroform is distilled off and the residue is then purified by column chromatography (Wakogel C-200) and then eluted with chloroform to give a colorless liquid with n _D ^23.5 = 1.5267.

Elemental Analysis for C ₁₄ H ₂₅ N ₂ OS

Calculation (%): C, 53.99; H, 8.09; N, 22.49

Found (%): C, 54.20; H, 7.78; N, 22.56

Example 126

In the same manner as in Example 125, the following compounds were prepared.

Example 127

1-methyl-5- (3-aminopropylthio) -1,2,3,4-tetrazole (0.9 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). Potassium carbonate (0.7 g) is added to this mixture, and 4-methoxy benzoylclide (1.1 g) is added dropwise thereto under ice cooling. Stirring is continued for 2 hours under ice cooling. After distilling off the acetone, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate.

Chloroform was distilled off and the residue was then purified by column chromatography (Wakogel C-200), which was then eluted with chloroform to give 1-methyl-5- (3- [N- (4-methoxybenzoyl) amino). Propylthio] -1,2,3,4-tetrazole (0.7 g) is obtained as a colorless needle (ethylacetate-ethanol) having a melting point of 118-122 占 폚.

Example 128

In the same manner as in Example 127, the following compound is prepared.

Example 129

1-Methyl-5- (3-chloropropylthio) -1,2,3,4-tetrazole (3.8 g) is dissolved in dimethylformamide (50 ml). The mixture is added sodium iodide (3 g) and diethylamine (4.4 g) and the mixture is stirred at 60-70 ° C. for 3 hours. Dimethylformamide was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (basic alumina manufactured by Merck), and then eluted with n-hexane to give 1-methyl-5- [3- (N, N- Diethylamino) propylthio] -1,2,3,4-tetrazole (1.1 g) is obtained as a colorless liquid with n _D ²⁵ = 1.5040.

Elemental Analysis for C ₉ H ₁₉ N ₅ S

Calculated (%): C, 47.13; H, 8. 35; N, 30.54

Found (%): C, 47,27; H, 8.39; N, 30.57

Example 130

In the same manner as in Example 129, the following compound is prepared.

Example 131

1-Methyl-5- (3- (phthalimido) propylthio] -1,2,3,4-tetrazole (3.5 g) is dissolved in ethanol (50 ml) To this mixture hydrazine hydrate (85%, 2 g) is added and the mixture is refluxed for 1 hour, after cooling the precipitate is filtered off and the ethanol is distilled off, the residue is dissolved in ethyl acetate and dried over magnesium sulfate, the ethyl acetate is distilled off and The residue was then purified by column chromatography (Aluminium Oxide from Merck Co.) and eluted with chloroform to give 1-methyl-5- (3-aminopropylthio) -1,2,3,4-tetrazole ( 1 g) is obtained with a dyeing liquid of n _D ^21.5 = 1.5384.

Elemental Analysis for C ₈ H ₁₁ N ₅ S

Calculation (%): C, 34.67; H, 6. 64; N, 40.43

Found (%): C, 34.58; H, 6. 36; N, 40.21

Example 132

In the same manner as in Example 131, the following compound is prepared.

1-phenyl-5- (3-aminopropylthio) -1,2,3,4-tetrazole, colorless liquid, n _D ^15.5 = 1. 5 930

Example 133

Dissolve 1-methyl-5- (3-aminopropylthio) -1,2,3,4-tetrazole (1.7 g) and 1,2-dimethylthiorea hydro iodide (2.3 g) in methanol (30 ml) And reflux this mixture for 3 hours. After methanol was distilled off, the residue was purified by column chromatography (basic alumina active grade II from Merck) and then eluted with chloroform-methanol (9: 1) to elute 1-methyl-5- [3- (3-methyl Guanidino) propylthio) -1,2,3,4-tetrazol hydro iodide (0.7 g) is obtained as a colorless liquid with n _D ^28.5 = 1.5684.

Example 134

3- (1-Methyl-1,2,3,4-tetrazol-5-yl) thiopropylamine (1.5 g) is dissolved in ethanol (5 ml) and methyl isothiocyanate in ethanol (5 ml) (0.8 g) was added dropwise with stirring under ice cooling and the mixture was refluxed for 1 hour. Ethanol was distilled off and the residue was then purified by column chromatography (Kieselgel 60) and eluted with chloroform-methanol (50: 1) to give 1- [3- (1-methyl-1,2,3,4- Tetrazol-5-yl) thiopropyl] -3-methylthiourea (0.7 g) (recrystallized in ethanol-ligroin) is obtained as pale yellow particles having a melting point of 99-101 ° C.

Example 135

Dissolve 1- (3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropyl] -3-methylthiourea (8 g) in methanol (80 ml). Methyl (5.7 g) is added and the mixture is refluxed for 5 h.To the reaction mixture is further added hydrazine hydrate (2.4 g) and the mixture is refluxed for 2 h. The solvent is distilled off and the resulting crystals are ethanol. Recrystallized in 1-amino-2-methyl-3- (3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropyl] guanidine hydroiodide (8.5 g), melting point 105 Obtained as a colorless prism at -108 ° C.

[Preparation 1]

Tablets are made by mixing, grinding, and stamping with a punch having a diameter of 10 mm, the compound of the present invention, Avicel, constantus and magnesium stearate. The tablets thus obtained are coated with a film coating solution consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000 and castor oil and methanol to make a film coated tablet.

[Preparation 2]

The compound of the present invention, citric acid, lactose secondary calcium diacid, Pluronic F-68 and sodium hourylsulfate were mixed and passed through screen 60. The resulting mixture is prepared into granules using an alcohol solution comprising polyvinylpyrrolidone and carbowax 1500 and carboax 6000. The powder mixture is added to the pasty material with alcohol if necessary. Cornstarch is added to this wet object and the mixture is continued until uniform granules are formed. The wet granules are passed through screen 10 and placed in a tray, placed in an oven and dried at 100 ° C. for 12-14 hours. The dry granules are passed through screen 16, mixed with anhydrous sodium lauryl sulfate and anhydrous magnesium stearate and then compressed into the required form. The core tablets thus obtained are varnished and sprayed with talc to prevent moisture absorption. The obtained tablets are subcoated and retreated with the varnish as many times as necessary to orally administer the tablets.

Subcoatings and smooth layers are also applied to the tablet surface to make the tablet round and smooth. The colored layer is added to make a tablet of the desired color. After drying, polishing is carried out to make tablets with a constant luster.

[Preparation 3]

The parabens, sodium metabisphosphite and sodium chloride are dissolved in about half the amount of distilled water with stirring at 80 ° C. The obtained solution is cooled to 40 ° C, and the above-described compound of the present invention, polyethylen glycol and polyoxyethylene sorbitan monooleate are dissolved in this solution. Residual distilled water is added to this solution to adjust the volume. This solution is filtered through a suitable filter paper and sterilized to form an injection.

[Preparation 4]

The compound of the present invention, Avicel, cornstarch and magnesium stearate are mixed and polished and stamped with a 10 mm diameter punch to make tablets. The tablet thus prepared is coated with a film coating solution consisting of hydroxypropyl methyl cellulose, polyethylene glycol 6000, castor oil and methanol to make a film coating tablet.

[Preparation 5]

The compound of the present invention, citric acid, lactose, secondary calcium phosphate, plutonic F-68 and sodium lauryl sulfate were mixed and passed through screen 60. The obtained compound is prepared into granules using an alcohol solution containing polyvinylphyllolidon, carbowax 1500 and carbowax 6000. This powder mixture is added into alcohol as necessary to form a paste. Cornstarch is added to this wet object and mixing continues until uniform granules are formed. The wet granules are passed through a screen 10 times and placed in a tray and dried in an oven at 100 ° C. for 12-14 hours. The dry granules are passed through screen 16 and mixed with anhydrous sodium lauryl sulfate and anhydrous magnesium stearate and then compressed into the required form.

The core tablets thus prepared are varnished and sprayed with talc for moisture proof. The obtained tablets are subcoated and retreated with the varnish as necessary for oral administration.

To make the tablets round and smooth, subcoats and smooth layers are applied to the surface. A colored layer is added to make a tablet of the desired color. After drying, polishing is carried out to produce a tablet of constant gloss.

[Preparation 6]

The above-mentioned parabens, sodium metabisphosphite and sodium chloride are dissolved in half amount of distilled water with stirring at 80 ° C. The obtained solution is cooled to 40 ° C, and the compound, polyethylene glycol, and polyoxyethyl sorbitan monooleate of the present invention are dissolved in this solution. The remaining volume of distilled water is added to this solution to adjust the volume. The solution is filtered through a suitable filter paper and sterilized to form a subject.

[Preparation 7]

The compound of the invention, Avicel, cornstarch and magnesium stearate are mixed and ground and then stamped with a 10 mm diameter punch to make tablets. The tablets thus prepared are coated with a film coating solution consisting of hydroxy propylmethyl cellulose, polyethylen glycol-6000, castor oil and methanol to make a film coating tablets.

[Preparation 8]

The compound of the present invention, citric acid, lactose, secondary calcium phosphate, plutonic F-68 and sodium lauryl sulfate were mixed and passed through screen 50. The resulting mixture is prepared into granules using an alcohol solution containing polyvinylphyllolidon, carbowax 1500 and carbowax 6000. This powder mixture is added as alcohol to make a pasty substance. Cornstarch is added to this wet object and mixing is continued until uniform granules are formed. The wet granules are passed through a screen 10 times in trays and dried in an oven at 100 ° C. for 12-14 hours. The dried granules are passed through screen 16, mixed with anhydrous sodium lauryl sulfate and anhydrous magnesium stearate and then compacted in the required form.

The core tablets thus prepared are varnished and sprayed with talc to be moisture proof. Sub-coportion is carried out to this obtained tablet. The tablets are varnished again as needed for oral administration. Subcoatings and smooth fillings are also applied to the tablet surface to make the tablet round and smooth. A colored layer is added to make a tablet of the desired color. Polishing after drying produces tablets with uniform gloss.

[Preparation 9]

The above-mentioned parabens, sodium metabisulfite and sodium chloride are dissolved in half a portion of distilled water with stirring at 80 ° C. The obtained solution is cooled to 40 ° C. and the compound, polyethylene glycol, and polyoxyethylene sorbitan monooleate of the present invention are dissolved in this solution. The remaining volume of distilled water is added to this solution to adjust the volume. This solution is filtered through a suitable filter paper and sterilized to form an injection.

[Preparation 10]

Compounds of the present invention, Avicel, cornstarch and magnesium stearate are mixed and ground, and stamped with a 10 mm diameter punch to make tablets. The tablets are coated with a film coating solution consisting of hydroxypropylmethyl cellulose, polyethylene glycol-6000, castor oil and methanol to make a film coating tablets.

[Preparation 11]

The compound of the present invention, citric acid, lactose, secondary calcium phosphate, polyuronic F-68 and sodium laurylsulfate are mixed and passed through screen 60. The resulting mixture is prepared from polyvinylpyrrolidone, carbowax 1500 and Alcohol solution containing Carbowax 6000 is prepared into granules using. This powder mixture is added as alcohol to make a paste material if necessary. Cornstarch is added to this wet object and the mixture is continued until uniform granules are formed. The wet granules are passed through a screen 10 times and placed in a tray and dried in an oven at 100 ° C. for 12-14 hours. The dry granules are passed through a screen 16 and mixed with anhydrous sodium lauryl sulfate and anhydrous magnesium stearate and compressed into the required form.

The core tablets thus obtained are varnished and sprayed with talc to be moisture proof. Sub-coating is applied to the surface of the obtained tablets and the tablets are treated with varnish again as many times as necessary for oral administration. In addition, a subcoating and a smooth layered film are applied to the tablet surface to make the tablet round and smooth. A colored layer is added to make the tablet of the desired color. Polishing after drying produces a tablet with a uniform gloss.

[Preparation 12]

The above-mentioned paraben, sodium metabisulphite and sodium chloride are dissolved while stirring at 80 DEG C which is half the amount of distilled water. The resulting solution is cooled to 40 ° C. and the compound, polyethylene glycol and polyoxyethylene sorbitan monooleate of the present invention are dissolved in this solution. The remaining volume of distilled water is added to this solution to adjust the volume. This solution is filtered and sterilized with a suitable filter paper to make an injection.

[Preparation 13]

The compound of the present invention, Avicel, cornstarch and magnesium stearate are mixed and ground and then stamped with a 10 mm diameter punch to make tablets. The tablets thus obtained are coated with a film coating solution consisting of hydroxypropyl methylcellulose, polyethyleneglycol-6000, castor oil and methanol to make a film coating tablets.

[Preparation 14]

The compound of the present invention, citric acid, lactose, secondary calcium phosphate, Pluronic F-68 and sodium lauril sulfate were mixed and passed through screen 60. The resulting mixture is prepared into granules using an alcohol solution containing polyvinylphyllolidon, carbowax 1500 and carbowax 6000. This powder mixture is added as alcohol to make a paste acid material. Cornstarch is added to this wet object and mixing is continued until uniform granules are formed. The wet granules are passed through a screen 10 times into trays and dried in an oven at 100 ° C. for 12-14 hours. The dry granules are passed through screen 16 and mixed with anhydrous sodium lauryl sulfate and compressed into the required form.

The core tablets thus prepared are varnished with moisture proof and talc is sprayed on them. The surface of the tablets obtained are subcoated. The tablets are then retreated as needed with varnish to allow for oral administration again. In addition, a subcoating and a smooth layer are applied to the tablet surface to make the tablet round and smooth. A colored layer is added to make the tablet of the desired color. Dry and polish to produce a uniform, glossy tablet.

[Formula 15]

The compound of the present invention, citric acid, lactose, secondary calcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed and passed through screen 60. The resulting mixture is prepared into granules using an alcohol solution containing polyvinylphyllolidon, carbowax 1500 and carbowax 5000. This powder mixture is added to the alcohol as necessary to form a paste. Cornstarch is added to this wet object and mixing is continued until uniform granules are formed. The wet granules are passed through a screen 10 times into trays and dried in an oven at 100 ° C. for 12-14 hours. The dry granules are mixed with anhydrous sodium lauryl sulfate and anhydrous magnesium stearate while pressing through a screen 16 and then compressed into the required form.

The core tablets thus obtained are varnished to make them waterproof and then talc is applied thereto. The resulting purified surface is subcoated. The tablets are reprocessed in two varnishes to allow for oral administration. Subcoatings and smooth layers are also applied to the tablet surface in order to round and smooth the tablet. Coloring is applied to obtain a tablet of the desired color. After drying, polishing is carried out to produce tablets with uniform gloss.

[Formula 16]

The above-mentioned parabens, sodium metabisulfite and sodium chloride are dissolved in half a portion of distilled water with stirring at 80 ° C. The resulting solution is cooled to 40 ° C. and the compound, polyethylene glycol and polyoxy-ethylene sorbitan monooleate of the present invention are dissolved in this solution. The remaining volume of distilled water is added to this solution to adjust the volume. This solution is filtered and sterilized with a suitable filter paper to make an injection.

[Formula 17]

The parabens, sodium metabisolphite and sodium chloride are dissolved in about half the amount of distilled water with stirring at 80 ° C. The resulting solution is cooled to 40 ° C. and the compound, polyethylene glycol and polyoxyethylene sorbitan monooleate of the present invention are dissolved in this solution. The remaining volume of distilled water is added to this solution to adjust the volume. This solution is filtered and sterilized with a suitable filter paper to make an injection.

Claims (1)

A method of preparing a tetrazole derivative of the following general formula (I) or a pharmaceutically acceptable salt thereof by reacting a compound of the following general formula (II) with a compound of the following general formula (II).

In the general formulas (I), (II) and (III), R ² ′ is hydrogen, lower alkyl, phenyl or cycloalkyl, l is 0, 1 or 2, m is 0 or 1, and 4 is Alkylene having 1 to 8 carbon atoms, X is -CO- or -S (O) _n- , n is 0, 1 or 2, and R ³ is lower alkyl; Cycloalkyl; Naphthyl; General formula

Wherein R ⁵ is lower alkyl; Phenyl (lower) alkyl, which may have a halogen substituent on the ringyl ring; Phenyl which may have from 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkanoylamino, hydroxy, carboxy and amino; Or a lower alkyl group by a heterocycle group selected from pyridyl, furyl and thiazolyl, or where L is O, X is CO, and m is 1 Selected from the group consisting of lower alkyl, halogen, carboxy, oxo, amino, lower alkoxycarbonyl, lower alkoxyhydroxy, nitro, phenyl, cycloalkyl and lower alkylamino provided that the heterocycle group is bound at the carbon atom on the ring Heterocycle group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur which may have 1 to 2 substituents, and when m is 0, R ³ is also a general formula -NR ⁶ R ⁷ Wherein R ⁶ is hydrogen, lower alkyl or phenyl (lower) alkyl, and R ⁷ is hydrogen, lower alkyl, a group of -CZ-NHR ⁸ wherein Z is sulfur; or lower alkyl Which may be amino and R ⁸ is lower alkyl or amino, tetrazol which may have lower alkyl substituents or a group of -CO-R ⁹ , wherein R ⁹ is lower alkyl, 1 to 3 lower alkoxy Phenyl, cycloalkyl, or a 5 or 6 membered unsaturated heterocycle group containing one hetero atom selected from nitrogen and oxygen, or R ⁶ and R ⁷ may be substituted with the nitrogen atom to which they are attached; Combined together

Z ¹ is Y ¹ or -S (O) 1 -AY ¹ , wherein Y ¹ is halogen, mercapto or amidinothio; Z ² when Z ¹ when Y1 is ^one Y ² -A- (X) _m -, or or Z ¹ is -S (O) ℓ-AY ¹ day when Y ² and; Wherein when Y ¹ is mercapto or amidinothio, Y ² is halogen, and when Y ¹ is halogen, Y ² is mercapto or imidinothio.