NO157502B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE TETRAZOLD DERIVATIVES. - Google Patents

Description

The present invention relates to the production of new tetrazole derivatives with pharmacological action against peptic ulcer and duodenal ulcer.

The compounds produced according to the invention are tetrazole derivatives of formula

wherein R<1> is hydrogen, C1-4 alkyl, cyclohexyl which is optionally substituted with C1-4 alkoxy, or phenyl which is optionally substituted with C1-4 alkyl,

A is sulfur or C1-4 alkylthio

laughs 0 or 1,

B is C,_. alkylene,

2

R is C 1-4 alkoxy or a group

3 in which R

and R 4 are the same or different and are each hydrogen; C 1-6 alkyl; C 1-4 cycloalkyl which is optionally substituted with a group selected from hydroxy, C 1-4 alkanoyloxy, C 1-4 alkoxy,

C 1-4 alkyl and N,N-di(C 1-4 alkyl)amino; phenyl which is optionally substituted with one or two substituents selected from amino-sulfonyl, N,N-di(C 1-4 alkyl)amino, C 1-4 alkyl, halogen, C 1-4 alkoxy and nitro; cyclohexyl-(C 1-4 )-alkyl, phenyl-(C 1-4 )-alkyl in which the phenyl ring is optionally substituted with C 1-4 alkoxy; hydroxy-(C 1 -alkyl; pyridyl; 2-furylmethyl; or 2-thienyl-3 4

methyl; or R and R can, together with the nitrogen atom to which they are attached, form a heterocyclic group selected from morpholino, piperidino and piperazino which is optionally substituted with C1-4 alkyl or C4-4 alkanoyl,

presumed that

a) when 0 and R<1> is hydrogen or alkyl of 1 to 4 carbon atoms, R is different from alkoxy, and NR<3>r<4> is different from amino;

b) when 0 or R<1> is n-butyl, B is not methylene and NR<3>R<4>

is not ethylamino; c) when i is 0 and R 1 is phenyl and B is methylene, R 2 is different from ethoxy, and NR 3 R 4 is different from amino,

methylamino and benzylamino;

d) when 0 and R 1 are phenyl and B is ethylmethylene, R 2 is not

3 4

ethoxy, and NR R is not amino;

e) when i is 0 and R<1> is cyclohexyl and B is ethylene or methyl-3 4

methylene, NR R is not amxno; and

f) when 0 and R<1> is cyclohexyl and B is dimethylmethylene, is

3 4

NR R different from amino, diethylamino, benzylamino and

morpholino,

and pharmaceutically acceptable salts thereof.

From US patent no. 3 743 646, 2H-tetrazole derivatives with anti-inflammatory properties are known which are stated to cause less stomach irritation than corresponding acids. The comparison tests below show, however, that these compounds do not have as good an effect against stomach ulcers as the compounds produced according to the invention.

The compounds produced according to the invention have prophylactic or therapeutic activity against peptic and/or duodenal ulcers, in particular stress ulcers and indomethacLn-induced ulcers with little side effects such as central nervous system activity, anti-cholinergic activity and gastric emptying activity, and are applicable as a drug for the treatment of such wound.

The production of the compounds is characterized by that

a) a carboxylic acid compound of formula

in which R"<1>", A, -£ and B are as defined above, or a reactive derivative thereof, is reacted with an amine of formula:

in which R 3 and R 4 are as defined above, or a reactive derivative thereof,

b) a 5-mercaptotetrazole derivative of formula

in which R and A are as defined above and - t' is 1, is converted

with a haloalkanecarboxylic acid derivative of formula:

wherein X is a halogen and B and R 2 are as defined above,

c) a carboxylic acid amide of formula:

R<5>OOC-B-CONHR<1> (VIII)

in which B and R<1> are as defined above and R<5> is alkyl with 1-6 carbon atoms, reacted with phosphorus pentachloride and then with hydrogen azide, or

d) a tetrazole compound of formula:

in which R is as defined above, D is the alkylene with 1-6 carbon atoms and X is a halogen, is reacted with a mercapto compound of formula:

in which B and R are as above defined,

after which, if desired, an obtained tetrazole derivative of formula

in which R<1>, A, i/and B are as defined above, subjected to esterification, and/or an obtained tetrazole derivative of formula:

wherein r\ A, and B are as defined above, and R^ is alkyl with 1 to 6 carbon atoms, is subjected to hydrolysis, and/or a tetrazole derivative obtained is converted into a pharmaceutically acceptable salt thereof.

Compounds (Ia) which are compounds of formula (I) 2

wherein R is the group

produced by a method as shown in the following

the following reaction scheme I:

Reaction nucleus I

wherein R<1>, R<3>, R<4>, A, B and 1 are as indicated above.

The method shown in Reaction Core I is carried out by subjecting a carboxylic acid (II) and an amine (III) to an amido bond-forming reaction.

In the above-mentioned method, a compound with an activated carboxyl group can be used instead of the carboxylic acid (II) and a compound with an activated amino group instead of the amine (III). The amido bond-forming reaction includes any conventional process such as (i) a mixed acid anhydride method, i.e. a process involving reaction of the carboxylic acid (II)

with an alkylhalocarboxylate to form a mixed acid anhydride, and reacting the mixed acid anhydride with the amine (III); (ii) an activated ester method, i.e. a method comprising converting the carboxylic acid (II) into an active ester, for example p-nitrophenyl ester, N-hydroxy-succinimide ester or N-hydroxybenzoetriazole ester, and reacting the active ester with the amine (III) ; (iii) the carbodiimide method, i.e. a method comprising condensation of the carboxylic acid (II) with the amine (III) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (iv) the carboxylic acid halide method, i.e. a process comprising reacting a halide compound of the carboxylic acid (II) with the amine (III); (v) a process comprising converting the carboxylic acid (II) into an acid anhydride compound thereof, using a dehydrating agent such as acetic anhydride, and then reacting the resulting acid anhydride with the anine (III); and (vi) a process comprising converting the carboxylic acid (II) into an ester with a lower alcohol, and thereby reacting the resulting ester with the amine (III) under a high pressure and at a high temperature. Among these processes, the mixed acid anhydride method and the carboxylic acid halide method are preferred. The alkyl halocarboxylate used in the mixed acid anhydride method includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride

can be prepared by the well-known Schotten-Baumann reaction, and can be used for the subsequent reaction with the amine (III) without isolation from the reaction mixture. The Schotten-Baumann reaction can be carried out in the presence of a basic compound. The basic compound includes all compounds commonly used in the Schotten-Baumann reaction, for example organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo-[4.3.0]nonen-5 (DBN ), 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) or the like, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or the like . The reaction is usually carried out at a temperature of from -20 to 100°C, preferably from 10 to 50°C, for from 5 minutes to 10 hours.

The mixed acid anhydride method is usually carried out

in a suitable solvent. The solvent includes all solvents known to be used in this method, for example halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethylether, tetrahydrofuran or dimethoxyethane, esters such as methyl acetate or ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, and the like. The carboxylic acid (II), the alkyl halocarboxylate and the amine (III) are usually used in such an amount that the alkyl halocarboxylate and the amine (III) are each at least equimolar with the carboxylic acid (II), preferably 1 - 1.5 mol to 1 mol carboxylic acid (II).

The carboxylic acid halide method is carried out by reacting the carboxylic acid (II) with a halogenating agent to form a halide compound of the carboxylic acid (II), and then reacting the resulting carboxylic acid halide with the amine (III) after isolation and purification of the halide from the reaction mixture or without isolation.

The reaction between the carboxylic acid (II) and the halogenating agent is carried out in the presence or absence of a solvent. The solvent includes all solvents that do not have an undesirable effect on the reaction, for example aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as dioxane, tetrahydrofuran or diethyl ether, aprotic polar solvents such as dimethylformamide or dimethylsulfoxide and the like. The halogenating agent includes any conventional halogenating agent that can convert the hydroxy group in the carboxyl group to halogen, for example thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide or the like

The ratio between the amount of the carboxylic acid (II) and the halogenating agent is not critical, but when the reaction is carried out in the absence of a solvent, the latter i.e. the acid (II) is used in a large excess, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount equivalent or more to the first, preferably 2 to 4 moles to 1 mole of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from room temperature to 100° C, preferably 50 - 80° C, for from 30 minutes to 6 hours.

The reaction between the carboxylic acid halide and the amine (III) is usually carried out in the presence of a dehydrohalogenating agent. The dehydrohalogenating agent is usually basic compounds. The basic compounds used as dehydrohalogenating agents include all conventional compounds, for example inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or silver carbonate, alkali metals such as sodium or potassium, alcoholates such as sodium methylate or sodium ethylate, organic bases such as triethylamine, pyridine, N,N-dimethyl-aminopyridine, 1,5-diazabicyclo[4.3.0]nonen-5 (DBN), 1,5-azabicyclo[5.4.0]undecene-5 (DBU) or 1 ,4-diazabicyclo[2.2.2]-octane (DABCO)] or the like. The amine (III) can be used in a large excess present to use the dehydrohalogenating agent. The reaction can be carried out in the presence or absence of a solvent. The solvent includes any inert solvent that does not adversely affect the reaction, for example halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene, toluene or xylene, esters such as methyl acetate or ethyl acetate , aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxyd or hexamethylphosphoric acid triamide and the like.

The ratio between the amount of carboxylic acid halide and the amine (III) is not critical, but when the reaction is carried out in the absence of a solvent, the latter, i.e. the amine (III) is used in a large excess, and when the reaction is carried out in the presence of a solvent, the latter usually in an amount equivalent or more of the former, preferably 1 to 2 moles to 1 mole of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from -30 to 100° C, preferably 0 to 50° C, for from 30 minutes to 12 hours.

The compounds (Ib), which are the compounds of formula (I) in which SL is 1, are produced by a process as shown in the following Reaction Core II:

Reaction nucleus II

wherein SL' is 1, X is halogen and R 1 , R 2 and A are as previously indicated.

The dehydrohalogenation reaction of a 5-mercaptotetrazole derivative (IV) and a haloalkanecarboxylic acid derivative (V)

in the above-mentioned Reaction Scheme II, is usually carried out in the presence of the same dehydrohalogenating agent as used in the above-mentioned Reaction Scheme I. The reaction can be carried out in the presence or absence of a solvent. The solvent includes all inert solvents that do not have an undesirable effect on the reaction, for example alcohols such as methanol, ethanol, propanol, butanol or ethylene glycol, ethers such as diethylether, tetrahydrofuran, dioxane, monoglyme or diglyme, ketones such as acetone or methylethyl ketone, aromatic hydrocarbons such as benzene, toluene or xylene, esters such as methyl acetate or ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide and the like. Furthermore, it is advantageous to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

The ratio between the amount of the compound (IV) and the compound (V) is not critical, but when the reaction is carried out in the absence of a solvent, the latter, i.e. the compound (V) is used in a large excess amount, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount of 1-5 mol, preferably 1-2 mol, to 1 mol of the former. The reaction temperature and reaction time are not critical, but the reaction is usually carried out at a temperature of from -30 to 200° C, preferably 0 to 160° C, for from 1 to 30 hours.

Compounds (Ic) which are compounds of formula (I)

2

in which i is 0 and R is c 4 alkoxy, is produced by a process as shown in the following Reaction Core III:

Reaction core III in which R"*" and B are as defined above, and R^ is C^_^ alkyl. The reaction of a carboxylic acid (VI) and an amine (VII) in the above-mentioned Reaction Scheme III can preferably be carried out under the same conditions as shown by the mixed acid anhydride method and carboxylic acid halide method as indicated in the previously mentioned Reaction Scheme I.

The reaction of a haloamide (VIII) with phosphorus pentachloro: PCI5 is preferably carried out in a solvent. The solvent includes all inert solvents that do not have an undesirable effect on the reaction, e.g. aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aromatic hydrocarbons such as chlorobenzene or bromobenzene, ethers such as diethyl ether or dioxane, aliphatic hydrocarbons such as n-hexane or n-heptane and the like. The ratio between the amount of the haloamide (VIII) and PCI5 is

not critical, but usually the latter is used, i.e. PCl^

in an amount of 1 to 2 mol, preferably 1 to 1.2 mol to 1 mol of the former. The reaction temperature and reaction time are not critical, but the reaction will usually be carried out at a temperature of from -20 to 50° C., preferably 0 to 25° C. for 30 minutes to 5 hours.

In the above-mentioned reaction between the haloamide (VIII) and PCI5, a haloimine derivative is formed, and this compound is then reacted with hydrogenaiz: HNg without isolation from the reaction mixture. The reaction is usually carried out in a suitable solvent such as benzene, xylene, diethyl ether, n-hexane, or the like. The hydrogen azide is usually used in an amount of 1 to 5 mol, preferably 1 to 3 mol, to 1 mol of the haloimine derivative. The reaction is usually carried out at a temperature of 0 to 150°C for 3 hours to 2 days.

Compounds of formula (Id) which are compounds of formula (I) in which A is . ci _ 4 alkylthio, is prepared by a method as shown in the following Reaction scheme IV:

Reaction scheme IV

wherein X, R , R' and B are as defined above, and D is C 1-8 alkylene.

In Reaction scheme IV, the reaction of a compound (IX) and a compound (VII) and the reaction of a compound (X) and PCI5, followed by a reaction with NH-j are carried out under the same reaction conditions as in the reaction of the compound (VI) and the compound (VII) and reaction of the compound (VIII) and PCI5 followed by reaction with HN3 in the above-mentioned Reaction Scheme III. Reaction of a compound (XI) and a compound (XII) is carried out under the same reaction conditions as in the reaction of compound (IV) and compound (V) in the previously described Reaction scheme II.

Furthermore, compounds of formula (Ie) which are compounds of formula (I) where R 2 is C, . alkoxy, and compounds (If) which are compounds of formula (I) in which R 2 is hydroxy, are reciprocally converted to each other by subjecting them to hydrolysis or esterification, as shown in the following

Reaction form V

1 5

wherein A, SL, B, R are as above and R is C1-6 alkyl.

Hydrolysis of the compound (le) can be carried out according to known methods, for example in the presence of a basic compound such as sodium hydroxide, potassium hydroxide or barium hydroxide, or a mineral acid such as sulfuric acid, hydrochloric acid or boric acid. This hydrolysis is preferably carried out in a suitable solvent. The solvent includes all conventional solvents which do not have an undesirable effect on the reaction, and suitable examples are water and lower alcohols such as methanol, ethanol, isopropanol or the like. The reaction temperature and reaction time are not critical,

but the hydrolysis is usually carried out at a temperature of from room temperature to 150°C, preferably 50 to 110°C for from 30 minutes to 10 hours.

Esterification of the compounds (If) can usually be carried out by reacting these with a lower alcohol in the presence of a catalyst. The catalyst includes all catalysts that are usually used in conventional esterifications, for example inorganic acids such as hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride or perchloric acid; organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalene sulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or ethanesulfonic acid; acid anhydrides such as trifluoromethanesulfonic anhydride; thionyl chloride; acetori-dimethyl acetal and the like. Cation exchange resins are also used as catalysts. The amount of catalyst is not critical, but is chosen within the range that is usually used.

The esterification can be carried out in the presence or absence of a solvent. The solvent includes all solvents normally used in conventional esterification reactions, e.g. aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane or ethylene glycol monoethyl ether and the like. The ratio between the amount of the compounds (If) and the lower alcohol is not critical, but when the reaction is carried out in the absence of a solvent, the latter is preferably used, i.e. the lower alcohol in a large excess amount, and when the reaction is carried out in the presence of a solvent, the latter is used in an amount of 1 to 5 mol, preferably 1 to 2 mol, to 1 mol of the former. It is also advantageous to carry out the esterification in the presence of a drying agent such as anhydrous copper sulphate, anhydrous calcium sulphate or phosphorus pentachloride, with which produced water is removed from the reaction system and the yield of the desired product is increased. The reaction temperature is not critical, but the reaction is usually carried out at a temperature of -20 to 200° C, preferably from 0 to 150° C. Furthermore, the reaction time may vary with the type of starting material and other reaction conditions, but is usually within the range of 10 minutes to 20 hours .

In the esterification reaction, the compounds (If) in which the carboxyl group is activated, for example carboxylic acid halide or carboxylic acid anhydride, can be used. When a carboxylic acid halide is used, the same reaction conditions are used as in the carboxylic acid halide method in Reaction Scheme I. When a carboxylic acid anhydride is used, the compounds (If) are treated with a conventional dehydrating agent, forming a carboxylic acid anhydride, and the resulting anhydride is then reacted with a lower alcohol of usual way.

The starting compounds used in the above-mentioned Reaction Schemes I to V are partially known. For example, the compounds (II) used in Reaction Scheme I can be prepared by the methods shown in Reaction Schemes II, III, IV and V. Other starting compounds (III) are partially known and are prepared by the methods shown in the subsequent Reaction Scheme VI and VII.

Reaction scheme VI

Reaction form VII

3 4

ivori R and R are as previously indicated, and X is a halogen.

In the above-mentioned Reaction Schemes VI and VII, the reaction between an amine (XIII) and a halogen compound (XIV) and the reaction between an amine (XV) and halogen compound (XVI) are carried out under the same reaction conditions as are used in the hydrohalogenation reaction in Reaction Scheme II.

The compounds (IV) used in Reaction Scheme II have been obtained, and other starting compounds (V) are partially known. For example, compounds (Va) are produced which are

compounds (V) in which

/ed a method as /ist in the following Reaction scheme VIII: Reaction scheme VIII

and 4

wherein X, B, R and R are as previously indicated.

The reaction between a known halocarboxylic acid (XVII) and an amine (III) can be carried out under the same reaction conditions as were used in the amido bond-forming reaction in Reaction Scheme I.

The starting compounds used in Reaction Schemes III and VI are known. The starting compounds used in Reaction Scheme V can be prepared by the same process as used in Reaction Schemes II - IV.

The compounds (I) having an acid group can be converted into a salt with a pharmaceutically acceptable basic compound. The basic compound includes metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal alcoholates such as sodium methylate or potassium ethylate and the like. The compounds (I) having a basic group can also be converted into a salt with a pharmaceutically acceptable acid. The pharmaceutically acceptable acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid,

and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid or benzoic acid.

The compounds obtained by the methods indicated above can be easily isolated from the reaction mixture and purified by conventional methods. For example, the isolation can be carried out by precipitation, extraction, recrystallization, distillation, column chromatography, preparative thin-layer chromatography and the like.

The compounds (I) or their pharmaceutically acceptable salts according to the invention are useful for the treatment of peptic and duodenal ulcers, and can usually be used in the form of conventional pharmaceutical preparations.

Trial report

Pharmacological tests:

The pharmacological effects of the compounds (I) produced according to the invention were tested using commonly known methods which are discussed below. The test compounds were the following: I . N, N-D in a hy 1-4-0-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (prepared according to example 1) 2. N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol<->5-yl)thio-butyramide (ex. 2) 3. N-Ethy1-N-cyclohexyl-5-(1-methyl-1,2, 3,4-tetrazol-5-yl)thio-valeramide (ex. 62) 4. N-Ethyl-N-cyclohexyl-5-O - phenyl-1,2,3,4 -

tetrazol-5-yl)valeramide (ex. 115)

5. N,N-Diethy1-5-O-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide (ex. 72) 6. N-Cyclohexyl-4-(1-methyl-1,2 ,3,4-tetrazol-5-yl)thio-butyramide (ex. 8) 7. N-[4-(N,N-Dimethylamino) phenyl]-4-(1-methyl-1,2,3,4 -tetrazol-5-yl)thio-butyramide (ex. 37) 8. N-Ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1 ,2,3,4-tetrazol-5-yl) thio-butyramide (ex. 48) 9. N-Ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 3) 10. N -Ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 42) II . N-Cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex.20) 12 N,N-Diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-ylmethylthio-propionamide (ex. 79) 13. N-Furfuryl-1»-( 1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyraride (ex. 35)

11". N, N-Diethyl-3-( 1-ethyl-1 , 2, 3 , 4-tet razol-5 -

yl)methylthio-propionamide (ex. 78)

20. N-Ethyl-N-cycloheptyl-1»-(1-methyl-1,2,3,4-tetrazol-5-yl)chloro-butyramide (ex. 57) 21. N,N-D in isopropyl-4 - (1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 17) 22. N-Isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3, 4-tetrazol-5-yl)thio-butyramide (ex. 46) 23. 5-(3-Piperidylcarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole • (ex. 56) 24. N-[ 2-(3,4-Dimethoxy phenyl )ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide -(ex. 6) 25. N-(2- Pyridyl)-4-(1-methyl-1,2,3.4-tetrazol-5 -

yl)thio-butyramide (ex. 91)

26. N,N-D imethyl-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramld (ex. 53) 27. N-Ethyl-N-cyclopentyl-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 44) 28 N-Ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol -5-yl)thio-butyramide <ex- 45> 29. N-Ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 58) 30. 5-C 3-(4-Acetyl-1-piperazinylcarbonylJpropyl-thio]-1-methyl-1 , 2, 3, 4-tetrazole (ex. 135) 31. 5-(3- Horfo linocarbonylpropylthio)- 1-methyl-1,2,3,4-tetrazole (ex. 130) 32. N-Ethyl-N-cyclohexy1-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio -propionamide (ex. 80) 33. Methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyrate (ex. 190) 34. N-Methyl-N-(2 -thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 90) 36. N-(4-Sulfamoylphenyl )-4-(1-methyl- 1,2,3,4-tetrazol-5-yl)thio-butyramide^ (ex. 36) 37 N-(2-Methyl-3-chloro-phenyl)-4-(1-methyl-1,2,3 ,4-tetrazol-5-yl)thio-butyramide -(ex. 38) 38. N-(4-Nitro phenyl. )-4-( 1 -methyl-1 ,2,3,4-tetrazol-5-yl )thio-butyramide (ex. 39) 39. N,N-Diethyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (ex. 78) 40. N-(4-Methoxycyclohexyl)-4 -(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 64) 41 . N-Butyl-N-cyclohexy 1-4-0 -methyl-1 ,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 14) 42. N-Ethyl-N-cyclooctyl-4-O -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 181) 43. N-[4-(N,N-Dimethylamino)phenyl. ]-4-(1-methyl-1 , 2, 3,4-tetrazol-5-yl)thio-butyramide (ex. 165) 44. N,N-Dicyclohexy1-4-(1-methyl-1 ,2, 3,4-tetrazol-5-yl)thio-butyramide (ex. 147) 46. N-Cyclododecanyl-4-0-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 10) 47 N-n-Hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide. (ex. 7) 48. N-Ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide. (ex. 98) 49. N-(4-Methylcyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 65) 50. N-[4 -(N,N-Dimethylamino)cyclohexy1]-4-(1 - methyl-1 , 2, 3, 4-tetrazol-5-yl )thio-but-yramide (ex. 66) 51. N-Ethyl-N- cyclohexy1-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (ex. 60) 52. 5-C3-(4-Methylpiperazinocarbonyl)propylthio]-1-methyl-1 ,2,3,4-tetrazole (ex. 55) 53- N Ethyl-N-cyclohexyl-4-[1-(2-methoxycyclo-hexyl)-1,2,3,4-tetrazol-5-yl)thio -butyramide (ex. 67) 54. N-Butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide (ex. 11) 55. N-Benzyl-N -[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 22) 56. N-(2- Methoxyphenyl )-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 40) 57. N-Cyclohexyl-N-(2-hydroxyethyl)-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (ex. 30)

Comparative compounds:

A. 2-(3-Bromophenyl)-5-(2-carbamoylethyl)-1,2,3,4-tetrazole (described in US Patent No. 3,743,646)

B. 2-(3-Bromophenyl)-5-(2-piperidinocarbonylethyl)-1,2,3,4-tetrazole (described in US Patent No. 3,743,646)

Pharmacological test 1:

The pharmacological effects of the compounds (I) were tested using a Shay rat gastric portoma ligation method

(cf. H. Shay et al: Gastroenterol., Vol. 5, page 42, 1945)

which is the most popular method for testing the secretion-inhibiting effect on gastric juice. The test was carried out using male Wistar rats weighing approx. 170 g and had fasted for 2 4 hours.

The test compounds were administered subcutaneously 30 minutes before gastric port ligation at a dose of 150 mg/kg and the volume, total acidity and/or pepsin activity of the gastric juice was measured 4 hours after ligation. As a control, a physiological saline solution was administered instead of the test compound. The inhibitory ratio (%) of the test compounds was calculated when the inhibitory effects of the control were determined to be zero. The results are shown in table 1.

In table 1, the inhibitory ratio (%) was assessed as follows:

-: less than 10%

+: 10 to less than 50%

++: more than 50%

Pharmacologist test 2: Stress-induced gastric ulcer

After male Wistar rats weighing approx. 170 g, had been fasted for 24 hours, the rats were confined. in a stress cage and immersed in a water bath at 23°C up to the chest of the animals. After 7 hours, the rats were euthanized and the stomach was isolated. 10% formalin (8 ml) was poured into the isolated stomach and it was set aside. The stomach was cut open along the greatest curvature and the length of each wound on the membrane was measured. The sum of the lengths of all the wounds was given as the wound index (Ul). The test compound was administered orally to the rats before they were closed in a stress cage in the form of 0.5% CMC suspension--3

tion in a concentration of 1 x 10 mol. As a control, the solvent alone (CMC solution) was administered in the same manner.

The inhibitory ratio (%) on stress ulcer for the test compounds was calculated using the following equation:

The results are shown in table 2.

In table 2, the inhibitory ratio (%) was assessed as follows:

-: less than 20%

+: 30 - 60%

++: more than 60%

Pharmacological test 3: Acetic acid-induced gastric ulcer

Male Wistar rats were used. Under anesthesia, the abdomen of the rats was opened to expose the stomach and then 30% aqueous acetic acid (0.015 ml) was injected under the serous membrane located in the border area between the gastric glands proper and gastric portal glands, and then the abdomen was closed, so that an experimental gastric ulcer was induced.

The test compounds were administered orally at that dose

which is shown in Table 3 in the form of 0.5% CMC suspension or

-solution twice daily for 12 days after the acetic acid-induced gastric ulcer had occurred. As a control, the solvent (CMC solution) alone was administered

same way.

After the newly formed mucosa was removed around the gastric ulcers, the open wound areas were measured with a micrometer and the sum of wound areas was given as the wound index (Ul). The inhibitory ratio (%) in acetic acid-induced gastric ulcer for the test compound was calculated in the same way as in pharmacological test 2.

The results are shown in table 3.

In table 3, the inhibitory ratio (%) was assessed as follows:

-: less than 10%

+: 30 to 60%

++: more than 60%

Pharmacological test 4: Indomethacin-induced gastric ulcer

After male Wistar rats weighing approx. 160 g had been fasted for 24 hours, indomethacin was administered subcutaneously to the rats at a dose of 20 mg/kg in the form of a suspension in a mixture of 0.5% CMC and a small amount of "Tween 80" (ie polyoxyethylene sorbitan monooleate ). The rats were euthanized after 5 hours and the stomach was isolated. 10% formalin (8 ml) was poured into the isolated stomach and it was set aside. The stomach was cut open along the greatest curvature and the length of each wound on the membrane was measured,

and based on these results, the inhibitory ratio of the indomethacin-induced gastric ulcer of the test compounds was calculated in the same manner as in pharmacological test 2. The test compounds were administered orally to the rats at a concentration of 3 x 10<4> mol in the form of 0.5 % CMC suspension 30 minutes before administration of indomethacin.

The results are shown in table 4.

In table 4, the inhibitory ratio (%) was assessed as follows: +: 30 - 60% ++: more than 60%

Acute toxicity:

The test compounds were administered orally to male Wistar rats and the lethal half dose (LD^q) was measured. The results are shown in table 5.

The following reference examples illustrate the production of starting compounds, while the examples illustrate the invention.

Reference example 1

To 400 ml of ethyl acetate was added 26 ml of N-methylcyclohexylamine, and to the mixture was added dropwise with stirring 25 ml of 4-chlorobutyryl chloride and 33.5 ml of triethylamine during 20 minutes while the internal temperature was maintained at 10-20°C at ice cooling. The mixture was further stirred at room temperature for 1 hour. After the reaction, water was added to the reaction mixture. The organic layer was washed with water and an aqueous saturated potassium carbonate solution, 10% aqueous hydrochloric acid and water, and was then dried over anhydrous sodium sulfate. After sodium sulfate filtration, the mother liquor was concentrated and distilled under reduced pressure to give N-methyl-N-cyclohexyl-4-chlorobutyramide (41.5 g), m.p. 133 - 136°C/2mmHg.

Reference example 2

2.6 g of N-ethyl-cyclohexylamine was dissolved in 20 ml of dry benzene. 2.6 g of chloroacetyl chloride and 2.4 g of triethylamine were added dropwise to the solution with stirring under ice cooling. The mixture was stirred under ice cooling for 1 hour, and a further 1 hour at room temperature. The reaction mixture was poured into ice water and extracted with ether. The ether layer was washed with aqueous sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution, and was dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was distilled under reduced pressure to give N-ethyl-N-cyclohexyl-chloroacetamide (3 g), m.p. 118 - 120°C/0.2mmHg.

Reference examples 3 and 4

In the same way as described in Reference Example 2,

the following compounds were prepared: N-ethyl-N-cyclohexyl-4-chlorobutyramide, b.p. 120 - 130°C/1.5 mmHg

N-ethyl-N-cyclohexyl-3-chloropropionamide, m.p. 103 - 110°C/0.15 mmHg

Reference example 5

6 g of monomethyl adipate was added to 10 ml of thionyl chloride, and the mixture was refluxed for 1 hour. Excess thionyl chloride was distilled off and benzene was added to the residue whereupon thionyl chloride was further removed by azeotropic distillation.

Separately, 4.2 g of aniline and 5.2 g of potassium carbonate were dissolved in 100 ml of acetone and 15 ml of water. To the mixture was added dropwise with stirring the chloride compound obtained as stated above under ice cooling. The mixture was stirred under ice cooling for 1 hour and then for 2 hours at room temperature. After distillation of acetone, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off to give methylphenyladipinamate (9 g).

NMR: ^<CDC1>3 1.40 - 1.90 (4H, m) , 2.10 - 2.50 (4H, m) ,

ppm

3.66 (3H, s), 6.80 - 7.70 (5H, m), 8.55

(1H, br.s)

Reference Examples 6 and 7

In the same manner as described in Reference Example 5, the following compounds were prepared: Nethyl-N-cyclohexyladipinamate, light brown prisms (recrystallized from methanol-water), m.p. 72 - 74° C,

Methyl-N-methyladipinamate, colorless liquid, b.p.

136 - 140°C/0.7mmHg.

Reference example 8

46.5 ml of a 40% aqueous methylamine solution was dissolved in 300 ml of acetone. 45.6 g of potassium carbonate and 100 ml of water were added to the solution, whereupon 24.3 ml of chloroethyl chloride was added dropwise with stirring under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and a further 2 hours at room temperature. After distilling off the acetone, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over magnetic

sium sulfate. After distillation of chloroform, the residue was distilled under reduced pressure to give N-methyl-chloroacetamide (15.5 g), colorless liquid, m.p. 107 - 109°C/27mmHg. Reference example 9

10.8 g of N-methyl-chloroacetamide was dissolved in 100 ml of benzene, and to the mixture was added with stirring 10.8 g of phosphorus pentachloride at a temperature below 15° C. The mixture was stirred at room temperature for 1 hour and then allowed to stand overnight . The mixture was slowly boiled under reflux for 2 hours. The reaction mixture was concentrated, and ice-water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, a dilute aqueous sodium hydroxide solution and water, dried over magnesium sulfate and distilled to remove chloroform. The resulting residue was subjected to column chromatography (Wakogel C-200, manufactured by Wako Pyre Chemical Industry, eluent, chloroform: methanol = 50:1, V/V) to isolate 8.5 g of 1-methyl-5-chloromethyl-1, 2,3,4-tetrazole.

Example 1

2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 30 ml of dry tetrahydrofuran, and 1.1 g of triethylamine was added to the mixture. 1.5 g of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes. A further 0.9 g of diethylamine was added dropwise to the mixture with stirring at room temperature, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was purified by subjecting it to column chromatography (Kieselgel 60). Elution with n-hexane-ethyl acetate (1:1) gave N,N-diethy1-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (1,4 g), colorless liquid, nD 17 ' 5 = 1.5227.

NMR. 6CDCl3 1.04 (3H, t, J = 7Hz); 1.12

ppm

(3H, t, J = 7Hz), 1.90 - 2.70 (4H, m), 3.00 -

3.60 (6H,m), 3.88 (3H,s)

Elemental analysis for C^qH-^N^OS :

Calculated (%): C 46.67 H 7.44 N 27.21

Found (%): C 46.78 H 7.51 N 27.29

Example 2-5

In the same manner as described in Example 1, the following compounds were obtained from suitable starting materials: (2) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio- butyramide, colorless liquid, nQ 17 ' 5 = 1.5327 cnci NMR: 6 ^3 0.90 - 1.40 (3H, m), 1.20 - 2.00 (10H, m), 2.00 - 2 .80 (4H, m), 3.00 - 3.60 (6H, m), 3.95 (3H, s), 3.50 - 4.50 (1H, m) (3) N-ethyl-N -phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, pale yellow liquid, nn 2 6 = 1.553 4 than NMR: 6 ppj^ 3 1.12 (3H, t, J = 7Hz), 1.70 - 2.40 (4H, m) , 3.32 (2H, t, J = 7Hz), 3.74 ( 2H, q, J = 14Hz, 7Hz), 3.90 (3H, s), 7.00 - 7.60 (5H, m) (4) 5-(3-morpholinocarbonylpropylthio)-1-methyl-1,2 ,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71 - 73° C. (5) 5-[3-(4-acetylpiperadinocarbonyl)propylthio]-1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone), sm .p. 90 - 91.5° C.

Example 6

45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of 2-(3,4-dimethoxyphenyl)ethylamine was added dropwise to the mixture and the mixture was further stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution,

and was dried over anhydrous sodium sulfate. After distilling off chloroform, the residue was subjected to column chromatography (Wakogel C-200, eluent chloroform) to isolate N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4- tetrazol-5-yl)thio-butyramide (yield 41%) which was recrystallized from hexane-chloroform, colorless flakes, m.p. 70.5 - 71.5° C.

Elemental analysis for cigH23N503^:

Calculated: C 52.59% H 6.34% N 19.16%

Found : C 52.51% H 6.16% N 19.10%

Examples 7- 58

In the same manner as described in Example 6, the following compounds were prepared from suitable starting materials: (7) N-hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (recrystallized from hexane-ether), m.p. 41 - 42° C (8) N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. 116.5 - 117.5° C (9) N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1.5323 (10) N-cyclododecanyl-4^(1-methyl-1,2,3,4-tetrazol-yl)thio-butyramide, colorless needles (hexane ethyl acetate), sm.p. 119 - 120° C (11) N-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, nj^'^ = 1.5198 ( 12) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 14 ' 5 = 1.5350 (13) N -eth.yl-N-benzyl-4-(1-methyl-1,2,3,4-tetra-19

zol-yl)thio-butyramide, colorless liquid, nD = 1.5596

(14) N-butyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-

19 tetrazol-5-yl) thio-butyramide, colorless liquid, nQ = 1.522

(15) N,N-dibutyl-4-(1-methyl-1,2,3,4-tetrazol-5-

1 19

yl)thio-butyramide, colorless liquid, nQ = 1.5049

(16) N,N-dibenzyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramide, colorless liquid, nn = 1.5773

(17) N,N-diisopropyl-4-(1-methyl-1,2,3,4-tetrazole-19 5

5-yl)thio-butyramide, colorless liquid;, nn ' = 1.511<1>

(18) N,N-dicyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p. 91 - 92°C (19) N-benzyl-N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), sm.p. 86.5 - 87.5° C

in

(20) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , n^<6> = 1.54 70 (21) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide , colorless liquid, n^6 = 1.5706 (22) N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol- 5-yl)thio-butyramide, colorless liquid, n^ = 1.5659 (23) N-[2-(3,4-dimethoxyphenyl)ethyl]-N-(2-hydroxy-ethyl)-4-(1- methyl-1,2,3,4-tetrazol-5-yl)thiobutyramide, 14 5

colorless liquid, nn ' = 1.5372

(24) N,N-dihexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5011 (25) N-ethyl- N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1 .54 51 (26) N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (hexane-ethyl acetate), m.p. 71 - 73° C (27) N-ethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n^ = 1.5319 (28) N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 65 - 66° C (29) N-hexyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5182 (30) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, 14 5 n^ ' ° = 1.5372 (31) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.ip. 106 - 107° C (32) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethylaceta-^, mp 95 - 96° C (33) N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (ethyl acetate) , mp 110.5 - 113° C (34) N-(2-pyrimidyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless granules (hexane-ethyl acetate), mp 108 - 110° C (35) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C I (36) N-(4-aminosulfonylphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide , colorless needles (methanol), mp 169.5 - 170.5° C (37) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3 ,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate), m.p. 144 - 147° C (38) N-(2-methyl-3-chlorophenyl)-4-(1 -methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate), m.p. 104.5 - 105.5° C (39) N- ( 4-nitrophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (ethyl acetate), m.p. 194 - 195° C (40) N-(2-methoxyphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate, mp 79.5 - 82° C (41) N-methyl-N-(2-tetrahydropyranyl)-4-1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, 14 1 nj* = 1.5273 (42) N-ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, njjj ^ = 1.5623 (43) N-ethyl-N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, 'colorless liquid, n ^ = 1.5618 (44) N-ethyl-N-cyclopenty1-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.5384 ( 45) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj1 = 1.5293 (46) N-isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-15 tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.523 8 ( 47) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, = 1.5363 (48) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate ), sm.p. 132 - 133° C (49) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj< 1> = 1.5218 (50) N,N-dipropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5151 ( 51) N-butyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 15 = 1.5509 (52) N-methyl -N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, pale yellow liquid

rn

NMR: 6UU-L4 1.00 - 2.00 (10H, br.), 1.80 - 2.70

ppm

(4H, m), 2.73 (3H, d, J = 6Hz), 3.28 (2H, t,

J = 6Hz), 3.85 (3H, s), 3.20 - 4.50 (1H, m)

(53) N,N-dimethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5327 (54) N-ethyl- N-cyclocyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<6> = 1.5309 (55) 5-[3-( 4-methylpiperazinocarbonyl)propyl-thio]-1-methyl-1,2,3,4-tetrazole, colorless flakes (hexane-ethyl-acetate), m.p. 65 - 68° C (56) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25

1,2,3,4-tetrazole, colorless liquid, nQ = 1.5310

(57) N-ethyl-N-cycloheptyl-4-(1-methyl-1,2,3,4-18 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5290 Example 58 45 mmol 4 -(1-phenyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and to the mixture was added 50 mmol of DBU. 50 mmol of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethylcyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. <1> After distilling off the solvent under reduced pressure, the residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous sodium chloride solution, and was dried over water

in

free sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to column chromatography (Wakogel C-200, eluent chloroform) to isolate N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5 -yl)thio-butyramide (yield: 43%), colorless liquid, n^ 18 = 1.5590. Elemental analysis for C^gH^OS:

Calculated: C 61.10% H 7.29% N 18.75%

Found : C 61.28% H-7.38% N 18.86%

IN

Example 59

In the same manner as described in Example 58, with the exception that N,N-diethylamine was used instead of N-ethyl-N-cyclohexylamine, N,N-diethyl-4-(1-phenyl-1,2) was obtained ,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

n^<8> = 1.5592.

Example 60

45 mmol of 2-(1-methyl-1,2,3,4-tetrazol-5-yl)thioacetic acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. To the mixture, 50 mmol of isobutyl formate was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. N-ethyl-cyclohexylamine was added dropwise to the mixture under ice-cooling, and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform was distilled from and the residue under throw column chromatograph in (Wakogel C-200, eluent benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-2-(1-methyl-1,2 ,3,4-tetrazol-5-yl)thioacetamide (yield: 52%) which was recrystallized from ether-petroleum ether, white prisms, m.p. 60 - 71° C.

Elementary analysis for C^^^NgOS:

Calculated: C 50.86% H 7.47% N 24.71%

found : C 50.75% H 7.55% N 24.78%

Examples 61 and 62

In the same manner as described in Example 60, the following compounds were prepared using suitable starting materials: (61) N-ethyl-N-cyclohexyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thio-propionamide, pale yellow liquid, n^ = 1.5273 (62) N-ethyl-N-cyclohexyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeramide, pale yellow liquid, nn 25 = 1.5227. Example 63 45 mmol of 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thiobutyric acid was dissolved in 50 ml of tetrahydrofuran and 50 mmol of DBU was added to the mixture. Isobutyl chloroformate was added dropwise to the mixture while stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethylcyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to column chromatography (Wakogel C-200, eluent benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-4-(1-cyclohexyl -1,2,3,4-tetrazol-5-yl)thiobutyramide

18

(yield: 47%), colorless liquid, nQ = 1.5290. Elemental analysis for C^H^N^OS:

Calculated: C 60.12% H 8.76% N 18.45%

Found : C 59.95% H 8.62% N 18.55%

Example 64

45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and 50 mmol of N-methylmorpholine were added to 50 ml of methylene chloride. To the mixture, 50 mmol of methyl chloroformate was added dropwise with stirring while the internal temperature was kept at 10 - 20° C, by ice cooling, and then the mixture was stirred at room temperature for 30 minutes. 54 mmol of 2-methoxycyclohexylamine was added to the mixture, and the mixture was stirred at the same temperature for 4 hours. After

in

reaction, water was added to the reaction mixture. The organic layer was separated and washed with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, and was dried

in

over sodium sulfate. Inorganic materials were filtered off and the mother liquor was concentrated. The resulting residue was subjected to column chromatography (Wakogel C-200, eluent : benzene:chloroform<1>= 4:1, v/v) to isolate N-

in

(4-Methoxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide (yield: 43 colorless liquid, n^ = 1.5263. Elemental analysis for C^. jH23N502^ :

Calculated: C 52.50% H 7.79% >N 23.55%

Found : C 52.56% H 7.71% ;N 23.63%

Example 65

45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and 50 mmol of pyridine were added to 50 ml of tetrahydrofuran, and the mixture was added dropwise with stirring while 50 mmol of bromoformate temperature was maintained at 5-15°C by ice-cooling, and then the mixture was stirred at room temperature for 1 hour. 55 mmol of 4-methylcyclohexylamine was added to the mixture, and the mixture was further stirred for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water, and was dried over sodium sulfate. Inorganic materials were filtered off and the mother liquor was concentrated. The resulting residue was subjected to column chromatography (Wakogel C-200, eluent: benzene:chloroform = 4:1, v/v) to isolate N-(4-methylcyclohexyl)-4-(1-methyl-1,2,3, 4-tetrazol-5-yl)thio-butyramide (yield: 45%).

Elemental analysis for C^J^-jN^-OS:

Calculated: C 52.50% H 7.79% N 23.55%

Found : C 52.31% H 7.65% N 23.80%

Example 66

45 mmol of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU was added to the solution. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes.

54 mmol of 4-(N,N-dimethylamino)cyclohexylamine was added dropwise to the mixture and the mixture was further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. Chloroform was distilled off, and the resulting residue was subjected to silica gel column chromatography (Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v) to isolate N-[4-(N,N-dimethylamino)-cyclohexyl) -4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiobutyramide (yield: 47%).

Elemental analysis for C^I^gNgOS:

Calculated: C 51.51% H 8.03% N 25.74%

Found : C 51.60% H 8.22% N 26.05%

Example 67

45 mmol of 4-[1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl)thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU was added to the solution. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethyl-cyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. After distilling off chloroform

the resulting residue was subjected to column chromatography

(Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v)

to isolate N-ethyl-N-cyclohexyl-4-(1-(2-methoxycyclohexyl)-1,2,3,4-tetrazol-5-yl]thiobutyramide (yield: 45%). Elemental analysis for C2QH35N5O2S:

Calculated: C 58.65% H 8.61% N 17.10%

Found : C 58.25% H 8.34% N 17.20%

Example 68

45 mmol of 4-[1-(4-ethylphenyl)-1,2,3,4-tetrazo,1-5-yl]-thiobutyric acid was dissolved in 50 ml of tetrahydrofuran, and 50 mmol of DBU. 50 mmol of isobutyl chloroformate was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 54 mmol of N-ethyl-cyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 2 hours. ! The solvent was distilled off under reduced pressure, and the resulting residue was extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and was then dried over anhydrous sodium sulfate. Chloroform was distilled from and the resulting residue subjected to column chromatography (Wakogel C-200, eluent, benzene:chloroform = 4:1, v/v) to isolate N-ethyl-N-cyclohexyl-4-[1-(4-ethylphenyl) )-1,2,3,4-tetrazol-5-yl]thio-butyramide

19

(yield: 43%), colorless liquid, nn = 1.5533. Elemental analysis for C2^H^N,-OS:

Calculated: C 62.81% H 7.78% N 17.44%

Found : C 63.05% H 7.84% N 17.81%

Example 69

2.5 g of 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid was dissolved in 50 ml of dimethylformamide, and 1.1 g of triethylamine was added to the solution. To the mixture, 1.5 g of isobutyl chloroformate was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes.

To the mixture, 0.9 g of diethylamine was added dropwise with stirring at room temperature, and the mixture was stirred for 2 hours. After distilling off dimethylformamide under reduced pressure, acetone was added to the resulting residue, and insoluble material was filtered off. The mother liquor was concentrated and then purified by column chromatography (Kieselgel 60). Elution with chloroform gave N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (1.2 g), 25

colorless liquid, nn = 1.53 03.

Elemental analysis for C,,H~oNc0:

-1 16 23 5

Calculated: C 56.40% H 6.63% N 21.92%

Found : C 56.69% H 6.80% N 21.71%

Example 70

2.5 g of 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valeric acid was dissolved in 50 ml of tetrahydrofuran, and 1.1 g of triethylamine was added to the solution. To the mixture was added dropwise with stirring 1.5 g of isobutyl chloroformate under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 1.5 g of N-ethylcyclohexylamine was added dropwise to the mixture with stirring at room temperature, and the mixture was further stirred for 2 hours. After distilling off tetrahydrofuran, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled off and the resulting residue was subjected to column chromatography (silica gel 60, eluent chloroform) to isolate N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide 12.6 g),

25

colorless liquid, nQ = 1.4970.

Elemental analysis for C^qH^N^O:

Calculated: C 66.44% H 9.76% N 19.37%

Found : C 66.78% H 9.56% N 19.52%

Example 71

1.8 g of 5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeric acid was dissolved in 50 ml of dimethylformamide, and 1.1 g of triethylamine was added to the solution. To the mixture, 1.5 g of isobutyl chloroform was added dropwise with stirring under ice cooling,

and the mixture was stirred at room temperature for 30 minutes.

To the mixture was added dropwise with stirring 0.9 g of diethylamine at room temperature, and the mixture was stirred in

2 hours. Dimethylformamide was distilled off under reduced pressure, and the residue was purified by column chromatography (WAkogel C-200). After elution with benzene-chloroform (1:1), the eluate was distilled under reduced pressure to give N,N-diethyl-5-(1-methyl-1,2,3l,4-tetrazol-5-y1)valer amide

(0.7 g), colorless liquid, b.p. 190 - 200° C (bath temperature)/ 0.07 mmHg, n^<5> 1.4907. j

Elemental analysis for c;qH21N5^:

Calculated: C 55.20% H 8.85%; N 29.27%

Found : C 55.48% H 8.98o.%; N 29.43%

Example 72-76

In the same way as described in example 71 was

in

following compounds prepared using suitable starting materials: j (72) N,N-diethyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless liquid, n^ = 1, 4970 (73) N,N-diethyl-5-(1,2,3,4-tetrazol-5-yl)-valeramide, colorless liquid, nn2<5> = 1.4867

(74) N-ethyl-N-cyclohexy1-5-(1-methyl-1,2,3,4-

18 tetrazol-5-yl)valeramide, colorless liquid, NQ = 1.5085 (75) N-ethyl-N-cyclphexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide , white? crystalline powder (ether), m.p. 92 - 95° C (76) N-ethyl-N-cyclphexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

Example 77

2 g of 3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionic acid was dissolved in 50 ml of tetrahydrofuran, and 1.1 g of triethylamine was added to the solution. 1.5 g of isobutyl chloroformate was added dropwise to the mixture with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise with stirring 0.9 g of diethylamine at the same temperature, and the mixture was further stirred for 3 hours. After distilling off the solvent, the resulting residue was subjected to column chromatography (silica gel 60, eluent, chloroform:

in

methanol = 50:1, v/v) to isolate N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (1.5 g), colorless liquid, n^<5> = 1.6200.

Elementary analysis for C-^qH^Ni-OS:

Calculated: C 46.67% H 7.44% N 27.21%

Found : C 46.85% H 7.61% N 27.39%

Example 78 - 80

In the same way as described in example 77 was

the following compounds prepared using suitable starting materials: (78) N,N-diethyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yDmethylthio-propionamide, colorless needles (recrystallized from ether), mp 58 - 59° C (79) N,N-diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)]methylthio-propionamide, colorless liquid , nQ 25 = 1.5499

(80) N-ethyl-N-cyclohexyl-3-(1-ethyl-1,2,3,4-

18 tetrazol-5-yl)methylthio-propionamide, light yellow liquid, nQ = 1.5277

Example 81

10 ml of thionyl chloride was added to 2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and the mixture was refluxed for 1 hour. After excess thionyl chloride was distilled off under reduced pressure, dry benzene was added to the residue and the remaining small amount of thionyl chloride was removed as benzene azeotrope. The residue was dissolved in 50 ml of dry benzene, and 2.8 g of N-methylcyclohexylamine were added dropwise to the solution with stirring under ice cooling. The mixture was stirred at room temperature for 1 hour and benzene was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and then saturated aqueous sodium chloride solution and was dried over sodium sulfate. After benzene was distilled off, the residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1 > v/v) to give N-methyl-N-cyclohexyl-4-(1-methyl -1,2,3,4-tetrazol-5-yl)thio-butyramide (2.3 g), pale yellow liquid.

CC1

NMR: 6ppm4 1.00 - 2.00 (10 H, br), 1.80 - 2.70 (4 H, m),

2.73 (3H, d, J = 6Hz), 3.28 ; (2H, t, J = 6Hz), 3.85

(3H, s), 3.20 - 4.50 (1H, m)

Elemental analysis for C13H23N5OS: |

Calculated: C 52.50% H 7.79% N '23.55%

Found : C 52.69% H 7.83% N.23.51%

Example 82 - 100

Using the same procedure as described in Example 81, the following compounds were prepared:

in

(82) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<7>'<5> = 1 .5327 (83) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nD = 1.5534 (84) 5-(3-morpholinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole-white needles (recrystallized from petroleum-3-ether-ethanol), m.p. 71 - 73° C (85) 5-[3-(4-Acethylpiperazinocarbonyl)propyl-thio]-1-methyl-1,2,3,4-tetrazole white crystalline powder (recrystallized from ligroin-acetone), m.p. . 90 - 91.5° C (86) N-[2-(3,4-dimethoxyphenylethyl]-4-(1-methyl-1,2,3,4-tetrazbl-5-yl)thio-butyramide', colorless flakes (recrystallized from hexane-ethyl acetate), mp 70.5 - 71.5° C

(87) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-

' 14 5 Tetrazol-5-yl)thio-butyramide, colorless liquid, nn ' = 1.5350

(88) N-ethyl-N-benzy1-4-(1-methyl-1,2,3,4-tetrazol-1 19

5-yl)thio-butyramide, colorless liquid, nn = 1.5596

(89) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , njjj<**> = 1.5470 (90) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-

1,2 , 3 ,4-tetrazol-5-yl) thio-butyramdld, colorless liquid, n^ =

IN

1.5706

(91) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95 - 96° C (92) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C (93) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate), sm.vp. 144 - 147° C (94) N-(2-methyl-3-chlorophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane- ethyl acetate), m.p. 104.5 - 105.5° C (95) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<4> = 1.5273 (96) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n = 1.5293 (97) N-ethyl-B-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butylamide, colorless liquid, nD q = 1.5363 (98) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n = 1 .5218 (99) 5-(3-piperidinocarbonylpropylthio)-1-methyl-1,2,3,4-tetrazole, colorless liquid, nn 25 = 1.5310

(100) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 18 = 1.5590 Example 101 10 ml thionyl chloride was added to 1.8 g of 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid and the mixture was refluxed for 1 hour. After excess thionyl chloride was distilled from under reduced pressure, dry benzene was added to the residue, and the remaining small amount of thionyl chloride was removed as the benzene azeotrope. The resulting residue was dissolved in 50 ml of dry pyridine, and to the mixture was added dropwise with stirring 1.5 g of N,N-diethylamine under ice-cooling. The mixture was stirred at room temperature for 1 hour and benzene was added to the reaction mixture. The mixture was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution and dried over sodium sulfate. After the benzene was distilled off, the residue was subjected to column chromatography in (silica gel 60) the column was eluted with chloroform to give N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl )-

25

valeramide (2.1 g), colorless liquid, nQ = 1.5303.

Elemental analysis for C16<H>23<N>5<0:>

Calculated: C 63.76% H 7.69% N 23.24%

Found : C 63.88% H 7.79% N 23.31%

Example 102 - 104

Proceeding as described in Example 101, the following compounds were obtained:

(102) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,tetrazol-5-yl)valeramide, white crystalline powder (recrystallized from ether), m.p. 92 95° C

(103) N-ethyl-N-cyclohexy1-5-(1-methy1-1,2,3,4-18 tetrazol-5-yl)valeramide, colorless liquid, nn = 1.5085

(104) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ester), m.p. 73 - 75° c

Example 105

2 g of 4-(1-methyl-1,2;3,4-tetrazol-5-yl)thiobutyric acid and 1.4 g of N-ethyl-N-cyclohexylamine were added to a mixed solvent of 20 ml of dioxari and 20 ml of methylene chloride, and a solution of 2.1 g of N,N<1->dicyclohiex<y>lcarbodiimi<d> in 5 ml of methylene chloride was added dropwise with stirring, which was maintained at a temperature of 10 - 20° C with stirring while external cooling in ice was carried out. After addition of the solution, stirring was continued at the same temperature for 5 hours. Crystals separated from the reaction mixture were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 100 ml of methylene chloride. The organic layer was washed with 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, and was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with chloroform to give N-ethyl-N-cyclohexyl-4-(1-methyl-1,2 ,3,4-tetrazole 5-yl)thio-butyramide (0.8 g/, colorless liquid, n^<7>'<5> = 1.5327 Elemental analysis for C^H^N^OS:

Calculated: C 53.99% H 8.09% N 22.49%

Found : C 54.12% H 8.14% N 22.56%

Example 106 - 115

By proceeding in the same manner as described in Example 105, the following compounds were obtained:

(106) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nn 2 6 = 1.5534

(107) 5-(3-morpholinocarbonylpropylthio)-1-methyl, 1,2,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71 - 73° C

(108) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (recrystallized from hexane- ethyl acetate), m.p. 70.5 - 71.5° C

(109) N-ethyl-N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 19 = 1.5596

(110) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5706

(111) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes, m.p. 71 - 73° C

(112) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn = 1.5293

(113) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5590

(114) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ether), m.p. 92 - 95° C

(115) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

Example 116

3.2 g of p-nitrophenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyrate was dissolved in 40 ml of dimethylformamide, and 2.0 g of cyclohexylamine was added to the solution. The reaction mixture was allowed to stand at room temperature overnight, and was then concentrated under reduced pressure. The resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1, v/v) and re-

crystallized from hexane-ethyl acetate to give N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (1.8 g), colorless needles, m.p. 116.5 - 117.5 C. Elemental analysis for C^2<H>21<N>5<OS:>

Calculated: C 50.86% H 7.47% N 24.71%

Found : C 50.85% H 7.37% N 24.65%

Examples 117 - 123

By proceeding as described in Example 116, the following compounds were obtained:

(117) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-175 tetrazol-5-yl)thio-butyramide, colorless liquid, nD' = 1.532'

(118) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, light yellow liquid, nn2° 6 = 1.5534

(119) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl; 1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate) , sm.p. 70.5 - 71.5° C

(120) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(121) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^"<*>" = 1.5293

(122) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, white prisms (ether), m.p. 73 - 75° C

(123) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ethei m.p. 92 - 95° C

Example 124

1.4 g of methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiobutyrate, 0.5 g of sodium ethylate and 5 ml of N-ethylcyclohexy]amine were added to 50 ml ethanol, and the mixture was reacted in an autoclave at 140 - 150° C under a pressure of 110 ato for 6

hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in 200 ml of chloroform. The solution was washed with 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water, and was dried over sodium sulfate. After the solvent was

distilled from, the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with chloroform to give N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5- yl)thio-butyramide (0.6 g), colorless

17 5

liquid, nQ ' = 1.5327.

Elemental analysis for C^I^^Nj-OS:

Calculated: C 53.99% H 8.09% N 22.49%

Found : C 54.19% H 8.21% N 22.68%

Example 125 - 127

By proceeding in the same manner as described in Example 124, the following compounds were obtained:

(125) N-12-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), sm.p. 70.5 - 71.5° C

(126) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, in colorless needles (hexane-ethyl acetate), m.p. 106 - 107° C

(127) N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide, white crystalline powder (ether), m.p. 92 - 95° C.

Example 128

3 g of N-ethyl-N-cyclohexyl-chloroacetamide and 1.8 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole were dissolved in 50 ml of acetone, and potassium carbonate was added to the solution. The mixture was boiled for 3 hours under reflux, and acetone was distilled off under reduced pressure. After addition of water, the residue was extracted with ether. The ether solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the ether was distilled off, the resulting residue was recrystallized from ether-petroleum ether to give N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (1.5 g), white prisms, m.p. 69 -. 71°C

Elemental analysis for C,-H„,N.-OS:

Calculated: C 50.86% H 7.47% N 24.71%

Found : C 50.78% H 7.57% N 24.75%

Example 129

6.6 g of N-methyl-N-cyclohexyl-4-chlorobutyramide was dissolved in 50 ml of dry benzene, and to the solution was added 3.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 4.5 g potassium carbonate and 0.2 g sodium iodide. The mixture was refluxed for 5 hours and diluted with benzene. The reaction mixture was washed with water, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution, and was dried over sodium sulfate. After the benzene was distilled off, the resulting residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene-chloroform (4:1, v/v) to give N-methyl-N-cyclohexyl-4-( 1-methyl-1,2,3,4-tetrazol-5-yl)thio-buryramide (5 g), pale yellow liquid.

-rn

NMR: Sppjn'! 1/00 - .2.00 (10H, br.), 1.80 - 2.70 (4H, m)

2.73 (3H, d, J = 6Hz), 3.28 (2H, t, J = 6Hz),

3.85 (3H, s), 3.20 - 4.50 (1H, m) Elemental analysis for C^3H23N^OS:

Calculated: C 52.50% H 7.79% N 23.55%

Found : C 52.72% H 7.85% N 23.61%

Example 130

1.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.1 g of 3-morpholine-carbonylpropyl chloride were added to 30 ml of ethanol , and the mixture was stirred at 70-80° C. for 4.5 hours. After the reaction was completed, the reaction mixture was poured into aqueous saturated sodium chloride solution, and the precipitated crystals were separated by filtration and washed with water. The impure crystals thus obtained were recrystallized from ether-petroleum ether to give 5-(3-morpholinecarbonyl propylthio)-1-methyl-1,2,3,4-tetrazole (2.2 g), white needles, m.p. 71 - 73° C.

Elemental analysis for cio<H>17°2S:

Calculated: C 44.27% H 6.37% N 25.81%

Found : C 44.10 H 6.30% N 25.59%

Example 131

1.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 1.4 g of sodium ethylate, 1.6 g of sodium iodide and 4.8 g of N-cyclohexyl-3-chlorobutyramide were added to 30 ml ethanol, and the mixture was refluxed for 6 h with stirring. After the reaction was complete, the reaction mixture was poured into aqueous saturated sodium chloride solution. The precipitated crystals were separated by filtration and washed with water. The impure crystals thus obtained were recrystallized from hexane-ethyl acetate to form N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, (2.1 g), colorless needles, m.p. 116.5 - 117.5° C.

Elemental analysis for C^2H2iN5OS:

Calculated: C 50.86% H 7.47% N 24.71%

Found : C 50.87% H 7.35% N 24.63%

Example 132 - 186

By proceeding in the same way as described in examples 128 - 131, the following compounds were prepared:

(132) N,N-diethyl-4-(1-methyl-1,2,3,4-tetrazol-17 5 5-yl)thio-butyramide, colorless liquid, nQ ' =1.52 27

(133) N-ethyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-175 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ' = 1.5327

(134) N-ethyl-N-phenyl-4-(1-methyl-1,2,3,4-tetra-2 6 zol-5-yl)thio-butyramide, light yellow liquid, nn = 1.5534

(13 5) 5-[3-(4-acetylpiperazinocarbonyl)propy1-thio]-1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone), m.p. 90 - 91.5° C

(13 6) N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate ), sm.p. 70.5 - 71.5° C

(13 7) N-hexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless flakes (recrystallized from hexane-ether), m.p. 41 - 42° C

(138) N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-14

5-yl)thio-butyramide, colorless liquid, nQ = 1.5323

(139) N-cyclododecanyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 119 - 120° C

(14 0) N-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n^'5 = 1.5198

(141) N-(2-hydroxyethyl)-4-(1-methyl-1,2,3,4-14 5 tetrazol-5-yl)thio-butyramide, colorless liquid, nn ' = 1.5350

(142) N-ethyl-N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nD 19 = 1.5596

(143) N-butyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-19 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5222

(144) N,N-dibutyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramide, colorless liquid, nD = 1.5049

(14 5) N,N-dibenzyl-4-(1-methyl-1,2,3,4-tetrazole-19

5-yl)thio-butyramide, colorless liquid, nn = 1.5773

(146) N,N-diisopropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nD 19 ' 5 = 1.5111

(14 7) N,N-dicyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p.

91 - 92° C

(148) N-benzyl-N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane), m.p. 86.5 - 87.5° C (14 9) N-cyclohexyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide,

16

colorless liquid, nn = 1.5470

(150) N-methyl-N-(2-thienylmethyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

n<*6> = 1.5706

(151) N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nj<6> = 1.5659

(152) N,N-dihexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5011

(153) N-ethyl-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid , n^<4> = 1.5451

(154) N-tert-butyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(155) N-ethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless liquid, n 1.5319

(156) N-benzyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate, m.p.

65 - 66° C

(157) N-cyclohexyl-N-(2-hydroxyethyl)-4-(1-methyl-14 5 1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ ' 1.5372

(158) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 106 - 107° C (15 9) N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)-thio-butyramide, colorless needles (hexane-ethyl acetate^, m.p.

106 - 107° C

(160) N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95 - 96° C

(161) N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless plates (ethyl acetate), m.p. 110.5 - 113° C

(162) N-(2-pyrimidyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless granules (hexane-ethyl acetate), m.p. 108 - 110° C

(163) N-furfuryl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 73° C

(164) N-(4-aminosulfonylphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (methanol), m.p. 169.5 - 170.5° C

(165) N-[4-(N,N-dimethylamino)phenyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless prisms (hexane-ethyl acetate) , sm.p. 144 - 147° C

(166) N-(2-methyl-3-chlorophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. p. 104.5 - 105.5° C

(167) N-(4-nitrophenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (ethyl acetate), m.p. 194 - 195° C

(168) N-(2-Methoxyphenyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl-acetate), m.p. 79.5 - 82° C

(169) N-methyl-N-(2-tetrahydropyranyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n<*4> = 1 ,5273

(170) N-ethyl-N-(2-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5623

(171) N-ethyl-N-(3-pyridyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n<*6> = 1 ,5618

(172) N-ethyl-N-cyclopentyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nn 9 = 1.5384

(173) N-ethyl-N-cyclohexylmethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

nj<1> = 1.5293

(174) N-isopropyl-N-cyclohexyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid,

nj<5> = 1.5238

(175) N-ethyl-N-(4-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, nQ 9 = 1.5363

(176) N-ethyl-N-(2-hydroxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless needles (hexane-ethyl acetate), sm. p. 132 133° C

(177) N-ethyl-N-(2-acetyloxycyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<1> = 1 ,5218

(178) N,N-dipropyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5151

(179) N-butyl-N-phenyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<5> = 1.5509

(180) N,N-dimethyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^<6> = 1.5327

(181) N-ethyl-N-cyclooctyl-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide, colorless liquid, n^ = 1.5309

(182) 5-[3-(4-methylpiperazinocarbonyl)propylthio]-1-methyl-1,2,3,4-tetrazole colorless granules (hexane-ethyl acetate), m.p. 65 - 68° C

(183) 5-(3-piperidinocarbonylpropylthio)-1-methyl-25'

1,2,3,4-tetrazole colorless liquid, nQ ..= 1.5310

(184) N-ethyl-N-cyclohexyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-propionamide, light yellow liquid, nn 2 6 = 1.5273

(185) N-ethyl-N-cyclohexyl-5-(1-methyl-1,2,3,4-

25 tetrazol-5-yl)thio-valeramide, light yellow liquid, nQ = 1.5227

(186) N-ethyl-N-cyclohexyl-4-(1-phenyl-1,2,3,4-

18 tetrazol-5-yl)thio-butyramide, colorless liquid, nQ = 1.5590 Example 187

0.1 mol of 1-methyl-5-mercaptomethyl-1,2,3,4-tetrazole was dissolved in 100 ml of acetone, and to the solution was added 0.12 mol of N,N-diethyl-3-bromopropionamide and 0.12 moles of potassium carbonate. The mixture was refluxed for 4 hours. After the acetone was distilled off under reduced pressure, water was added to the residue, and the aqueous mixture was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the solvent was distilled off, the resulting residue was subjected to column chromatography (silica gel 60) and the column was eluted with chloroform-methanol (50:1, v/v) to give N,N-diethyl-3-(1-methyl- 1,2,3,4-tetrazol-5-yl)methylthio-propionamide (yield 48%), colorless

25

liquid, nQ = 1.5200.

Elemental analysis for C^pH^gN^OS:

Calculated; C 46.67% H 7.44% N 27.21%

Found : C 46.72% H 7.53% N 27.29%

Examples 188 and 189

By proceeding in the same way as described in example 187, the following compounds were prepared:

(188) N,N-diethyl-3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl]methylthio-propionamide, colorless liquid, n^ = 1.5499

(189) N-ethyl-N-cyclohexyl-3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide, light yellow liquid, nn 18= 1.5277

Example 19 0

11.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole were dissolved in 100 ml of acetone and 21.7 g of methyl-4-bromobutyrate and 15 g of potassium carbonate were added to the solution. The mixture was refluxed for 4 hours. After the acetone was distilled off under reduced pressure, water was added to the resulting residue, and the aqueous mixture was extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. After the chloroform had been distilled off, the residue was subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene ether (5:1, v/v). The eluate was distilled under reduced pressure to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyrate (20 g), colorless liquid, m.p. 175 - 177°C/0.fl mmHg, n^<6> = 1.5083. Elemental analysis for C^H^2N4OS:

Calculated: C 38.88% H 5.59% N 25.91%

Found : C 38.98% H 5.67% N 25.83%

Examples 191 and 192

Use of 1-phenyl- or 1-cyclohexyl-5-mercapto-1,2,3,4-tetrazole instead of 1-methyl-5-mercapto-1,2,3,4-tetrazole in the method according to example 190 gave the following compounds:

(191) methyl-4-(1-phenyl-1,2,3,4-tetrazol-5-yl)-18

thio-butyrate, colorless liquid, nn = 1.5654

(192) methyl-4-(1-cyclohexyl-1,2,3,4-tetrazol-

18

5-yl)thiobutyrate, pale yellow liquid, nD = 1.5162

Example 193

0.1 mol of 1-methyl-5-mercapto-1,2,3,4-tetrazole was dissolved in 100 ml of acetone, and to the solution was added dropwise a solution of 0.12 mol of 4-bromobutyric acid and 0.25 moles of sodium hydroxide in 50 ml of water. The mixture was heated with stirring to 50-60°C for 4 hours, and acetone was distilled off under reduced pressure. The resulting residue was acidified with dilute hydrochloric acid, saturated with sodium chloride and extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate.

The solvent was distilled from and the residue subjected to column chromatography (Kiselgel 60) and. the column was eluted with chloroform-methanol (10:1, v/v) to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid (yield 23%) colorless liquid .

NMR: <<5pp>£<l>3 1' 80 2'80 <6H' m) ' 3'42 (2H' t'

J = 7Hz), 3.96 (3H, s), 11.18 (1H, s)

Elemental analysis for C-gH^N^C^S:

Calculated: C 35.63% H 4.98% N 27.70

Found: C 35.79% H 5.12 N 27.84

Examples 194 and 195

Use of 1-phenyl- or 1-cyclohexyl-5-mercapto-1,2,3,4-tetrazole instead of 1-methyl-5-mercapto-1,2,3,4-tetrazole in the method according to example 193

gave the following compounds:

(194) 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid, light yellow liquid, NMR: 3 2.00 - 2.70 (4H, m) ,

3.44 (2H, t, J = 7Hz), 7.55 (5H, s), 10.98 (1H, br.s)

(195) 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thiobutyric acid, colorless prisms (ether), m.p. 67.5 - 69.5° C. Example 196 1.6 g of 2-mercaptopropionic acid was dissolved in 4 5 ml of IN aqueous sodium hydroxide solution, and to the solution was added dropwise a solution of 15.2 g of 1-methyl-5-chloromethyl-1,2,3,4-tetrazole in 20 ml acetone with stirring and under ice-cooling. Stirring was continued for 3 hours under ice cooling. Acetone was distilled off and the residue acidified with concentrated hydrochloric acid, saturated with sodium chloride and then extracted with chloroform. The chloroform solution was dried over magnesium sulfate. After chloroform was distilled off, the residue was subjected to column chromatography (Kieselgel 60) and the column was eluted with chloroform-methanol (10:1, v/v), yielding 3-(1-methyl-1,2,3,4 -tetrazol-5-yl)methylthio-propionic acid (2.1 g) as a colorless liquid, mn NMR: <5pp^x3 2.40 - 3.00 (4H, m) , 4.05 (2H, s) ,

4.12 (3H, s), 9.79 (1H, s)

Elemental analysis for CgH^^N^ >2^:

Calculated: C 35.63% H 4.98% N 27.70%

Found : C 35.81% H 4.83% N 27.83%

Examples 197 and 198

Proceeding as described in Example 196, the following compounds were obtained using suitable starting materials:

(197) 3-(1-ethyl-1,2,3,4-tetrazol-5-yl)methylthio-propionic acid, colorless prisms (acetone-ether), m.p.

68 - 70° C

(198) 3-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)-CDC1 methylthio-propionic acid, colorless liquid, NMR: ^ppm 3

1.28 (3H, t, J = 7Hz), 2.40 - 3.10 (6H, m), 3.97 (2H, s), 7.43 (4H, br.s.), 10.02 (1H, br.s)

Example 199

9 g of methyl-N-phenyladipinamate was dissolved in 70 ml of benzene, and to the solution was added 9 g of phosphorus pentachloride with stirring at a temperature below 15° C. The mixture was stirred at room temperature for 1 1/2 hours and concentrated to 1/ 3 of the volume under reduced pressure. A solution of hydrogen azide in benzene (0.0172 mol/10 mL, 44.2 mL) was added dropwise to the resulting imino chloride solution with stirring under ice-cooling. The mixture was stirred at room temperature for 1 hour, allowed to stand overnight and then gently boiled under reflux for 2 hours. The reaction mixture was concentrated and then 50 ml of ice/water was added and the mixture was extracted with chloroform. The chloroform solution was washed with water, aqueous dilute sodium hydroxide solution and water, and then dried over magnesium sulfate. Chloroform was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column eluted with benzene-ether (5:1, v/v) to give methyl-5-(1-phenyl-1,2,3,4 -tetrazol-5-yl)-valerate (7.3 g) as a colorless liquid.

NMR: Spp^1<3> i'50 _ 2'10 (4H' m)' 2'30 <2H' t, J = 6Hz),

2.90 (2H, t, J = 6Hz), 3.62 (3H, s), 7.30 - 7.70

(5H, m)

Elemental analysis for C^2H16N4°2:

Calculated: C 59.98% H 6.20% N 21.53%

Found : C 60.19% H 6.32% N 21.71%

Example 200 - 202

Proceeding as described in Example 199, the following compounds were obtained using suitable starting materials:

(200) methyl-5-(1-methyl-1,2,3,4-tetrazol-5-yl)-CDC1 3

valerate, colorless liquid, NMR: 6ppm 1.50 " 2.20 (4H' m)' 2.36 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz) , 3.65 (3H, s), 4.05 (3H, s)

(201) methyl 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valerate, colorless liquid, NMR: ^pp^<1>"3 1'00 " 2'20 d4H ' m)• 2.38 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz), 3.70 (3H, s), 3.90 - 4.50 (1H, m )

(202) methyl 5-(1,2,3,4-tetrazol-5-yl)valerate, colorless liquid, NMR: «Spp^<3>"<3> 1/50 - 2.20 (4H, m ) , 2.34 (2H,

t, J = 6Hz), 3.02 (2H, t, J = 6Hz), 3.60 (3H, s)

Example 203

100 ml of 20% aqueous hydrochloric acid was added

9.3 g of methyl 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)valerate, and the mixture was refluxed for 4 hours. After cooling, water was added and the mixture was extracted with chloroform. The chloroform solution was extracted with aqueous saturated sodium bicarbonate solution. The aqueous layer was acidified with concentrated hydrochloric acid and again extracted with chloroform. The latter chloroform extract was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled from to give 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (8.2 g), pale yellow liquid. NMR: 6CDCl3 1.40 - 2.10 (4H, m), 2.33 (2H, t, J = 6Hz),

ppm

2.92 (2H, t, J = 6Hz), 7.30 - 7.70 (5H, m), 10.56 (lH,s)

Elemental analysis for C-^H^N^C^:

Calculated: C 58.52% H 5.73% N 22.75%

Found : C 58.61% H 5.85% N 22.88%

Examples 204 to 206

Proceeding as described in Example 203, the following compounds were prepared using the compounds of Examples 200 to 202 as starting material:

(204) 5-(1-methyl-1,2,3,4-tetrazol-5-yl)valeric acid, colorless prisms (ether-ethanol), m.p. 107 - 109° C, NMR: 6CDCl3 1.40 - 2.20 (14H, m), 2.28 (2H, t, J = 2.87

ppm'

(2H, t, J = 6Hz), 4.02 (3H, s), 9.30 (1H, br.s)

(205) 5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-valeric acid, colorless prisms (recrystallized from ethanol-water), m.p. 100 - 102° C

(206) 5-(1,2,3,4-tetrazol-5-yl)valeric acid, colorless liquid, NMR: 5<p>^~DMS° 1.30 - 2.00 (4H, m), 2.30 (2H,

t, J = 6Hz), 2.87 (2H, t, J = 6Hz)

Example 207

150 ml of 20% aqueous hydrochloric acid was added

17 g of methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiovalerate, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with chloroform. The chloroform solution was washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform was distilled from to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, color-2 6

loose liquid, nQ = 1.5133.

NMR: : <5pp£l3 1.80 - 2.80 (6H, m) , 3.42 (2H, t, J =

7Hz), 3.96 (3H, s), 11.18 (1H, s) elemental analysis for CgH^gN^C^S:

Calculated: C 35.63% H 4.98% N 27.70%

Found : C 35.76% H 5.11% N 27.81%

Examples 208 and 209

Use of methyl 4-(1-phenyl- or cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-valerate instead of methyl-4-(1-methyl-1,2,3,4 -tetrazol-5-yl)thio-valerate in the procedure according to Example 207 gave the following compounds:

(208) 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, light yellow liquid, NMR: 5ppm 2'00 " 2'70 <4H'

m), 3.44 (2H, t, J = 7Hz), 7.55 (5H, s), 10.98 (1H, br.s)

(209) 4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)-thio-valeric acid, colorless prisms (ether), m.p. 67.5 - 69.5° C

Example 210

400 mg of thionyl chloride was added to 10 ml of methanol with stirring and external cooling with ice, and stirring was continued for 10 minutes. 500 mg of 4-(1-phenyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous saturated sodium chloride solution (100 mL) and was extracted with chloroform. The chloroform layer was washed with aqueous saturated sodium bicarbonate solution and water, and was dried over sodium sulfate. Chloroform was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column eluted with benzene-ether (5:1, v/v) to give methyl-4-(1-phenyl-1,2,3,4 -tetrazol-5-yl)thio-butyrate (350 mg), colorless liquid, nQ 18 = 1.5654.

Elemental analysis for C^2H14N4°2S:

Calculated: C 38.88% H 5.59% N 25.91%

Found : C 38.95% H 5.61% N.25.81%

Example 211

10 ml of thionyl chloride was added to 2 g of 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyric acid and the mixture was refluxed for 1 hour. After the excess of thionyl chloride was distilled off under reduced pressure, dry benzene was added to the residue and the remaining small amount of thionyl chloride was removed as the benzene azeotrope.

The residue thus obtained was dissolved in 50 ml of dry benzene, and 2 ml of pyridine was added to the solution. 2 ml of methanol was added dropwise with stirring while the reaction mixture was cooled with ice.- After the mixture had been stirred at room temperature for 1 hour, the benzene layer was washed with dilute hydrochloric acid, aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution, and was dried over sodium sulfate. The benzene was distilled from and the residue subjected to column chromatography (Wakogel C-200) and the column was eluted with benzene ether (5:1, v/v). The eluate was distilled under reduced pressure to give methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyrate (1.2 g), colorless liquid, m.p.

175 - 177°C/0.8mmHg.

Elemental analysis for C^H^2N4°2S:

Calculated: C 38.88% H 5.59% N 25.91%

Found : C 38.92% H 5.53% N 25.83%

Example 212

Proceeding in the same manner as described in Example 63, N,N-diethy1-4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyramide was obtained, colorless liquid, nD 20 = 1.5237.

Example 213

By proceeding in the same way as described in example 190, methyl-4-[1-(4-ethylphenyl)-1,2,3,4-

14 Tetrazol-5-yl)thio-butyrate, light yellow liquid, nn = 1.5581.

Example 214

Proceeding in the same manner as described in Example 193, 4-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl)-thio-butyric acid was obtained, light yellow liquid, NMR : ^ppm"^3 1.28 (3H, t, J 7.5 Hz), 2.00 - 2.90 (6H, m), 3.44 (2H, t, J = 7Hz), 7.36

(2H, d, J = 9Hz), 7.48 (2H, d, J = 9Hz), 10.60 (1H, br.s).

Example 215 - 220

By proceeding in the same manner as described in Examples 71 and 77, the following compounds were obtained:

(215) N-hexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)-valeramide, colorless needles (ethyl acetate-hexane), m.p.

80.5 - 82.5° C

(216) N-isopropyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless needles (ether), m.p. 91 - 92.5° C

(217) N-ethyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)butyramide, colorless needles (ether), m.p. 77.5 - 80° C

(218) N-butyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)-butyramide, colorless needles (ethyl acetate-hexane), m.p. 76.5 - 78.5° C

(219) N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless needles (ethyl acetate-hexane), m.p. 100 - 102° C

(220) N-methyl-N-cyclohexyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide, colorless oily substance, nD 21 = 1.5396

Claims (1)

Analogous method for the preparation of pharmacologically active tetrazole derivatives of formula: wherein R"*" is hydrogen, £-4 alkyl, cyclohexyl which is optionally substituted with C^_^ alkoxy, or phenyl which is optionally substituted with C 1-4 alkyl, A is sulfur or C 1-4 alkylthio, JL is 0 or 1, B is C, . alkylene, 2 R is C 1-4 alkoxy or a group and R 4 are the same or different and are each hydrogen; cj__g alkyl; C^_^2 cycloalkyl which is optionally substituted with a group selected from hydroxy, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkyl and N,N-di(C 1-4 alkyl)amino; phenyl which is optionally substituted with one or two substituents selected from amino- sulfonyl, N,N-di(C1-4 alkyl)amino, C1-4 alkyl, halogen, C^_4 alkoxy and nitro; cyclohexyl-(C 1-4 )-alkyl, phenyl-(C 1-4 )-alkyl wherein the phenyl ring is optionally substituted with C 1-4 alkoxy; hydroxy-(C 1-6 )-alkyl; pyridyl; 2-furylmethyl; or 2-thienyl- 3 4 methyl; or R and R can together with the nitrogen atom as they is bonded to, form a heterocyclic group selected from morpholino, piperidino and piperazino which are optionally substituted tuated with C^_4 alkyl or C^_4 alkanoyl, provided that a) when 0 and R<1> are hydrogen or alkyl of 1 to 4 carbons atoms, R is different from alkoxy, and NR<3>R<4> is for different from amino; b) when 0 or R1 is n-butyl, B is not methylene and NR<3>R<4 > is not ethylamino; c) when i is 0 and R 1 is phenyl and B is methylene, R 2 is for- 3 4 different from ethoxy, and NR R is different from amino, methylamino and benzylamino; d) when 0 and R 1 are phenyl and B is ethylmethylene, R 2 is not 3 4 ethoxy, and NR R is not amino; e) when 0 and R<1> is cyclohexyl and B is ethylene or methyl- 3 4 methylene, NR R is not amino; and f) when Jt is 0 and R"*" is cyclohexyl and B is dimethylmethylene, NR 3 R 4 is different from amino, diethylamino, benzylamino and morpholino, and pharmaceutically acceptable salts thereof, characterized in that a) a carboxylic acid compound of formula in which R<1>, A, -^ and B are as defined above, or a reactive derivative thereof, is reacted with an amine of formula: in which R and R are as defined above, or a reactive derivative thereof, b) a 5-mercaptotetrazole derivative of formula in which R<1> and A are as defined above and t' is 1, is reacted with a haloalkanecarboxylic acid derivative of formula: in which X is a halogen and B and R 2 are as defined above, c) a carboxylic acid amide of formula: 1 5 in which B and R are as defined above and R is alkyl with 1-6 carbon atoms, reacted with phosphorus pentachloride and then with hydrogen azide, or d) a tetrazole compound of formula: in which R<1> is as defined above, D is the alkylene with 1-6 carbon atoms and X is a halogen, is reacted with a mercapto compound of formula: 2 in which B and R are as above defined, after which, if desired/ an obtained tetrazole derivative of formula in which R<1>, A, Voq B are as defined above, subjected to esterification, and/or an obtained tetrazole derivative of formula: wherein R 1 , A, - t/ and B are as defined above, and R 5 is alkyl with 1 to 6 carbon atoms, is subjected to hydrolysis, and/or a tetrazole derivative obtained is converted into a pharmaceutically acceptable salt thereof.