DK162047B - Analogy process for preparing 5-aminocarbonylalkyl- and 5- aminocarbonylalkylthiotetrazole derivatives - Google Patents

Description

in

DK 162047 B

The present invention relates to an analogous process for the preparation of novel 5-aminocarbonylalkyl and 5-aminocarbonylalkylthio-tetrazole derivatives of the general formula III l s y (A), - * B-CON <.

I, Νϊ4

R

wherein R.1 represents hydrogen; alkyl; cyclohexyl optionally substituted with C 1-4 alkoxy; or phenyl optionally substituted with C 1-6 alkyl; 10A represents sulfur or g-alkylthio; 1 is 0 or 1; B represents g-alkylene; R 3 and are the same or different and each represents hydrogen; g-alkyl, C5-12 cycloalkyl, which is optionally substituted with a substituent selected from hydroxy, C1-6alkanoyloxy, C1-6alkoxy, C1-6 alkyl and N, N-di (C1-6 alkyl) amino; phenyl optionally substituted with one or two substituents selected from aminosulfonyl, N, N-di (C 1-6 alkyl) amino, C 1-6 alkyl, halogen, C 1-6 alkoxy and nitro; cyclohexyl-g-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-thienylmethyl; or R 3 and R 2, together with the nitrogen atom to which they are attached, may form a heterocyclic group selected from piperidino, piperazino and morpholino which may be optionally substituted with g-alkyl or g-alkanoyl; With the proviso that a) if 1 is 0 and R 2 is hydrogen or C 1-4 alkyl then NR% 2 is different from amino; b) if 1 is 0 and R R * is n-butyl, then B does not denote methylene and NR3R ^ does not denote ethylamino; C) if 1 is 0, R1 represents phenyl and B represents methylene, then NR3R4 is different from amino, methylamino and benzylamino;

DK 162047B

2 d) if 1 is O, rA represents phenyl and B is ethylmethylene, then NR 1 R 2 does not represent amino; e) if 1 is 0, R 1 - represents cyclohexyl and B represents ethylene or methyl ethylene, then NR% 2 does not represent amino; and f) if 1 is 0, R 4 represents cyclohexyl and B represents dimethyl methyl, then NR% does not represent amino, diethylamino, benzylamino and morpholino, or pharmaceutically tolerable salts thereof.

The compounds prepared have prophylactic or therapeutic action against peptic and / or duodenal ulcers, especially stress ulcers and indomethacin-induced ulcers with minor side effects such as central nervous system activity, anticholinergic activity and gastric emptying rate, and are useful as medicines for the treatment of such ulcers. The compounds also have anti-inflammatory activity and are useful as an anti-inflammatory drug.

The term "C 1-6 alkyl" here refers to straight or branched chain alkyl groups having 1-6 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. The term "C5-12 cycloalkyl" means a cycloalkyl group having 5-12 carbon atoms and includes, for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecanyl, cycloundecanyl or cyclododecanyl. The term "C1-6 alkylenthio" refers to a group formed by combining a straight or branched alkylene group of 1-6 carbon atoms and a sulfur atom in which one terminal carbon atom of the C1-6 alkylene chain is bonded to the carbonator at the 5-position of the tetrazole ring. and the sulfur atom is bonded to the carbon atom at the end of the C ^gg alkyl group "B" and comprises e.g. methylenthio, ethylenthio, tri-methylenthio, tetramethylenthio, pentamethylenthio, hexamethylenthio, 2-methyltrimethylenthio,. 2,2-dime thyl trimethylthio or 1-methyl-30-trimethylthio. The term "C 1-6 alkylene" denotes a straight or branched alkylene group having 1-6 carbon atoms and includes, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexa-methylerf, methylmethylene, 2-methyltrimethylene, 2,2-dimethyl-trimethylene and 1-methylethyl trimethylene.

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3

The term "cyclohexyl-C 1-4 alkyl" refers to a group formed by combining a straight or branched alkylene group with 1-6 carbons and a cyclohexyl ring and includes, for example, cyclohexylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl, 3-cyclohexylpropyl, 1,1-dimethyl-2-cyclohexylethyl, 4-cyclohexylbutyl, 5-cyclohexylpentyl and 6-cyclohexylhexyl. The term "phenyl-C 1-6 alkyl" refers to a group formed by combining a straight or branched alkylene group having 1-6 carbon atoms and a phenyl group and includes, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl and 6-phenylhexyl. The term "hydroxy-C1-6 alkylene" refers to a group formed by combining a straight or branched alkyl group having 1-6 carbon atoms and a hydroxy group and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4- hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl and 6-hydroxyhexyl.

The term "C 1-6 alkoxy" means a straight or branched alkoxy group having 1-6 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "N, N-20 di- (C1-6 alkyl) amino" denotes a Ν, Ν-dialkylamino group having 1-6 carbon atoms in each alkyl moiety and includes, for example, N, N-dimethylamino, Ν, Ν-diethylamino, N-methyl-N-ethylamino, Ν, Ν-dipropylamino, N, N-di-isopropylamino, Ν, Ν-dibutylamino, N-methyl-N-tert-butylamino, N, N-dipentylamino and Ν, Ν-dihexylamino. The term "C 1-6 alkanoyloxy" denotes an alkanoyloxy group having 1-6 carbon atoms and includes, for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy and hexanoyloxy. The term "C 1-6 alkanoyl" refers to an alkanoyl group of 1-6 carbon atoms and includes, for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl. Cg. Cyc cycloalkyl, phenyl and phenyl-C Cggalkyl substituted on the cycloalkyl or phenyl ring as defined above include, e.g. 2-hydroxycyclohexyl, 3-hydroxy-cyclohexyl, 4-hydroxycyclohexyl, 2-hydroxycyclopentyl, 4-hydroxy-cyclooctyl, 2-acetyloxycyclohexyl, 4-butyryloxycyclohexyl, 2-methyl-cyclohexyl, 3-ethylcyclohexyl, 3-ethylcyclohexyl methoxy-cyclohexyl, 3-methoxycyclohexyl, 4-methoxycyclohexyl, 4-tert-butoxy-cyclohexyl, 3-methylcycloheptyl, 4- (N, N-dimethylamino) cyclohexyl, 3- (Ν, Ν-diethylamino) cyclohexyl, 2-methylphen 3-methylphenyl, 4-

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4 ethylphenyl, 3,4-dimethylphenyl, 2,5-diethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,5-diethoxy-phenyl, 4-isopropoxyphenyl, 2-chlorophenyl, 3 -bromophenyl, 4-fluorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 4- (N, N-dimethylamino) phenyl, 2- (N, N-dimethylamino) phenyl, 3- (N, N-diethylamino) phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2-aminosulfonylphenyl, 4-aminosulfonylphenyl, 4-methoxy-2-chlorophenyl, 2-me -thyl-3-chlorophenyl, 2-methoxybenzyl, 4-methoxybenzyl, 2- (3,4-dimethoxyphenyl) ethyl, 1- (3,4-dimethoxy-3-phenyl) ethyl, 2- (2,5-diethoxyphenyl) ) ethyl, 1,1-dimethyl-2- (3,4-dimethoxyphenyl) ethyl and 6- (3,4-dimethoxyphenyl) hexyl.

Representative of the compounds of this invention are: N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide

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N-Butyl-N-cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclopentyl-4- (1-methyl-1, 2,3,4-tetrazol-5-yl) thio-butyramide N-Isopropyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Hexyl -N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-methyl-N-cyclododecanyl-4- (1-methyl-1,2, 3,4-Tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclohexyl-4- (1-ethyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N -cyclohexyl-4- (1-tert-butyl-1,2,3,4-tetrazol-5-yl) thio-butyramide * N-Methyl-N-cyclohexyl-4- (1-hexyl-1,2,3 (4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-4-CL-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide; N-Cyclododecanyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 6 N-Methyl-N-cyclohexyl-3- (1-methyl-1,2,3, 4- tetrazol-5-yl) thio-propionamide

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N-Methyl-N-cyclohexyl-2- (1-methyl-1,2,3,4-tetrazol-5-yl) thioacetamide N-Methyl-N-cyclohexyl-5- (1-methyl-1,2 3,4-Tetrazol-5-yl) thio-valeramide N-Methyl-N-cyclohexyl-7- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-heptanamide N- Methyl N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-3-methylbutyramide N-Ethyl-N-cyclohexyl-4- (1-ethyl-1, 2,3,4-tetra-zol-5-yl) thio-3,3-dimethylbutyramide.

N-Ethyl-N-cyclohexyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N-cyclohexyl-4- (1-cyclooctyl-1,2 3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclohexyl 3- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-propionamide N-Methyl-N-cyclohexyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5 -yl) thio-3-methylbutyramide N-Methyl-N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N-cyclohexyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-propionamide N-methyl-N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) ) thio-3-methylbutyramide N, N-Dicyclohexyl-4- (1-methyl-1,2,3,4-tetrazole-N-Cyclohexyl-N-cyclooctyl-4- (1-methyl-1,2,3, 4- tetrazol-5-yl) thio-butyramide

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7-yl) thio-butyramide N, N-Dicyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-valeramide N / N-Dicyclohexyl-4- (1-cyclohexyl) -1,2,3,4-Tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclohexyl-4- [1- (2-methoxycyclohexyl) -1,2 / 3/4-tetrazole -5-yl] thio-butyramide N-Cyclohexyl-4- [1- (4-methoxycyclohexyl) -1,2,3,4-tetrazol-5-yl] thio-butyramide N-Methyl-N-cyclohexyl-4- [ 1- (3,4-Dimethoxycyclohexyl) -1,2,3,4-tetrazol-5-yl] thio-butyramide N-Ethyl-N- (2-hydroxycyclohexyl) -4- (1-methyl-1.2). 3,4-Tetrazol-5-yl) thio-butyramide N-Methyl-N- (3-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- ( 4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (4-hydroxycyclohexyl) -4- (1-cyclohexyl-1,2, 3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N- (2-hydroxycyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 1 N- ( 4-Hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (2-Hydroxycyclohexyl) -4- (1-cyclohexyl-1,2 ', 3 4- (tetrazol-5-yl) thio-butyramide

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8 N- (3-Hydroxycyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N- (4-acetyloxycyclohexyl) -4- (1- ethyl 1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (3-acetyloxycyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl -N- (3-acetyloxycyclohexyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (2-Acetyloxycyclohexyl) -4- (1-cyclohexyl) 1,2,3,4-tetrazol-5-yl) thio-butyramide N, N-Di (4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- Methyl N- (2-methylcyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (4-methylcyclohexyl) -4- (1-cyelohexyl-1.2) (3,4-tetrazol-5-yl) thio-butyramide N-methyl-N- (3-methylcyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-methyl-N- (4-methoxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (2-methoxycyclohexyl) -4- (1-cyclohexyl-1,2 3,4-Tetrazol-5-yl) thio-butyramide N-Methyl-N- (3-methoxycyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyram id N- (4-Methoxycyclohexyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide

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N, N-Di (4-methoxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 9 N-Methyl-N- [4- (Ν, Ν-) dimethylamino) cyclohexyl] - 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N-phenyl-4- (1-methyl-1,2,3, 4-tetrazol-5-yl) thio-butyramide N-methyl-N-phenyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-methyl-N phenyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Phenyl-4- (1-phenyl-1,2,3,4-tetrazole-5-yl) Yl) -thio-butyramide N-Methyl-N-phenyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-valeramide N-Methyl-N- (2-methylphenyl) - 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (2-Methyl-3-chlorophenyl) -4- (1-methyl-1,2,3,4 -tetrazol-5-yl) thio-butyramide N-methyl-N- (2,5-dimethylphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-methyl-N- (2-Methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N- (3-methoxyphenyl) -5- (1-phenyl-1) (2,3,4-Tetrazol-5-yl) thio-valeramide N-Methyl-N- (3,4-dimethoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio- butyramide 10

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N- (2-Methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (3,4-Dimethoxyphenyl) -4- (1-methyl- 1,2,3,4-Tetrazol-5-yl) thio-butyric oxide N-Methyl-N- (2-chloro-phenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) ) thio-butyramide N-methyl-N-C4-fluorophenyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (4-chlorophenyl) -4- ( L-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- [4- (N, N-Dimethylaraino) pheyl] -4- (1-methyl-1,2,2,3. (4-Tetrazol-5-yl) thio-butyramide. .

· N '(4-Nitrophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (4-Aminosufonylphenyl) -4- (1-methyl) -1,2,3,4- (tetrazol-5-yl) thio-butyramide N, N-Dimethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N , N-Diethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N, N-Diisopropyl-4- (1-methyl-1,2,3,4- tetrazol-5-yl) thio-butyramide ...

N, N-dihexyl-4- (1-methyl-l, 2,3,4-tetrazol-5-

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11-yl) thio-butyramide N-Methyl-N-ethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide-N, N-Diethyl-5- (1- ethyl-1,2,3,4-tetrazol-5-yl) thio-valeramide N, N-Dimethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-3- methylbutyramide N, N-Diethyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N, N-Dimethyl-4- (1-phenyl-1,2,3, 4-Tetrazol-5-yl) thio-butyramide N-tert.Buty 1-4- (.1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 4- (1-Methyl) 1,2,3,4-Tetrazol-5-yl) thio-butyramide 4- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) thiobutyramide N-Ethyl-N-cyclohexylmethyl-4 - (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (2-cyclohexylethyl) -4- (1-cyclohexyl - 1,2,3,4 -tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclooctylmethyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexylmethyl-4- (1 -methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Phenyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) ) thio-butyramide N, N-Dicyclohexylmethyl-4- (1-cyclohexyl-1,2, 3,4- tetrazol-5-yl) thio-butyramide Cyclohexyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N-benzyl-4- (1-methyl-1,2,3) (4-Tetrazol-5-yl) thio-butyramide N, N-Dibenzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramic (N-Methyl-N-benzyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N-benzyl-4- (1-phenyl-1,2,3,4-tetrazole-4-yl) 5-yl) thio-butyramide N- (1-Phenylethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-N-benzyl-4- ( 1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Phenyl-N-benzyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Methyl-N-cyclohexyl-4- (1,2,3,4-tetrazol-5-yl) thio-butyramide N, N-Dicyclohexyl-4- (1,2,3,4-tetrazole-4-yl) 5-yl) -thio-butyramide N-methyl-N-phenyl-4- (1,2,3,4-tetrazol-5-yl) -thio-butyramide N-methyl-N-cyclohexylmethyl-3- (1 *) (2,3,4-Tetrazol-5-yl) thio-propionamide N, N-Dicyclohexylmethyl-4- (1,2,3,4-tetrazol-5-yl) thio-butyramide

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13. N-Methyl-N-benzyl-4- (1 / 2,3,4-tetrazol-5-yl) -thio-butyramide 4- (1 / 2,3 / 4-Tetrazol-5-yl) thio-butyramide N - (2-Hydroxyethyl) -4-. (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) ) thio-butyramide N-Methyl-N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-N- (2-hydroxyethyl) ) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

N-Ethyl-N- (2-hydroxyethyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Phenyl-N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-methyl-N- (4-hydroxybutyl) -4- (1-methyl-1,2,2,4-tetrazole) -5-ylj thio-butyramide N, N-Di (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (2-Hydroxyethyl) - N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N- (2-Hydroxyethyl) -N-cyclohexylmethyl-4- (1-cyclohexyl-1,2 3,4-Tetrazol-5-yl) thio-butyramide N- (2-Hydroxyethyl) -N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-1,2,3 (4-Tetrazol-5-yl) thio-butyramide 5- (3-Morpholinocarbonylpropylthio) -1-methyl-Γ, 2,3,4-tetrazole 5- (3-Piperidinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole

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5- (3-Piperazinocarbonylpropylthio) -1-cyclohexyl-1,2,3,4-tetrazole 5- [3- (4-Acetylpiperazine) carbonylpropylthio] -1-methyl-1,2,3, 4-Tetrazole N- (2-Pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Ethyl-N- (2-pyridyl) -4- ( 1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-Cyclohexyl-N- (4-pyridyl) -4- (1-methyl-1,2,3,4-tetrazole) 5-yl) thio-butyramide N-Methyl-N- (3-pyridyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide N-furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4- tetrazol-5-yl) thio-butyramide N-Ethyl-N-cyclohexyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) valeramide N-Butyl-N-cyclooctyl-5 -Cl-methyl-1,2,3,4-tetrazol-5-yl) valeramide N-Ethyl-N-cyclohexyl-4- (1-tert-butyl-1,2,3,4-tetrazole-5 -yl) butyramide N-Methyl-N-cyclohexyl-7- (1-methyl-1,2,3,4-tetrazol-5-yl) heptanamide N-Methyl-N-cyclohexyl-4- (1-methyl-1) (2, -3,4- (tetrazol-5-yl) -3-methylbutyramide

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N-Ethyl-N-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide N-Ethyl-N-cyclohexyl-5- (1-phenyl-1,2, 3,4-Tetrazol-5-yl) valeramide N, N-Dicyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide N, N-Dicyclohexyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Methyl-N-cyclohexyl-5- II- (4- CN, N-dimethylamino) -cyclohexyl) -1,2 3,4-Tetrazol-5-yl] valeramide N-Ethyl-N- (4-hydroxycyclohexyl) ~ 4- (1-ayclo · hexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Methyl-N- (2-hydroxycyclohexyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide N- (4-Hydroxycyclohexyl) -5- (1-phenyl-1) , 2,3,4-tetrazol-5-yl) valeramide N-Methyl-N- (4-acetyloxycyclohexyl) -4- (1-ethyl-1,2,3,4-tetrazol-5-yl) butyramide N-Ethyl-N- (2-Acetyloxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide N-Ethyl-N- (3-acetyloxycyclohexyl) -4- (1-cyclohexyl-1 , 2,3,4-tetrazol-5-yl) butyramide. N-Ethyl-N- (4-methylcyclohexyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Ethyl-N- (2-methoxycyclohexyl) -5- (1-cyclohexyl) -1,2,3,4-tetrazol-5-yl) valeramide

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16 N-Methyl-N- [4- (N, N-dimethylamino) cyclohexyl] - 4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide N-Ethyl-N-phenyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) butyramide * N-Methyl-N-phenyl-5- (1-phenyl-1,2,2,4,4-tr azo 1- 5-yl) valeramide N, N-Diphenyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide N-Phenyl-4- (1-phenyl-1) (2,3,4-Tetrazol-5-yl) -butyramide N-Methyl-N- (4-methylphenyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide N -Methyl-N- (2,5-dimethylphenyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide N-methyl-N- (3,4-dimethoxyphenyl) -4- (1- phenyl-1,2,3,4-tetrazol-5-yl) butyramide N-Methyl-N- (3,4-dichlorophenyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Methyl-N-phenyl-5- [1- (4-methylphenyl) -1,2,3,4-tetrazol-5-yl] valeramide N, N-Diethyl-5- (1-ethyl-1, 2,3,4-tetrazol-5-yl) -valeramide N-methyl-N-tert. buty 1-4- (1-methyl-1,2,3,4-tetrazol-5-yl) butyramide N, N-Diethyl-5- (1-cyclohexyl-1,2,3,4-tetrazole-5 yl) valeramide N, N-Diethyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide

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17 N-tert.Butyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide 5- (1-Phenyl-1,2,3,4-tetrazol-5-yl) valeramide N-Ethyl-N-cyclohexylmethyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) valeramide N, N-Dicyclohexylmethyl-5- (1-cyclohexyl-1,2,3 4-Tetrazol-5-yl) valeramide * N-Cyclohexyl-N-cyclohexylmethyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Cyclohexylmethyl-N- , 2-cyclohexylethyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Ethyl-N-benzyl-4- (1-phenyl-1,2,3,4 -tetrazol-5-yl) butyramide N-Cyclohexy1-N-benzyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide N-Ethyl-N- [2- ( 3,4-dimethoxyphenyl) ethyl] -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide N-Benzyl-N- [2- (3,4-diipethoxyphenyl) ethyl] - 4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide N-Phenyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-phenyl-1, 2,3,4-tetrazol-5-yl) butyramide N-methyl-N-cyclohexyl-5- (1,2,3,4-tetrazol-5-yl) valeramide. N-Phenyl-N-cyclohexyl-4- (1,2,3,4-tetrazol-5-yl) butyramide 5- (1,2,3,4-Tetrazol-5-yl) valeramide N-Cyclohexyl-N- (2-hydroxyethyl) -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butyramide

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18 N-Methyl-N- (2-hydroxyethyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide 5- (4-Piperidinocarbonylbutyl) -1-phenyl-1,2 , 3,4-Tetrazole 5- (4-Piperidinocarbonylbutyl) -1-methyl-1,2,3,4-tetrazole 5- [4- (4- Methylpiperazine) carbonylbutyl] -1-phenyl-1,2 3,4-Tetrazole "5- [3- (4-Acetylpiperazino) carbonylpropyl] -1-methyl-tetrazole N- (2-Pyridyl) -5- (1-methyl-1,2,3,4-tetrazole) 5-yl) valeramide N-Ethyl-N- (2-pyridyl) -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide N, N-Diethyl-3-C1-methyl -1,2,3,4-tetrazol-5-yl) methylthio-propionamide N, N-Diethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N, N-Diethyl-3- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N / N-Diethyl-3- [2- (1-methyl-1,2,3 (4-Tetrazol-5-yl) ethylthio] propionamide N-Ethyl-N-cyclohexyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl N-cyclohexyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N-cyclohexyl-3- (1-cyclohexyl-1,2,3 , 4-tetrazol-5-yl) methylthio-propionamide

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19 N-Ethyl-N-cyclohexyl-3- [2-methyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) propylthio] propionamide N, N-dicyclohexyl-3- (1-cyclohexyl-1 (2,3,4-Tetrazol-5-yl) methylthio-propionamide N-Ethyl-N-phenyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N-phenyl-3- (1-cyclohexyl-1,2,3,4-tetrazol-yl) methylthio-propionamide N-Ethyl-N-phenyl-3- (1-phenyl-1,2 3,4-Tetrazol-5-yl) methylthio-propionamide N, N-Diphenyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N cyclohexyl-4- (1-methyl-1,2,3,4-tetrazole-5-yl) methylthio-butyramide N-Ethyl-N-benzyl-3- (1-methyl-1,2,3, 4-Tetrazol-5-yl) methylthio-propionamide * N-Ethyl-N-cyclohexylmethyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- (4-hydroxycyclohexyl) -3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -3- (1- methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- (4-methylphenyl) -3- (1-methyl-1,2,3,4-tetrazol-5 yl) methylthio-propionamide N-Ethyl-N-cyc lohexyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N, N-Diethyl-3- [1- (4-ethylphenyl) -1,2,3,4 tetra-zol-5-yl) methylthio-propionamide

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N-Ethyl-N-cyclohexyl-3- (1,2,3,4-tetrazol-5-yl) methylthio-propionamide 3- (1-Methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- (2-hydroxyethyl) -3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- (2-pyridyl) -3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Ethyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) -methylthio-propionamide · N-Cyclohexyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide N-Phenyl-3- (1-methyl-1,2,3, 4-Tetrazol-5-yl) methylthio-propionamide N-Ethyl-N- (2-thienylmethyl) -3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide · 5 - [(2-Piperidinocarbonylethyl) thiomethyl] -1-methyl-1,2,3,4-tetrazole 5 - [(2-Morpholinocarbonylethyl) thiomethyl] -1-methyl-1,2,3,4-tetrazole

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21

The process in question is shown in Scheme I below.

Reaction Scheme I N-N

jl hm- "r

N I + H

-B-COOH

E ^ E1 11111 ^ Amidb inducing reaction

N-N

11 II T 3

N II JBT

-B-CONC ^ 4 [la] ll 5 where R ^ ·, R ^, R ^, A, B and 1 have the meaning given above.

The process of Scheme I is carried out by subjecting a carboxylic acid II and an amine III to an amide-forming reaction.

In the above process, instead of the carboxylic acid II, a compound with an activated carboxyl group can be used, and furthermore a compound with an activated amino group can be used instead of the amine III. The amide bond-forming reaction comprises any conventional method, e.g.

i) a mixed acid anhydride method, i. a process which involves reacting the carboxylic acid II with an alkyl halogen carboxylate to form a mixed acid anhydride and reacting the mixed acid anhydride with the amine III; ii) an active ester method, i. a process which involves converting the carboxylic acid II to an activated ester, e.g. the p-nitro-phenyl ester, the N-hydroxysuccinimide ester or the N-hydroxybenzotriazole ester, and then the reaction of the active ester with the amine III; iii) a carbodiimide method, i.e. a process comprising condensation of the carboxylic acid II with the amine III in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole,

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Iv) a 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 involving converting the carboxylic acid II to an acid anhydride compound thereof using a dehydrating agent such as acetic anhydride and then reacting the resulting acid anhydride with the resulting acid anhydride. And vi) a process comprising converting the carboxylic acid II to a lower alcohol ester and reacting the resulting ester 10 with the amine III under high pressure and at a high temperature. Among these methods, the mixed acid anhydride and carboxylic acid halide method is preferred. The alkyl halide carboxylate used in the mixed acid anhydride method is e.g. methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethylbromoformate or isobutyl chloroformate. The mixed 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 may be any of the compounds usually used in the Schotten-Baumann reaction, e.g. 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] undecen- ( DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate or sodium hydrogen carbonate. The reaction is usually carried out at a temperature of from -20 to + 100 ° C, preferably from 10 to 50 ° G, for from ca. 5 minutes to approx. 10 hours.

The mixed acid anhydride method is usually carried out in a suitable solvent. The solvent may be any of the solvents commonly used in this process, e.g. halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dimethoxyethane, esters such as methyl acetate or ethyl acetate or aprotic polar solvents such as dimethylformamide or dimethylsulfoxide or dimethylsulfoxide or The carboxylic acid

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II, the alkyl halogen carboxylate and amine III are usually used in such an amount that the alkyl halogen carboxylate and amine III are each at least equimolar to the carboxylic acid II, preferably 1-1.5 moles per mole. moles of the carboxylic acid II.

The carboxylic acid halide method is carried out by reacting the carboxylic acid II with a hole alloying agent to form a halide compound of the carboxylic acid II and then reacting the resulting carboxylic acid halide with the amine III after isolating the halide from the reaction mixture and purifying or without isolation.

The reaction of the carboxylic acid II and the halogenating agent is carried out in the presence or absence of a solvent. The solvent may be any of the solvents which have no undesirable effect on the reaction, e.g. 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 or aprotic polar solvents such as dimethylformamide or dimethylsulfoxide. The halogenating agent comprises any hollowing agent which can replace the hydroxy group of the carboxyl group with halogen, e.g.

Thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride or phosphorus pentabromide.

The amount ratio of the carboxylic acid II to 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 may be used in an amount equivalent or greater to the former, preferably 2-4 moles for each mole of the former. The reaction temperature and reaction time are also not critical, but the reaction is usually carried out at a temperature of from room temperature to 100 ° C, preferably from 50 to 80 ° C, for from 30 minutes to 6 hours.

The reaction of the carboxylic acid halide with the amine III is usually carried out in the presence of a dehydrohalogenating agent. The dehydrohalogenating agent is usually a basic compound. The basic

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24 binders used as dehydrohalogenating agents include all conventional compounds, e.g. inorganic bases - such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or silver carbonate, alkali metals (e.g., sodium or potassium), alcoholates such as sodium methylate or sodium ethylate, or organic bases such as triethylamine, , Ν-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] nonen-5 (DBN), 1,5-azabicyclo [5.4.0] undecen-5 (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO). The amine III can be used in a large excess instead of using the dehydrohalogenating agent. The reaction may be carried out in the presence or absence of a solvent. The solvent may be any inert solvent which does not produce undesirable effects on the reaction, e.g. 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 or aprotic polar solvents such as N, N-dimethyl sulfide or dimethylsulfide .

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

Intermediate Compounds Ib, Compounds of Formula II, wherein 1 is 1, can be prepared by a process as shown in Scheme II below:

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25

N-N N-N

5 L. ! 1

+ x-b-COOH> NN / Ax (A) J? f-B-COOH

1 1 H 1 IV 1b where 1 'is 1, X represents halogen and R 2, B and A have the meaning given above.

The dehydrohalogenation reaction of a 5-mercaptotetrazole derivative IV and a haloalkanecarboxylic acid derivative V in the above reaction scheme II is usually carried out in the presence of the same dehydrohalogenating agent used in the above reaction scheme I. The reaction can be carried out in the presence or absence of a solution. The solvent may be any of the inert solvents which do not produce undesirable effects on the reaction, e.g. alcohols such as methanol, ethanol, propanol, butanol or ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyc or diglyme, ketones such as acetone or methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene or xylene, esters such as methyl acetate or ethyl acetate or aprotic polar solvents such as Ν, Ν-dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide. Furthermore, it is desirable to carry out the reaction in the presence of a metal iodide such as sodium iodide or potassium iodide.

The amount ratio of compound IV to compound V is not critical, but when the reaction is carried out in the absence of a solvent, the latter is used, i.e. compound V, 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 from 1 to 5 moles, preferably 1 to 2 moles, per ml. moles 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 from 0 to 160 ° C, for from ca. 1 to 30 hours.

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26

Compounds Ic, which are lower alkyl ester derivatives of compounds II, where 1 is 0, can be prepared by a procedure as shown in Scheme III below: - R'NH9 [VII] -,

R OOC-B-COOH ---> R OOC-B-CONHR

VI VIII

(1) pci5 (2) HN3 | ~ N i N j

No. B-COOR 5 Ic R1 5 wherein R 1 and B have the meaning given above and R 1 represents lower alkyl.

The reaction of a carboxylic acid VI and an amine VII of the above Scheme III can preferably be carried out under the same conditions 10 as shown for the mixed acid hydride method and the carboxylic acid halide method as described in Scheme I.

The reaction of a halogenamide VIII with phosphorus pentachloride (PCI5) is usually carried out in a solvent. The solvent may be any inert solvent which does not cause undesirable effects 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 or aliphatic hydrocarbons such as n-hexane or n-heptane. The amount ratio of the halogenamide VIII to phosphorus pentachloride is not critical, but usually the latter is used, i.e. PCI5, in an amount of from 1 to 2 moles, preferably from 1 to 1.2 moles, per moles of the former. The reaction temperature and reaction time are also not critical, but the reaction is usually carried out at a temperature of from -20 to + 50 ° C, preferably from 0 to 25 ° C, for from 30 minutes 25 to 5 hours.

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27

In the above reaction of the halogenamide VIII with phosphorus pentachloride, a halogenimine derivative is formed and this compound is then reacted with hydrogen azide (HN3) without isolation from the reaction mixture. The reaction is usually carried out in a suitable solvent such as benzene, xylene, diethyl ether or n-hexane. The hydrogen azide is usually used in an amount of from 1 to 5 moles, preferably from 1 to 3 moles, per liter. moles of the halogenimine derivative. The reaction is usually carried out at a temperature of from 0 to 150 ° C for from 3 hours to 2 days.

Subsequent hydrolysis of the compound Ic to the corresponding acid can be carried out by conventional methods, e.g. 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 can. be any of 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 or isopropanol. 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 from 50 to 110 ° C, for from ca. 30 minutes to 10 hours.

Compounds Id, which are compounds II wherein A represents lower alkylthio, can be prepared by a process as shown in Scheme IV below:

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28

in T (1) Ρ € 1ς N-N

X “D-COOH + ITNH2- * X-D-CONHR1 -i *. [(I

(2) HN3 N II

ϊχ 711 x 7 ΥΧ-χ / i *

/ XI

HS-B-COOH / [XII] / N-N / ll N xD-S-B-COOH Id R 1 where X, R 2 - and B have the meaning given above and D represents lower alkylene.

In Scheme IV, the reaction of a compound IX and a compound VII and the reaction of a compound X and PCI5 is followed by the reaction with hydrogen azide under the same reaction conditions as the reaction of compound VI and compound VII and the reaction of compound VIII and PCI5, respectively, followed by reaction 10 with hydrogen azide in Scheme III of the above reaction. Furthermore, the reaction of Compound XI and Compound XII is carried out under the same reaction conditions as the reaction of Compound IV and Compound V in Scheme II above.

The other starting compounds III used in the above Reaction Schemes I - IV are partly known and comprise novel compounds prepared by the methods shown in Reaction Schemes VI and VII below.

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29

Scheme VI

J & 2 R3 HN <^ - + R4x -hn ^ \ 4

R

XIII XIV III

Scheme VII

S H. R3 HN ^ + R3X - * HN \.

XR4 XR4

XV XVI III

where and R 1 has the meaning given above and X represents halogen.

In Reaction Schemes VI and VII, the reaction of a 10 amine XIII and a halogen compound XIV and the reaction of an amine XV and a halogen compound XVI are carried out under the same reaction conditions used in the dehydrohalogenation reaction of Reaction Scheme II.

The compounds IV used in Scheme II are known, and other starting compounds V are partly known and partly hitherto unknown. Eg. are prepared compounds Va, which are compounds V, which represents / * 3

by a procedure as shown in Scheme VIII below

20 p3 Amide bond dc.n- "3 X-B-COOH + end-reaction ^ X-B '~ CON" ^^' ^ * \ r4 XVII III Va where X, B, R · * and R4 have the meaning given above.

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The reaction of a known halogenated carboxylic acid XVII and an amine III can be carried out under the same reaction conditions as used in the amide bond-forming reaction in Scheme I.

The starting compounds used in Reaction Schemes III and VI 5 are known.

The compounds Ia containing an acidic group can be converted into a salt thereof with a pharmaceutically tolerable basic compound. The basic compound comprises metal hydroxides such as sodium hydroxide or potassium hydroxide and alkali metal alcoholates such as sodium methylate or potassium methylate. The compounds Ia having a basic group can also be converted into a salt with a pharmaceutically tolerable acid. Pharmaceutically tolerable 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 prepared by the above processes can be readily isolated from the reaction mixture and purified by conventional methods. The insulation can e.g. is performed by precipitation, extraction, recrystallization, distillation, column chromatography or preparative thin layer chromatography.

The compounds 1a and their pharmaceutically tolerable salts are useful in the treatment of peptic and duodenal ulcers and are usually used in the form of conventional pharmaceutical compositions. The pharmaceutical compositions can be prepared using conventional diluents and carriers such as fillers, swelling agents, binders, wetting agents, disintegrators, surfactants or lubricants. The compositions may be in various forms such as tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories or injections (solution, suspension, etc.). The tablets may be prepared using conventional carriers such as excipients, e.g. lactose, sucrose, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders, e.g. water, ethanol, propanol, simple syrup, aqueous glucose solution, aqueous starch solution,

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31 aqueous gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate or polyvinylpyrrolidone, disintegrators, e.g. dry starches, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceryl stearate, starches or lactose, disintegration inhibitors, e.g. sucrose, stearin, cocoa butter or hydrogenated oils, absorption accelerators, e.g. quaternary ammonium salts or sodium lauryl sulfate; humectants, e.g. glycerol or starches, adsorbents, e.g. starches, lactose, kaolin, bentonite or colloidal silica, lubricants, e.g. purified talc, stearic acid salts, boric acid powder or polyethylene glycol. The tablets may be in the form of sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double or multilayer tablets. Pills can be prepared using conventional carriers such as excipients, for example, glucose, lactose, starches, cocoa butter, hardened vegetable oils, kaolin or talc, binders, e.g. gum arabic powder, tragacanth powder, gelatin or ethanol, disintegrants, e.g. laminaria or agar. The suppositories may be prepared using conventional carriers such as polyethylene glycol, cocoa butter, higher alcohols or their esters, gelatin or semi-synthetic glycerides. When the active compounds are prepared in the form of an injection, a solution or suspension containing the active compound is sterilized and made isotonic with the blood. Solution, emulsion or suspension injection preparations can be prepared using conventional diluents such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol or polyoxyethylene sorbitan grease testers. The injection preparation may be made isotonic by the addition of a sufficient amount of sodium chloride, glucose or glycerol and may optionally be added to conventional solubilizers, buffer solutions, painkillers, colorants, preservatives, fragrances, flavorings, sweeteners or other drugs.

The anti-ulcer preparations may contain very different amounts of the active compounds and usually contain from 1 to 70

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32% by weight, preferably from 5 to 50% by weight, of the active compounds, based on the total weight of the compositions.

The route of administration of the anti-ulcer preparations is not limited, and an appropriate route of administration is determined by the form 5 of the formulations as well as the age, sex and other conditions of the patient to be treated, the severity of the disease and the like. Tablets, pills, solutions, suspensions, emulsions, granules and capsules are usually administered by oral route. Injection preparations are usually administered by intravenous route alone or optionally with a suitable adjuvant such as glucose or amino acids or can be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally alone.

The dosage of the active compounds may vary with the use, age, gender and other conditions of the patient to be treated, the severity of the disease or the like, but usually ranges from 0.6 to 50 mg / kg body weight per day. day. The active compounds of this invention are preferably contained in the anti-ulcer preparations at a dosage unit of 10 to 1000 mg.

Pharmacological Tests: The pharmacological activities of compounds Ia were tested by conventional methods as described below and with respect to the test compounds listed below.

The test compounds are as follows: 1. N, N-diethyl -4- (1-methyl-1,2,3,4-thea trazol-5-yl) thio-butyramide 2. N-ethyl-N-cyclohexyl-4 - (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 3. N-ethyl-N-cyclohexyl-5- (1-methyl-1,2,3,4- tetrazol-5-yl) thiovaleramide

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4. N-Ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide 5. N, N-diethyl -5- (1-cyclohexyl-1, 2,3,4-tetrazol-5-yl) valeramide 6. N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 7. N- (4 - (N, N-dimethylamino) phenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 8. N-ethyl-N- (2-hydroxycyclohexyl) - 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 9. N-ethyl-N-phenyl-4- (1-methyl-1,2,3,4-tetrazole) N-ethyl-N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 11. N-cyclohexyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 12. N, N -diethyl-3- (1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl) methylthio-propionamide 13. N-furfuryl-4- (1-methyl-1,2 , 3,4-tetrazol-5-yl) thio-butyramide.

14. N, N-Diethyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide.

15. N-Ethyl-3- (1-butyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide.

16. N-Ethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide.

17. N- thyl -4- (1- ethyl -1,2,3,4-tetrazol-5-yl) methyl thio-butyramide.

18. N, N-Diethyl-4- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiobutyramide.

19. 3- (1-Ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide.

20. N-Ethyl-N-cycloheptyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

21. N, N-diisopropyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butarmide.

22. N-isopropyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide.

23. 5- (3-piperidylcarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole.

24. N- [2- (3,4-Dimethoxyphenyl) ethyl] -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

25. N- (2-pyridyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide).

26. N, N-dimethyl -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

27. N-Ethyl-N-cyclopentyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

28. N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide.

29. N-Ethyl-N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

30. 5- [3- (4-Acetyl-1-piperazinylcarbonyl) propylthio] -1-methyl-1,2-, 3,4-tetrazole.

31. 5- (3-morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole.

32. N-Ethyl-N-cyclohexy-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide.

33. Methyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyrate.

34. N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

35. N- (2-hydroxyethyl) -N-phenyl -4- (1-methyl -1,2,3,4-tetrazol-5-yl) -thio-butyramide.

36. N- (4-sulfamoylphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide.

37. N- (2-methyl-3-chlorophenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide.

38. N- (4-nitrophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

39. N, N-Diethyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide.

40. N- (4-methoxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

41. N-butyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide.

42. N-ethyl-N-cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

43. N- [4- (N, N-dimethylamino) phenyl] -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

44. N, N, dicyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

45. N-Ethyl-2- (1-ethyl-1,2,3,4-tetrazol-5-yl) propylthioacetamide.

46. N-cyclododecanyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

47. N-n-hexyl-4- (1-methyl-1,2,3,4-tetrazol'-5-yl) -thio-butyramide.

48. N-ethyl-N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

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49. N- (4-methylcyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

50. N- [4- (N, N-dimethylamino) cyclohexyl] -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

51. N-ethyl-N-cyclohexyl-2- (1-methyl-1,2,3,4-tetrazol-5-yl) thioacetamide.

52. 5- [3- (4-Methylpiperazinocarbonyl) proprylthio] -1-methyl-1,2,3,4-tetrazole.

53. N-Ethyl-N-cyclohexyl-4- [1- (2-methoxycyclohexyl) -1,2,3,4-tetrazol-5-yl) thio-butyramide.

54. N-Butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide.

55. N-benzyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-1,2,3,4-tetrazole-5-yl) thio-butyramide.

56. N- (2-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide.

57. N-cyclohexyl-N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide.

Test 1:

The pharmacological activities of compounds 1a are tested by a 20 Shay rat pylorus ligation method (cf. H. Shay et al .: Gastroen terol., Vol. 5, pages 43, 1945), which is the most widely used method for testing mavesaftsekretionsinhiberingsaktivitet. The test is performed using Wistarhan rats weighing approx. 170 g and has been fasting for 24 hours.

The test compounds are administered subcutaneously 30 minutes before the pylorus ligation at a dose of 100 mg / kg and the volume, total acidity and pepsin activity in the gastric juice are measured 4 hours after the ligation. As a control, a saline solution is administered instead of the test compound. The inhibition ratio (%) of the test compound is calculated, with the inhibitory activity of the control set to 0. The results are shown in Table 1 below.

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36 In the table, the inhibition ratio (%) is calculated as follows: + = from 10 to less than 50% ++ = more than 50%.

TABLE 1 5

Irihiberingsforhold

Test Stomach Juice- Total Pepsin Binding Volume Acidity Activity 10 1 ++++++ 2 ++++++ 3 ++ ++ A +++ 5 +++ 15 6 +++ 7 ~ ++ ++ 8 ++ ++ 9 ++ ++ ++ 10 ++ ++ 20 11 ++ ++ 12 ++ 13 ++ ++ 20 ++ ++ 21 ++ ++ 25 ++ ++ 23 ++ ++ 24 ++ ++ 25 ++ ++ 26 ++ ++ + 30 27 +++++ '28 ++ ++ 29 ++ ++ 30 +++ 31 ++ ++ 35 32 ++ - - 33 +

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37 34 ++ + 35 +++ 36 + - + 37 ++ - 5 38 +++ 39 +++ 40 + - 57 ++.

Test 2: Stress ulcer

After male Wistar rats weighing approx. 170 g had fasted for 24 hours, the rats were trapped in a stress cage and dipped in a water bath at 23 ° C up to the animal's chest. After 7 hours, the rats were sacrificed and the stomach was isolated. Into the isolated stomach was poured 10% formalin (8 ml) which was allowed to settle. The stomach was cut along the largest curve and the length of each ulcer on the diaphragm was measured. The sum of the length of all ulcerations was calculated as an index of ulceration (TJX). Before the rats were entrapped in a stress cage, the test compound was administered orally in the form of one

ISLAND

20 0.5% CMC suspension ion at a concentration of 1 x ΙΟ "- * mol. As a control, only the solvent (CMC solution) was administered in the same manner.

The degree of irradiation of the test compounds (%) to stress ulcer was calculated by the following equation: 25 (UI for control - (UI for test compound rats) part-administered rats)

Inhibition rate - - x 100 (UI for control rats) 30 The results are shown in Table 2.

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38 In Table 2 the rate of inhibition (%) is given as follows:: less than 20% +: 30-60% ++: more than 60% TABLE 2

Testforb. Inhibition Test Comp. Degradation No. Degree No. Degree 10 1 ++ 31 ++ 7 ++ 34 + 8 ++ 39 ++ 10 ++ 45 + II - 46 + 15 12 + 47 ++ 13 + 48 + 14 ++ 49 + 15 ++ 50 + 16 + 51 ++ 20 17 + 52 ++ 18 + 53 + 23 + 54 + 25 55 -H- 30 - 56 ++ 25 _.

Test 3: Acetic acid-induced ulcer

Male Wistar rats were used. Under anesthesia, the rat's abdomen was opened to expose the stomach, and then 30% aqueous acetic acid (0.015 ml) was injected under the serosa membrane, which was located in the border region between the actual gastric gland and the pyloric gland, after which the abdomen was closed, as an experimental ulceration was induced in this procedure.

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39

The test compound was administered orally in the dose shown in Table 3 in the form of a 0.5% CMC suspension or solution twice daily for 12 days after the acetic acid-induced ulceration was induced. Similarly, only 5 solvents (CMC solution) were administered as a control.

After the recovered mucosa was removed around the ulcerations, the open area of the ulcerations was measured by a micrometer and the sum of the ulcer area was indicated as the ulceration index (UI). The degree of inhibition (%) of the test compounds against acetic acid-induced ulceration was calculated in the same way as in Test 2. The results are shown in Table 3.

In Table 3, the degree of inhibition (%) was given as follows:: less than 10% +: 30-60% 15 ++: more than 60% TABLE 3

Test Compound No. Dose Inhibition Rate 20 3 x ΙΟ "- * mole 22 kg · day + 2 20 mg / kg * day + 9 - + 25 24 + 26 - + 33 - + 41 - + 42 - + 30 43 + 44 - +

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40

Test 4: Indomethacin-induced ulceration

After male Wistar rats weighing approx. 160 g had 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 5 and a small amount of Tween 80 (i.e., polyeoxyethylene sorbitan monooleate).

After 5 hours, the rats were sacrificed and the stomach was isolated. Into the isolated stomach was poured 10% formalin (8 ml) which was allowed to settle. The abdomen was cut along the largest curve and the length of each ulcer on the membrane was measured, and on the basis of this result, the degree of inhibition of the test compounds against indomethacin-induced ulceration was calculated in the same manner as in test 2. The test compound was administered orally to the rats. at a concentration of 3 x 10 6 mole in the form of a 0.5% CMC suspension 30 minutes prior to the administration of indomethacin. The results are shown in Table 4.

In Table 4, the degree of inhibition (%) was given as follows: +: 30-60% ++: more than 60% TABLE 4 20

Testforb. Inhibition No. Grade 34 + 25 40 ++

Acute toxicity:

The test compounds are administered orally to Wistarhan rats and the LD, -q-30 value is calculated. The results are shown in Table 5Γ

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41 TABLE 5

Test Ratio Test Test LD5Q Value Bond (mg / kg, Bond (mg / kg, 5 no. Oral) no. Oral) 1> 500 30> 500 2> 500 31> 500 3> 500 32> 500 10 4> 500 33> 500 5> 500 34> 500 6> 500 35> 500 7> 500 36> 500 8> 500 37> 500 15 9> 500 38> 500 10> 500 39> 500 11> 500 40> 500 12> 500 41> 500 13> 500 42> 500 20 14> 500 43> 500 15> 500 44> 500 16> 500 45> 500 17> 500 46> 500 18> 500 47> 500 25 19> 500 48> 500 20> 500 49> 500 21> 500 50> 500 22> 500 51> 500 23> 500 52> 500 30 24> 500 53> 500 25> 500 54> 500 26> 500 55> 500 27> 500 56> 500 28> 500 57> 500 35 29> 500

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42

The invention is further illustrated by the following reference examples and examples.

Reference Example 1.

To 400 ml of ethyl acetate are added 26 ml of N-me thy 1 eye lohexy 1 amine and to the mixture is added dropwise with stirring 25 ml of 4-chlorobutyryl chloride and 33.5 ml of triethylamine over a period of 20 minutes, keeping an inner layer. temperature of from 10 to 20 ° C on ice cooling.

The mixture is further stirred at room temperature for 1 hour. After the reaction, water is added to the reaction mixture. The organic phase is separated and washed with water and saturated aqueous potassium carbonate solution, 10% aqueous hydrochloric acid and water in the above order and then dried over anhydrous sodium sulfate. After filtration of sodium sulfate, the mother liquor is evaporated and distilled under reduced pressure to give 41.5 g of N-methyl-N-cyclohexyl-4-chlorobutyramide, boiling point 133 - 136 ° C / 2 mm Hg.

Reference Example 2.

Dissolve 2.6 g of N-ethyl-cyclohexylamine in 20 ml of dry benzene. To the solution is added dropwise with stirring 2.6 g of chloroacetyl chloride and 2.4 20 g of triethylamine and under ice-cooling. The mixture is stirred under ice-cooling for 1 hour and further at room temperature for 1 hour. The reaction mixture is poured onto ice water and extracted with ether. The ether phase is washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue obtained is distilled off under reduced pressure to give 3 g of N-ethyl-N-cyclohexyl chloroacetamide, bp 118-120 ° C / 0.2 mm Hg.

Reference Examples 3 and 4.

In the same manner as described in Reference Example 2, the following compounds are prepared:

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43 N-Ethyl-N-cyclohexyl-4-chlorobutyramide, boiling point 120 - 130 ° C / 1.5 mm Hg.

N-Ethyl-N-cyclohexyl-3-chloropropionamide, bp 103 - 110 ° C / 0.15 mm Hg.

Reference Example 5.

To 6 g of monomethyl adipate are added 10 ml of thionyl chloride and the mixture is heated under reflux for 1 hour. Excess thionyl chloride is evaporated and the residue is added benzene and thionyl chloride is further evaporated by azeotropic distillation.

10 g of aniline and 5.2 g of potassium carbonate are dissolved separately in 100 ml of acetone and 15 ml of water. To the mixture is added dropwise while stirring under ice-cooling the chloride compound obtained above. The mixture is stirred under ice-cooling for 1 hour and further at room temperature for 2 hours. After evaporation of acetone, water is added to the residue and the mixture is extracted with chloroform. The chloroform phase is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform of steam gives 9 g of thylpheny ladip inamate.

NMR Spectrum (CDCl3): δ (ppm) = 1.40 - 1.90 (4H, m), 2.10 - 2.50 (4H, m), 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 are prepared.

Methyl N-cyclohexyl adipinamate, slightly brown prisms (recrystallized from methanol-water), m.p. 72-74 ° C.

25 Methyl N-methyladipinamate, colorless liquid, boiling point 136 - 140 ° C / 0.7 mm H g.

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44

Reference Example 8.

Dissolve 46.5 ml of 40% aqueous methylamine solution in 300 ml of acetone.

To the solution, 45.6 g of potassium carbonate and 100 ml of water are added and 24.3 ml of chloroacetyl chloride are added dropwise with stirring under ice-cooling. The mixture is stirred under ice-cooling for 1 hour and further at room temperature for 2 hours. After evaporation of acetone, water is added to the residue and the mixture is extracted with chloroform. The chlorophyll worm is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of chloroform, the residue is distilled off under reduced pressure to give 15.5 g of N-methyl-chloroacetamide in the form of a colorless liquid, boiling point 107 - 109 ° C / 27 mm Hg.

Reference Example 9.

10.8 g of N-methyl-chloroacetamide are dissolved in 100 ml of benzene and 10.8 g of phosphorus pentachloride is added with stirring at a temperature below 15 ° C. The mixture is stirred at room temperature for 1 hour and then allowed to stand overnight. The mixture is slowly heated to reflux for 2 hours. The reaction mixture is evaporated, ice water is added and the mixture is extracted with chloroform. The chloroform phase 20 is washed with water, a dilute aqueous sodium hydroxide solution and water, dried over magnesium sulfate and distilled to remove chloroform. The resulting residue is subjected to column chromatography ("Wakogel" C-200, manufactured by Wako Pure 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.

Dissolve 2 g of 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid in 30 ml of dry tetrahydrofuran and add 1.1 g of triethylamine. To the mixture is added dropwise with stirring under ice-cooling 1.5 g of isobutane.

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45 tyl chloroformate. The mixture is stirred at room temperature for 30 minutes.

To the mixture is added dropwise with stirring 0.9 g of diethylamine at room temperature and the mixture is stirred for 2 hours. The mixture is evaporated under reduced pressure and the resulting residue is purified by subjecting the column chromatography ("Kieselgel" 60, manufactured by Merck & Co.). Eluting with n-hexane-ethyl acetate (1: 1) gives 1.4 g of N, N-diethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide in the form of a colorless liquid, n - 1.5227.

NMR Spectrum (CDCl3): δ (ppm) = 1.04 (3H, t, J - 7Hz), 1.12 (3H, t, J 10 7Hz), 1.90 - 2.70 (4H, m ), 3.00 - 3.60 (6H, m), 3.88 (3H, s).

Analysis:

Calculated for C C ^H ^^ OS OS: C 46.67 H 7.44 N 27.21

Found: C 46.78 H 7.51 N 27.29

Examples 2-5.

In the same manner as described in Example I, the following compounds are prepared from corresponding starting materials.

2) N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n 'p = 1.5327.

NMR Spectrum (CDCl3): δ (PP®) δ 90 ° 1 · 40 (3H> m) * 1 δ 20 * 2> 00 20 (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) thiobutyramide, 26 pale yellow liquid, nj - 1.5534.

NMR Spectrum (CDCl 3): δ (ppm) = 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).

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46 4) 5- (3-Morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), mp 71-73 ° C.

5) 5- (3- (4-Acetylpiperazinocarbonyl) propylthio) -1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone, m.p. 90 - 91.5 ° C.

Example 6

Dissolve 45 millimoles of 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid in 50 ml of tetrahydrofuran and add 50 millimoles of DBU. To the mixture is added dropwise with stirring 50 millimoles of isobutyl chloroformate under ice cooling and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 54'millimol of 2- (3,4-dimethoxyphenyl) ethylamine and the mixture is further stirred at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the resulting residue is extracted with chloroform.

The chloroforph ash is washed with 5% aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporation of chloroform, the residue is subjected to column chromatography ("Wakogel" 20 C-200, chloroform eluent) to isolate N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2 (3,4-tetrazol-5-yl) thiobutyramide (41% of theory), which is recrystallized from hexane-chloroform to give colorless flakes, mp 70.5 - 71.5 ° C.

Calcd. For CH gH₂NN50O3 ^: C, 52.59; H, 6.34; N, 19.16

Found: C, 52.51; H, 6.16; N, 19.10.

Examples 7-55.

In the same way as described in Example 6, the following compounds are prepared from corresponding starting materials.

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47) N - Hexyl -4- (1-methyl -1,2,3,4-tetrazol-5-yl) thlobutyramide, colorless flakes (recrystallized from hexane ether), mp 41-42 ° C, 8) N- cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, mp 116.5 - 117.5 ° C (recrystallized from hexane-ethyl acetate), 9) N -cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5323, 10) N-cyclododecanyl-4- (1-methyl -1,2,3,4-tetrazol-yl) thiobutyramide, colorless needles, mp 119-120 ° C (recrystallized from hexane-ethyl acetate), 11) N-Butyl-4- (1-methyl-1,2 , 3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n + p = 1.5198, 12) N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4- tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5350, 13) N-ethyl-N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-yl) thiobutyramide, 19 colorless liquid, np - 1.5596, 14) N-butyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid , np = 1.5222, 15) N, N-dibuty 1- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 19 colorless liquid, np = 1.5049, 16) N, N-dibenzyl-4- (1-methyl) -1,2,3,4-tetrazol-5-yl) thiobutyramide, 19 colorless liquid, np - 1.5773, 17) N, N-diisopropyl-4- (1-methyl-1,2,3,4- tetrazol-5-yl) thiobutyramide, colorless liquid, n 'p - 1,511,18) N, N-dicyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, melting point 91 - 92 ° C (recrystallized from hexane), 19) N-benzyl-N-tert-butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) ) thiobutyramide, colorless needles, mp 86.5 - 87.5 ° C (recrystallized from hexane), 20) N-cyclohexyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1- methyl 1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n-p - 1.5470, 21) N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2, 3,4-tetrazol-5-yl) - 16 thiobutyramide, colorless liquid, np - 1.5706, 22) N -benzyl - N- (2- (3,4-dime thoxyphenyl) ethyl) -4- (1) -methyl-1,2,3,4-16 tetrazol-5-yl) thiobutyramide, colorless liquid, np - 1.5659, 23) N- (2- (3,4-dimethoxyphenyl) ethyl) -N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n 'p - 1,5372, 48

DK 162 O 47 B

24) N, N-dihexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, * = 1.5011, 25) N-ethyl-N- (2) - (3,4-Dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4- 14 tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5451, 5 (26) N-tert butyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless plates, mp 71-73 ° C (recrystallized from hexane-ethyl acetate),.

27) N-Ethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid = 1.5319, 28) N-benzyl-4- (1-methyl) -1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 65-66 ° C (recrystallized from hexane-ethyl acetate), 29) N-hexyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n + p = 1.5182, 30) N-cyclohexyl-N- (2-hydroxyethyl) -4- ( 1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n = 1.5372, 31) N-phenyl-4- (1-methyl-1,2,3, 4-tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 106 - 107 ° C (recrystallized from hexane-ethyl acetate), 32 (N) (2-pyridyl) -4- (1-methyl-1, 2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 95-96 ° C (recrystallized from hexane-ethyl acetate), 33) N- (3-pyridyl) -4- (1-methyl-1,2 , 3,4-Tetrazol-5-yl) thiobutyramide, colorless plates, m.p. 110.5 - 113 ° C (recrystallized from ethyl acetate), 34) N-furfuryl-4- (1-methyl-1,2,3 , 4-tetrazol-5-yl) thiobutyr amide, colorless flakes, mp 71-73 ° C (recrystallized from hexane-ethyl acetate), 35) N- (4-aminosulfonylphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) Thiobutyramide, colorless needles, melting point 169.5 - 170.5 ° C (recrystallized from methanol), 36) N- (4 - (N, N-dimethylamino) phenyl) -4- (1-methyl-1) , 2,3,4-tetrazol-5-yl) thiobutyramide, colorless prisms, m.p. 144 - 147 ° C (recrystallized from hexane-ethyl acetate), 37) N- (2-methyl-3-chlorophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) - thiobutyramide, colorless needles, mp 104.5 - 105.5 ° C (recrystallized from hexane-ethyl acetate),

DK 162047 B

49 38) N- (4-nitrophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, mp 194 - 195 ° C (recrystallized from ethyl acetate), 39) N- (2-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrimide, colorless needles, mp 79.5 - 82 ° C, (recrystallized of hexane-ethyl acetate), 40) N-ethyl-N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n.p. (1,5623, 41) N-Ethyl-N- (3-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, up * 1,5618, 42) N-Ethyl-N-cyclopentyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-9-butyramide, colorless liquid, np - 1.5384, 43) N-Ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid, n-p - 1.5293, 44) N- isopropyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n * p = 1.5238, 45) N-ethyl-N- (4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-9 yl) thiobutyramide, colorless liquid, np - 1.5363, 46) N-Ethyl-N- (2-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 132 - 133 ° C, (recrystallized (hexane-ethyl acetate), 47) N-Ethyl-N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n 1.5218, 48) N, N-dipropyl -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5151, 49) N-butyl -N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5509, 50) N-methyl-N-cyclohexyl-4 (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, pale yellow liquid, NMR Spectrum (CCl4): δ (ppm) = 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), 51) N, N-dimethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 16 colorless liquid, np = 1 (5327, 52) N-Ethyl-N-cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np - 1.5309, 53 ) 5- (3- (4-thym lp iperaz inocarbony 1) propylthio) -1-methyl -1,2,3,4-te-trazole, colorless flakes, mp 65 - 68 ° C (recrystallized from hexane-ethyl acetate), 54) 5 - (3-piperidinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, colorless liquid, nj = 1.5310, 55) N-ethyl-N-cycloheptyl-4- (1-methyl-1 , 2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, nj = 1.5290.

Example 56

45 millimoles of 4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid are dissolved in 50 ml of tetrahydrofuran and 50 millimoles of DBU are added. To the mixture is added dropwise with stirring under ice cooling 50 millimoles of isobutyl chloroformate. The mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 54 millimoles of N-ethylcyclohexylamine and the mixture is stirred at room temperature for an additional 2 hours. After evaporation of the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform phase is washed with 5Z aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Chloroform is evaporated and the resulting residue is subjected to column chromatography ("Wakogel" C-200, eluent solvent 20 chloroform) to isolate N-ethyl-N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazole-5 -yl) thiobutyramide (yield 43% of theory) in 18 form of a colorless liquid, nj) = 1.5590.

Analysis:

Calculated for: C, 61.10; H, 7.29; N, 18.75. Found: C, 61.28; H, 7.38; N, 18.86.

Example 57.

In the same manner as described in Example 56 except that N, N-diethylamine is used in place of N-ethyl-N-cyclohexylamine, N, N-diethyl-4- (1-phenyl-1,2,3,3) is prepared. (4-Tetrazol-5-yl) thiobutyramide, in the form 18 30 of a fair-anhydrous liquid, np = 1.5592.

Example 58

DK 162047 B

Dissolve 45 millimoles of 2- (1-methyl-1,2,3,4-tetrazol-5-yl) thioacetic acid in 50 ml of tetrahydrofuran and add 50 millimoles of DBU. To the mixture is added dropwise with ice cooling 50 millimoles of 5 isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise under ice-cooling N-ethyl-cyclohexylamine and the mixture is further stirred at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform phase is washed with 10 5% aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is evaporated, the residue is subjected to column chromatography ("Wakogel" C-200, eluent benzene: chloroform -4: 1, v / v) to isolate N-ethyl-N-cyclohexyl-2- (1-methyl-1,2 , 3,4-15 tetrazol-5-yl) thioacetamide (yield 52% of theory), which is recrystallized from ether-petroleum ether to give white prisms, mp 69-71 ° C.

Analysis:

Calcd for C12 H21 N5OS: C 50.86 H 7.47 N 24.71 Found: C 50.75 H 7.55 N 24.78.

Examples 59 and 60.

In the same manner as described in Example 58, the following compounds are prepared using similar starting materials.

59) N-Ethyl-N-cyclohexyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropionamide, pale yellow liquid, np = 1.5273, 60) N- ethyl N-cyclohexyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) thiovaleramide, pale yellow liquid, np = 1.5227.

Example 61.

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52 45 millimoles of 4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid are dissolved in 50 ml of tetrahydrofuran and 50 millimoles of DBU are added. To the mixture is added dropwise with ice-cooling isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes.

To the mixture is added dropwise 54 millimoles of N-ethylcyclohexylamine and the mixture is further stirred at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform phase is washed with 5% aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is evaporated and the resulting residue is subjected to column chromatography ("Wakogel" C-200, eluting solvent benzene: chloroform-4: 1, v / v) to isolate N-ethyl-N-cyclohexyl-4- (1-cyclohexyl) -1,2,3,4-tetrazol-5-yl) thiobutyramide (yield 47% of the 18 theory) in the form of a colorless liquid, np = 1.5290.

Analysis:

Calc'd for ^HH33N5OS: C 60.12 H 8.76 N 18.45

Found: C 59.95 H 8.62 N 18.55.

Example 62.

To 50 ml of methylene chloride is added 45 millimoles of 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid and 50 millimoles of N-methylmorpholine. To the mixture is added dropwise with stirring 50 ml of methyl chloroformate, keeping the internal temperature with ice cooling at 10-20 ° C and then stirring the mixture at room temperature for 30 minutes. To the mixture is added 54 millimoles of 2-methoxycyclohexylamine and the mixture is stirred at such temperature for 4 hours. After the reaction, water is added to the reaction mixture. The organic phase is separated and washed with dilute aqueous sodium hydroxide solution, dilute hydrochloric acid and water in the order mentioned and dried over sodium sulfate. Inorganic materials are filtered off and the mother liquor is evaporated. The resulting residue is subjected to column chromatography ("Wakogel" C-200, eluent solvent benzene: chloroform-4: 1, v / v) to isolate N- (4-methoxyphenol).

DK 162047 B

53 cyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide (yield 43% of theory) as a colorless liquid, 11 n 5 = 1.5263.

For C 52.50 H 7.79 N 23.55

Found: C, 52.56; H, 7.71; N, 23.63.

Example 63

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

Analysis:

Calcd for C 13 H 23 N 5 OS: C 52.50 H 7.79 N 23.55 Found: C 52.31 H 7.65 N 23.80.

Example 64

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

DK 162047B

54

To the mixture is added dropwise 54 millimoles of 4- (N, N-dimethylamino) cyclohexylamine and the mixture is further stirred at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform phase 5 is washed with 5% aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. Chloroform of vapor and the resulting residue are subjected to silica gel column chromatography ("Wako gel" C-200, eluent solvent 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% of theory).

Analysis:

Calculated for C 14 H 26 N 6 O 5: C, 51.51; H, 8.03; N, 25.74

Found: C, 51.60; H, 8.22; N, 26.05.

Example 65

45 millimoles of 4- (1- (2-methoxycyclohexyl) -1,2,3,4-tetrazol-5-yl) thiobutyric acid are dissolved in 50 ml of tetrahydrofuran and 50 millimoles of DBU are added. To the mixture is added dropwise under ice-cooling 50 millimoles of isobutyl chloroformate, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 54 millimoles of N-ethylcyclohexylamine and the mixture is further stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the residue is extracted with chloroform. The chloroform phase is washed with 5% aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After evaporation of chloroform the column chromatography of the resulting residue ("Wakogel" C-200, eluting solvent benzene: chloroform - 4: 1, v / v) is subjected to isolation of N-ethyl-N-cyclohexyl-4- (1- (2-methoxycyclohexyl) -1,2,3,4-tetrazol-5-yl) thiobutyramide (yield 45% of theory).

Analysis:

Calculated for C₂2H35NN5O₂S: C, 58.65; H, 8.61; N, 17.10

Found: C, 58.25; H, 8.34; N, 17.20.

Example 66.

DK 162047 B

Dissolve 45 millimoles of 4- (1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl) thiobutyric acid in 50 ml of tetrahydrofuran and add 50 millimoles of DBU.

To the mixture is added dropwise with ice-cooling 50 5 millimoles of isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 54 millimoles of N-ethylcyclohexylamine and the mixture is further stirred at room temperature for 2 hours. The solvent is evaporated under reduced pressure and the resulting residue is extracted with chloroform. The chloroform phase 10 is washed with 5% aqueous hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. Chloroform is evaporated and the resulting residue is subjected to column chromatography ("Wakogel" C-200, eluent solvent benzene: chloroform-4: 1, v / v) to isolate N-ethyl-N-cyclohexyl-4- (1- (4- ethylphenyl) -1,2,3,4-tetrazol-5-yl) thiobutyramide (yield 43% of theory) in the form of a 19 colorless liquid, nj - 1.5533.

Analysis:

Calcd. For 22 ^3 ^5 ^: C 62.81 H 7.78 N 17.44 Found: C 63.05 H 7.84 N 17.81.

Example 67

Dissolve 2.5 g of 5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeric acid in 50 ml of dimethylformamide and add 1.1 g of triethylamine. To the mixture is added dropwise with ice-cooling 1.5 g of isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring at room temperature 0.9 g of diethylamine and the mixture is stirred for 2 hours. After evaporation of dimethylformamide under reduced pressure, acetone is added to the resulting residue and the insoluble materials are filtered off. The mother liquor 30 is evaporated and then purified by column chromatography ("Kieselgel" 60, manufactured by Merck & Co.). Elution with chloroform gives 1.2 g

DK 162047 B

56 N, N-diethyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide in the form of a colorless liquid, n q = 1.5303,

Analysis:

Calcd. For C 213.5 ° C 56.40 H 6.63 N 21.92 Found: C 56.69 H 6.80 N 21.71.

Example 68.

Dissolve 2.5 g of 5- (1-cyclohexy1-1,2,3,4-tetrazol-5-yl) valeric acid in 50 ml of tetrahydrofuran and add 1.1 g of triethylamine. To the mixture is added dropwise with stirring and ice-cooling 1.5 g of isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring at room temperature 1.5 g of N-ethylcyclohexylamine and the mixture is further stirred for 2 hours. After evaporation of tetrahydrofuran, water is added to the residue and the mixture is extracted with chloroform. The chloroform phase 15 is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Chloroform of vapor and the resulting residue are subjected to column chromatography ("Kieselgel" 60, manufactured by Merck & Co., elution solvent chloroform) to isolate 2.6 g of N-ethyl-N-cyclohexyl-5- (1-cyclohexyl-1, 2,3,4-tetrazol-5-yl) valeramide in the form of a colorless liquid, nil = 1.4970.

Analysis:

Calculated for C₂2H35NN5O: C, 66.44; H, 9.76; N, 19.37

Found: C 66.78 H 9.56 N 19.52.

Example 69

Dissolve 1.8 g of 5- (1-methyl-1,2,3,4-tetrazol-5-yl) valeric acid in 50 ml of dimethylformamide and add 1.1 g of triethylamine. To the mixture is added dropwise with stirring and under ice-cooling 1.5 g of isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes.

To the mixture is added dropwise with stirring at room temperature 0.9 g of diethylamine and the mixture is stirred for 2 hours. Dimethylformamide

DK 162047 B

57 is evaporated under reduced pressure and the residue is purified by column chromatography ("Wakogel" C-200). After eluting with benzene chloroform (1: 1), the eluate is distilled under reduced pressure to give 0.7 g of N, N-di-ethyl-5- (1-methyl-1,2,3,4-tetrazole-5). yl) valeramide in the form of a colorless liquid, boiling point 190 - 200 ° C (bath temperature) / 0.07 mm Hg, n2jj - 1.4907.

Analysis:

Calculated for C C ^^ j ^ jO: C 55.20 H 8.85 N 29.27

Found: C, 55.48; H, 8.98; N, 29.43.

Examples 70 - 74.

In the same manner as described in Example 69, the following compounds are prepared using similar starting materials.

70) N, N-Diethyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, nq - 1.4970, 71) N, N-diethyl 5- (1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, η2β - 1.4867, 72) N-ethyl-N-cyclohexy 1-5 - (1-methyl-1,2,2, 3,4-tetrazol-5-yl) valeramide, 18 colorless liquid, N₂j = 1.50585, 73) N-ethyl-N-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazole -5-yl) valer-amide, white crystalline powder, m.p. 92 - 95 ° C (recrystallized from ether), 74) N-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3, 4-tetrazol-5-yl) valeramide, white prisms, m.p. 73-75 ° C (recrystallized from ether).

Example 75

Dissolve 2 g of 3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthiopropionic acid in 50 ml of tetrahydrofuran and add 1.1 g of triethylamine. To the mixture is added dropwise with stirring and under ice-cooling 1.5 g of isobutyl chloroformate and the mixture is stirred at room temperature for 30 minutes. To the mixture, 0.9 g of diethylamine is added dropwise with stirring at the same temperature and the mixture is further stirred for 3 hours.

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58

After evaporation of the solvent, the resulting residual column chromatography ("Kieselgel" 60, manufactured by Merck &

Co., eluent solvent chloroformmethanol - 50: 1, v / v) to isolate 1.5 g of N, N-diethyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) - Of methylthio-propionamide, in the form of a colorless liquid, np = 1.5200.

Analysis:

Calculated for C c øHigNNO:: C, 46.67; H, 7.44; N, 27.21

Found: C, 46.85; H, 7.61; N, 27.39.

Examples 76-78.

In the same manner as described in Example 77, the following compounds are prepared using similar starting materials.

76) N, N - Diethyl 3- (1-ethyl -1,2,3,4-te trazol-5-yl) methylthio-propionamide, colorless needles, mp 58-59 ° C (recrystallized from ether) 77) N, N-Diethyl-3- (1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl) methylthio-propionamide, colorless liquid, n D = 1, 5499, 78) N-ethyl-N-cyclohexyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide, pale yellow liquid, np = 1.5277.

Example 79

20 ml of thionyl chloride are added to 2 g of 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid and the mixture is heated under reflux for 1 hour. After evaporation of excess thionyl chloride under reduced pressure, dry benzene is added to the residue and the remaining small amount of thionyl chloride is removed as the benzene azeotrope. The residue is dissolved in 50 ml of dry benzene and 2.8 g of N-methylcyclohexylamine are added dropwise with stirring and under ice-cooling. The mixture is stirred at room temperature for 1 hour and to the reaction mixture is added benzene. The mixture is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution 30 and dried over sodium sulfate. After evaporation of the benzene,

DK 162047 B

The column residue was chromatographed ("Wakogel" C-200) by eluting the column with benzene chloroform (4: 1, v / v) to give 2.3 g of N-methyl-N-cyclohexy 1-4- (1- methyl 1,2,3,4-tetrazol-5-yl) thiobutyramide in the form of a pale yellow liquid.

NMR Spectrum (CCl4): δ (ppm) = 1.00 - 2.00 (10H, broad), 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).

Analysis:

Calculated for G 13 H 23 N 5 OS: C 52.50 H 7.79 N 23.55 Found: C 52.69 H 7.83 N 23.51.

Examples 80 - 97.

By the same method as described in Example 81, the following compounds are prepared: 80) N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid N = ethyl-N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, pale yellow liquid, n (5-3-morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, white needles, mp 71-73 ° C (recrystallized from petroleum ether-ethanol) 83) 5- (3- (4-acetylpiperazinocarbonyl) propylthio) -1-methyl-1,2,3,4-tetrazole, white crystalline powder, mp 90 - 91.5 ° C (recrystallized from ligroin-acetone) 84) N- (2 - (3,4-dimethoxyphenylethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, m.p. 70.5 - 71.5 ° G (if crystallized by hexane-ethyl acetate (85) N- (2-hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n N-ethyl-N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 19 colorless liquid, np = 1.5596 87) N-cyclohexyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-16,1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, rip = 1.5470

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60 88) N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) - 16 thiobutyramide, colorless liquid, nq = 1,570,689) N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, mp 95-96 ° C (recrystallized from hexane-ethyl acetate) 90 N-furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, mp 71-73 ° C (recrystallized from hexane-ethyl acetate) 91) N- (4) - (N, N-dimethylamino) phenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-10 yl) thiobutyramide, colorless prisms, m.p. 144 - 147 ° C (recrystallized from hexane-ethyl acetate 92) N- (2-methyl-3-chlorophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless needles, mp 104.5 - 105.5 ° C (recrystallized from hexane-ethyl acetate) 93) N-Ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid, n N-ethyl-N- (4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, njj = 1 . 5363 95) N-Ethyl-N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n ) 5- (3-piperidinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, colorless liquid, np = 1.53 97) N-ethyl-N-cyclohexyl-4- (1-phenyl-1 , 2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5590, Example 98.

10 ml of thionyl chloride is added to 1.8 g of 5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeric acid, and the mixture is heated under reflux for 1 hour. After evaporation of excess thionyl chloride under reduced pressure, dry benzene is added to the residue and the remaining small amount of thionyl chloride removed as benzene azeotrope. The resulting residue is dissolved in 50 ml of dry pyridine and 1.5 g of Ν, Ν-diethylamine added dropwise with stirring and under ice-cooling. The mixture is stirred at room temperature for 1 hour and to the reaction mixture is added benzene. The mixture is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution.

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61 and dried over sodium sulfate. After evaporation of the benzene, the residue is subjected to column chromatography ("Kieselgel" 60, manufactured by Merck) by eluting the column with chloroform to give 2.1 g of N, N-diethyl-5- (1-phenyl-1,2,3,4 -tetrazol-5-yl) valeramide in the form of a colorless velor liquid, np = 1.5303.

Analysis:

Calculated for C 63.76 H 7.69 N 23.24

Found: C, 63.88; H, 7.79; N, 23.31.

Examples 99 - 101.

By the same procedure as described in Example 98, the following compounds are prepared: 99) N-Ethyl-N-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide, white crystalline powder, m.p. 92 - 95 ° C (recrystallized from ether) 100) N-ethyl-N-cyclohexyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n J = 1.5085101) N-Ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, white prisms, m.p. 75 ° C (recrystallized from ether).

Example 102.

2 g of 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid and 1.4 g of N-ethyl-N-cyclohexylamine are added to a mixed solvent of 20 ml of dioxane and 20 ml. and a solution of 2.1 g of N, N'-dicyclohexylcarbodiimide in 5 ml of methylene chloride kept at a temperature of 10-20 ° C, with stirring and under external cooling with ice, is added dropwise with stirring. . After adding the solution, stirring is continued at the same temperature for 5 hours. Crystals separated from the reaction mixture are filtered off and the filtrate is evaporated under reduced pressure. The resulting residue is dissolved in 100 ml of methylene chloride. The organic phase is washed with 5% aqueous hydrochloric acid,

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62 5% aqueous sodium bicarbonate solution and water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the resulting residue is subjected to column chromatography ("Wakogel" C-200) by eluting the column with chloroform to give 0.8 g of N-ethyl-N-5 cyclohexyl-4- (1-methyl). 1,2,3,4-Tetrazol-5-yl) thiobutyramide in the form of a colorless liquid, n + p = 1.5327.

Analysis:

Calculated for C 14 H 25 N 5 O: C, 53.99; H, 8.09; N, 22.49

Found: C, 54.12; H, 8.14; N, 22.56.

Examples 103 - 112.

By the same procedure as described in Example 105, the following compounds are prepared: 103) N-ethyl-N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, pale yellow liquid , np - 1.5534 (104) 5- (3-morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, white needles, mp 71-73 ° C (recrystallized from petroleum ether-ethanol) 105 ) N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, m.p. 70.5 - 71 5 ° C (recrystallized from hexane-ethyl acetate) 106) N-ethyl-N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5596 107) N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid, n N = furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide,

colorless flakes, melting point 71 - 73 ° C

109) N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid, n N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np - 1.5590 111) N-ethyl-N-cyclohexy-5 - (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) -valeramide, white crystalline powder, m.p. 92 - 95 ° C (recrystallized from ether)

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63 112) N-Ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, white prisms, m.p. 73-75 ° C (recrystallized from ether) .

Example 113.

Dissolve 3.2 g of p-nitrophenyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrate in 40 ml of dimethylformamide and add 2.0 g of cyclohexylamine. The reaction mixture is left at room temperature overnight and then evaporated under reduced pressure. The resulting residue is subjected to column chromatography ("Wakogel" C-200) by eluting the column with benzene chloroform (4: 1, v / v) and recrystallized from hexane-ethyl acetate to give 1.8 g of N-cyclohexyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide in the form of colorless needles, mp 116.5 - 117.5 ° C.

Calcd for C 50.86 H 7.47 N 24.71

Found: C, 50.85; H, 7.37; N, 24.65.

Examples 114 - 120.

By the same procedure as described in Example 113, the following compounds are prepared.

114) N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n -ethyl-N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, pale yellow liquid, nq - 1.5534 116) N- (2- (3) (4-Dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, mp 70.5 - 71.5 ° C (recrystallized from hexane ethyl acetate) 117) N-Furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, mp 71-73 ° C (recrystallized from hexane-ethyl acetate)

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64 118) N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid = 1.5293 119) N - ethyl - N - cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, white prisms, mp 73-75 ° C (recrystallized from 5 ether) 120) N-ethyl-N -cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) -valeramide, white crystalline powder, mp 92 - 95 ° C (recrystallized from ether).

Example 121.

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-ethylcyclohexylamine are added to 50 ml of ethanol and the mixture is reacted with an autoclave at 140 - 150 ° C under 110 atmospheric pressure for 6 hours. After cooling, the reaction mixture is evaporated under reduced pressure and the resulting residue is dissolved in 200 ml of chloroform. The solution is washed with 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water and dried over sodium sulfate. After evaporation of the solvent, the column residue of the resulting residue ("Wakogel" C-200) is subjected to elution of the column with chloroform to give 0.6 g of N-ethyl-N-cyclohexyl-4- (1-20 methyl-1.2). 3,4-tetrazol-5-yl) thiobutyramide in the form of a colorless liquid, n

Analysis:

Calcd. For C 14 H 25 N 5 S: c 53.99 H 8.09 N 22.49

Found: C, 54.19; H, 8.21; N, 22.68.

Examples 122 - 124.

Using the same procedure as described in Example 121, the following compounds are prepared: 122) N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazole-5) yl) thiobutyramide, colorless flakes, melting point 70.5 - 71.5 ° C (crystallized from hexane-ethyl acetate)

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65 123) N-Phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, mp 106 - 107 ° C (recrystallized from hexane-ethyl acetate) 124) N-Ethyl-N-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) -5-valeramide, white crystalline powder, m.p. 92 - 95 ° C (recrystallized from ether).

Example 125.

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

Analysis:

Calcd for C12 H21 N5OS: C 50.86 H 7.47 N 24.71 Found: C 50.78 H 7.57 N 24.75.

Example 126.

Dissolve 6.6 g of N-methyl-N-cyclohexyl-4-chlorobutyramide in 50 ml of dry benzene and add 3.6 g of 1-methyl-5-mercapto-1,2,3,4-tetrazole, 4.5 g of potassium carbonate and 0.2 g of sodium iodide. The mixture is heated under reflux for 5 hours and diluted with benzene. The reaction mixture is washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After evaporation of benzene, the column of the resulting residue is subjected to column chromatography ("Wakogel" C-200) by eluting the column with benzene chloroform (4: 1, v / v) to give 5 g of N-methyl-N-cyclohexyl. 4- (L-

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66 methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, in the form of a pale yellow liquid.

NMR Spectrum (GCI 4): δ (ppm) - 1.00 - 2.00 (10H, broad), 1.80 - 2.70 (4H, m), 2.73 '(3H, d, J - 6Hz) ), 3.28 (2H, t, J = 6Hz), 3.85 (3H, s), 5.20 - 4.50 (1H, m).

Analysis:

Calcd for C 21 H 23 N 5 OS: C 52.50 H 7.79 N 23.55

Found: C, 52.72; H, 7.85; N, 23.61.

Example 127.

1.6 g of i-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-morpholinocarbonylpropyl chloride are added to 30 ml of ethanol and the mixture Stir at 70 - 80 ° C for 4+ hours. After completion of the reaction, the reaction mixture is poured into saturated aqueous sodium chloride solution and the precipitated crystals are isolated by filtration and washed with water. The crude crystals thus obtained are recrystallized from ether-petroleum ether to give 2.2 g of 5- (3-morpholino-carbonylpropylthio) -1-methyl-1,2,3,4-tetrazole in the form of white needles, mp 71-73 ° C .

Calcd. For C1 () h1702S: C 44.27 H 6.37 N 25.81

Found: C 44.10 H 6.30 N 25.59.

Example 128.

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 are added to 25 ml. ethanol, and the mixture is heated at reflux and with stirring for 6 hours. After completion of the reaction, the reaction mixture is poured into saturated aqueous sodium chloride solution. The precipitated crystals are isolated by filtration and washed with water. The crude crystals thus obtained are recrystallized from hexane-ethyl acetate, thereby

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67 are obtained 2.1 g of N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyridamide in the form of colorless needles, m.p. 116.5 - 117.5 ° C .

Analysis:

Calcd for C12 H21 N5OS: C 50.86 H 7.47 N 24.71 Found: C 50.87 H 7.35 N 24.63

Examples 129 - 182.

Following the same procedure as described in Examples 128-131, the following compounds are prepared: 129) N, N-Diethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless wash, n N-ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n * 7 N-ethyl-N-phenyl -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, pale yellow liquid, ng = 1.5534 (132) - (3- (4-acetylpiperazinocarbonyl) propylthio) -1-methyl-1,2,3,4-tetrazole, white crystalline powder, m.p. 90-191.5 ° C (recrystallized from ligroin-acetone) 133) N- ( 2- (3,4-Dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, m.p. 70.5 - 71.5 ° C (about 20 crystallized from hexane-ethyl acetate) 134) N-Hexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, mp 41-42 ° C (recrystallized from hexane N-Cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless = 1.5323 (136) N-cyclododecanyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 119-120 ° C ( recrystallized from hexane-ethyl acetate) 137) N-Butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, - hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrimide, colorless liquid, n (1) = 1.5350 139) N-ethyl-N- benzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide 19, colorless liquid, np - 1.5596

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68 140) N-Butyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5222 141) N, N -dibuty 1 -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 19 colorless liquid, ri jj = 1.5049 5 142) N, N-diberizyl-4- (1 -methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 19 colorless liquid, np = 1.5773 143) N, N- diisopropyl - 4- (1-methyl -1,2,3,4 - tetrazol-5-yl) thiobutyramide, colorless liquid, n (1) = 1.5111 144) N, N-dicyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid -10 µm, colorless needles, melting point 91 - 92 ° C (recrystallized from hexane) 145) N-benzyl-N-tert-butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) ) thiobutyramide, colorless needles, mp 86.5 - 87.5 ° C (recrystallized from hexane) 146) N-cyclohexyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1, 2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n 1 = 1.5470 147) N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2, 3,4-Tetrazol-5-yl) -thiobutyramide, colorless liquid, n * p - 1.5706 148) N-benzyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n p = 1,5659 149) N, N-dihexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n ethyl N- (2- (3,4-dimethoxyphenyl) ethyl) -4- (1-methyl-1,2,3,4-14 tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5451 151) N-tert, butyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless flakes, mp 71-73 ° C (recrystallized from hexane-ethyl acetate) 152) N -ethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n + j = 1.5319 153) N-benzyl-4- (1-methyl-4-yl) 1,2,3,4-Tetrazol-5-yl) thiobutyramide, colorless needles, m.p. 65-66 ° C (recrystallized from hexane-ethyl acetate) 154) N-hexyl-N-cyclohexyl-4- (1- methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5182 155) N-Cyclohexyl-N- (2-hydroxyethyl) -4- (1-methyl) 1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n 'd = 1.5372 156) N-phe Nyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, color

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69 loose needles, melting point 106 - 107 ° C (recrystallized from hexane-ethyl acetate) 157) N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, melting point 95 - 96 ° C (recrystallized from hexane-ethyl acetate) 158) N- (3-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless plates, m.p. 110.5 - 113 ° C (recrystallized from ethyl acetate) 159) N- (2-pyrimidyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide , 10 colorless granules, m.p. 108-110 ° C (recrystallized from hexane-ethyl acetate) 160) N - fur fury 1-4 - (1- methylthel 1,2,3,4 - te trazol-5-yl) thiobutyramide, colorless flakes, m.p. 71-73 ° C (recrystallized from hexane-ethyl acetate) 161) N- (4-aminosulfonylphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) - thiobutyramide, colorless needles, melting point 169.5 - 170.5 ° C (recrystallized from methanol) 162) N- (4- (N, N-dimethylamino) phenyl) -4- (1-methyl-1,2,3 4-Tetrazol-5-yl) thiobutyramide, colorless prisms, m.p. 147 ° C (recrystallized from hexane-ethyl acetate) 163) N- (2-methyl-3-chlorophenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide , colorless needles, m.p. 104.5 - 105.5 ° C (recrystallized from hexane-ethyl acetate) 164) N- (4-nitrophenyl) -4- (1-methyl-1,2,3,4-tetrazole-5 yl) thiobutyrimide, colorless needles, mp 194 - 195 ° C (recrystallized from ethyl acetate) 165) N- (2-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazole-5 yl) thiobutyramide, colorless needles, mp 79.5 - 82 ° C (recrystallized from hexane-ethyl acetate) 166) N-ethyl-N- (2-pyridyl) -4- (1-methyl-1,2,3,4- tetrazol-5-yl) thio-16-butyramide, colorless liquid, nq = 1.5623 167) N-Ethyl-N- (3-pyridyl) -4- (1-methyl-1,2,3,4-tetrazole) 5-yl) thio-16-butyramide, colorless liquid, np = 1.5618 168) N-ethyl-N-cyclopentyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) 9 butyramide, colorless liquid, np = 1.5384 169) N-Ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) - 11 thiobutyramide, colorless liquid, np = 1.5293

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70 170) N-isopropyl-N-cyclohexy-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n + p = 1.5238 (171) N- ethyl N- (4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5363 (172) N-ethyl-N - (2-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless needles, mp 132 - 133 ° C (recrystallized from hexane-ethyl acetate) 173) ethyl N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1.5218 174) N 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np = 1,515,175) N-butyl-N-phenyl-4- (1-methyl-1, 2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, n-p - 1,5509,176) N, N-dimethyl-4- (1-methyl-1,2,3,4-tetrazole -5-yl) thiobutyramide, colorless liquid, np = 1,5327 177) N-Ethyl-N-cyclooctyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide , colorless liquid, n = p = 1.5309 178) 5- (3- (4-methylpiperazinocarbonyl) propylthio) -1-methyl-1 , 2,3,4-tetrazole, colorless granules, m.p. 65-68 ° G (recrystallized from hexane-ethyl acetate) 179) 5- (3-piperidinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, 25 colorless liquid, np = 1.5310 180) N-ethyl-N-cyclohexyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropionamide, pale yellow liquid, np = 1.5273 (181) N-Ethyl-N-cyclohexyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) thiovaleramide, pale yellow liquid, np = 1,5227,182 ) N-Ethyl-N-cyclohexy-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, np - 1.5590.

Example 183.

Dissolve 0.1 mol of 1-methyl-5-mercaptomethyl-1,2,3,4-tetrazole in 100 ml of acetone and add 0.12 mol of N, N-diethyl-3-bromopropionamide and 0.12 mol of potassium carbonate. . The mixture is heated at reflux for 4 hours. After evaporation of acetone under reduced pressure, water is added to the residue and the aqueous mixture is extracted with chloroform, the chloroform phase is washed with saturated aqueous sodium chloride solution and

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71 is dried over magnesium sulfate. After evaporation of the solvent, the column residue of the resulting residue ("Kieselgel" 60 made by Merck) is subjected to elution of the column with chloroform-methanol (50: 1, v / v) to give N, N-diethyl-3- (1-methyl -1,2,3,4-tetrazol-5-yl) methylthiopropionamide (yield 48% of theory) in the form of a colorless liquid, np = 1.5200.

Analysis:

Calcd for C 18 H 19 N 5 OS: C 46.67 H 7.44 N 27.21

Found: C, 46.72; H, 7.53; N, 27.29.

Examples 184 and 185,

Following the same procedure as described in Example 183, the following compounds are prepared: 188) N, N-Diethyl-3- (1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless liquid, η β - 1,5499 (189) N-ethyl-N-cyclohexyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methyl-18-thiopropionamide, pale yellow liquid, n D = 1.5277.

Example 186

In the same manner as described in Example 61, N, N-diethyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, 20 n2j = 1.5237 is prepared.

Examples 187 - 192.

Following the same procedure as described in Examples 71 and 77, the following compounds are prepared.

187) N-Hexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless needles, mp 80.5 - 82.5 ° C (recrystallized from ethyl acetate-hexane)

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72 188) N-isopropyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless needles, m.p. 91 - 92.5 ° C (recrystallized from ether 189) N-Ethyl-N-cyclohexyl-4- (1-phenyl-1,2) 3,4-tetrazol-5-yl) butyramide, colorless needles, mp 77.5 - 80 ° C (recrystallized from ether ) 190) N-Butyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide, colorless needles, mp 76.5 - 78.5 ° C (recrystallized from ethyl acetate-hexane) N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless needles, m.p. 100 - 102 ° C (recrystallized from ethyl acetate-hexane) 192) N-methyl -N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless oily substance, nq = 1.5396.

Examples 193 - 235.

In the same manner as described in Examples 6 and 79, the following compounds are prepared: 193) N - Ethyl -3- (1-methyl -1,2,3,4-tetrazol-5-yl) methyl thio-propionic acid

amide, colorless flakes (hexane-ethyl acetate), mp 61.5 - 62.5 ° C

194) N-ethyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, 27 pale yellow liquid, n = 1.5253 195) N-ethyl-3- (1- isopropyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless liquid, n + = 1.5179 196) N-ethyl -3- (1-butyl -1,2,3,4 - tetrazole-5-yl) methylthiopropionamide, 1 ft. pale yellow liquid, η β = 1.5149 197) N-ethyl-3- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) methylthiopro -pionamide, colorless needles, melting point 131-132 ° C (recrystallized from hexane-ethyl acetate) 198) N-ethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless needles, melting point 88 - 89.5 ° C (recrystallized from hexane-ethyl acetate) 199) N-ethyl-3- [1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl] methylthio-propionamide, colorless needles, melting point 88 - 89.5 ° C (recrystallized from hexane-ethyl acetate)

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73,200) N, N-diethyl-3- (1-butyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, reddish brown liquid, n diethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, yellowish-brown liquid, 1.5625 N, 202) N-ethyl-4- (1-ethyl- 1,2,3,4-tetrazol-5-yl) methyl thiobutyramide, 26 pale yellow liquid, η β - 1.5224 203) N-ethyl -2- (1-ethyl -1,2,3,4-tetrazole - 5-yl) methylthioacetamide, 22 pale yellow liquid, η β = 1.5305 204) N-ethyl-2- (1-ethyl-1,2,3,4-tetrazol-5-yl) ethylthioacetamide, 22 pale yellow liquid N - 1.5274 205) N-Ethyl-2- (1-ethyl-1,2,3,4-tetrazol-5-yl) propylthioacetamide, 23 pale yellow liquid, n + = 1.5210 206) N, N-Diethyl-4- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiobutyramide, pale yellow liquid, n - 1,5128,207) N-methyl -3- (1 - ethyl -1,2,3,4-tetrazole-5-yl) methylthiopropionamide, 24 colorless liquid, n = 1.5320 208) N-butyl-3- (1-ethyl-1,2,3,4-tetrazole -5-yl) methylthiopropionamide, 21 pale yellow liquid, n + = 1.5111 209) N-methyl-N- (2-thienylmethyl) -3- (1-ethyl 1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless liquid, n = 1.5697 210) N, N-diethyl-4- (1-phenyl-1,2,3,4- tetrazol-5-yl) thiobutyramide, 18 colorless liquid, n + = 1.5592 211) N, N-diethyl -4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, 20 colorless liquid, n - 1.5237 (212) N-pentyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless crystals, m.p. 5 ° C (recrystallized from hexane ether) 213) N- (4-methoxyphenyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless crystals, m.p. 148-150 , 5 ° C (recrystallized from ethanol) 214) N-Butyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless crystals, m.p. 71-73 ° C (recrystallized of ethyl acetate-hexane 215) N- (4-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless crystals, m.p. 122.5 - 124 ° C (recrystallized from hexane-ethyl acetate) 216) N- (3-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyl

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74 tyramide, colorless crystals, m.p. 122.5 - 124 ° C (recrystallized from hexane-ethyl acetate) 217) N- (1-methylpropyl) -4- (1-methyl-1,2,3,4-tetrazole-5 yl) thiobutyramide, colorless liquid, η β = 1.5066 5 218) N-Butyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, color liquid, n22, jj - 1,5590 219) N-Butyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) thiopropionamide, colorless crystals, mp 80.5 - 82.5 ° C (recrystallized from ethyl acetate-hexane) 220) N-Butyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) thiovaleramide, colorless crystals, mp 53.5-55 ° C ( recrystallized from diethyl ether (221) N-ethyl-N-phenyl-5- (1-phenyl-1,2,3,4- (4-tetrazole-5-yl) valeramide, colorless liquid, n = 1.5640 222) N-ethyl-N-cyclohexyl-5- [1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl] valeramide, colorless needles, m.p. 54-55.5 ° C ( recrystallized from ethyl acetate-hexane (223) N-ethyl-N-cyclohexyl-5- (1-butyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n = 1,5013 20 224) 5- [3- (4-Methylpiperazinylcarbonyl) propyl] -1-phenyl-1,2,3,4-tetrazole, pale yellow needles, mp 62-64 ° C (recrystallized from ethyl acetate-hexane) 225 ) N-Ethyl-N-cyclohexyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) propionamide, colorless prisms, mp 137-138 ° C (recrystallized from ethanol) 226 ) 5- [4- (4-methylpiperazinylcarbonyl) butyl] -1-phenyl-1,2,3,4-tetrazole, pale yellow liquid, n + = 1.5543 227) N- (4-methoxycyclohexyl ) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless needles, mp 89-90.5 ° C (recrystallized from hexane-ethyl acetate) 228) N-ethyl N- (2-hydroxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, η β = 1.5501 229) N, N-dipropyl-5 - (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, = 1,5311,230) N-methyl-N- (2-furylmethyl) -5- (1-phenyl) -1,2,3,4-tetrazol-5-yl) -valeramide, colorless liquid, n + = 1.5490 231) N-ethyl-N-cyclooctyl-5- (1-phenyl-1,2, 3,4-tetrazol-5-yl) valeramide, goodbye = fluid, n '= 1.5418

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75 232) N-Ethyl-N- (4-hydroxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n N-Ethyl-N-cyclopentyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n Q - 1.5446 (234) N-ethyl -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless flakes, m.p. 60 - 61.5 ° C (recrystallized from ethyl acetate-hexane) 235) N, N-diethyl-3- (1-Phenyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, yellowish-brown liquid, n = 1.5625 Example 236.

To 20 g of 3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionic acid is added 30 ml of thinonyl chloride and the mixture is stirred at 50 ° C for 30 minutes. The excess amount of thionyl chloride is distilled off and removed completely by azeotropic distillation with benzene.

15 ml of 25% aqueous ammonia and 12.8 g of potassium carbonate are dissolved separately in acetone / water (150 ml / 30 ml). To the solution is added dropwise with ice-cooling, and with stirring, a solution of the acid chloride obtained above in 30 ml of acetone and the mixture is stirred for 2 hours.

After acetone removal, the aqueous phase is saturated with sodium chloride and then extracted with chloroform. The chloroform solution is dried over magnesium sulfate and evaporated under reduced pressure.

The resulting residue is recrystallized from ethyl acetate to give 9.2 g of 3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide in the form of colorless flakes, mp 74-76 ° C.

Example 237.

Dissolve 0.1 mole of 1-phenyl-5-mercapto-1,2,3,4-tetrazole in 100 ml of acetone and dropwise add a solution of 0.12 mole of 4-bromopropionamide and 0.25 mole of sodium hydroxide in 50 ml of water. The mixture is heated under stirring at 50 - 60 ° C for 4 hours and acetone of steam is evaporated under reduced pressure. The resulting residue is acidified with dilute hydrochloric acid, saturated with sodium chloride and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated, and

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76 residue is subjected to column chromatography ("Kieselgel" 60, manufactured by Merck) to give 3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methyltiopropionamide in the form of colorless prisms (recrystallized from ethyl acetate ), mp 91 - 92 ° C.

Example 238.

In the same manner as described in Example 6 and Example 236, the following compounds are obtained: 3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide, colorless prisms (recrystallized from ethyl acetate), m.p. 91 -92 ° C, 3- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless needles (recrystallized from ethanol), mp 137-140 ° C, 4- (1-methyl) -1,2,3,4-tetrazol-5-yl) thio-butyl: amide, colorless prisms (recrystallized from ethanol), mp 90-92 ° C, 3- (1-butyl-1,2,3,4 -tetrazol-5-yl) methylthio-propionamide, colorless flakes (recrystallized from ethyl acetate), mp 79-81 ° C, 3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthio propionamide, white granules (recrystallized from ethanol), mp 105.5-108 ° C, 4- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiobutyramide, colorless prisms (recrystallized from ethyl acetate / hexane ), m.p. 72-73 ° C, 4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (recrystallized from ethyl acetate-hexane ), mp 115-116.5 ° C, N- (2-phenylethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide, colorless needles (recrystallized from ethyl acetate / hexane), mp 58.5-60 ° C.

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77

Preparation 1.

Ingredients Amount, g of N-ethyl-N- (2-hydroxycyclohexy1) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 150 "Avicel", (microcrystalline cellulose prepared of Asahi-kasei Co., Ltd.) 40

Corn starch 30

Magnesium stearate 2 10 Hydroxypropyl methyl cellulose 10

Polyethylene Glycol-6000 3

Castor oil 40

Methanol 40 The present compound, "Avicel", corn starch and magnesium stearate is mixed, ground and then pressed into tablets having a 10 mm diameter punch. The tablets thus obtained are coated with film-coating solution consisting of hydroxypropyl methylcellulose, polyethylglycol-6000, castor oil and methanol to give 20 film-coated tablets.

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78

Preparation 2.

Ingredients Amount, g of N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide 150

Citric Acid 1

Lactose 33.5

Dicalium Hydrogen Phosphate 70 "Pluronic" ® F-68 30 10 Sodium Lauryl Sulfate 15

Polyvinylpyrrolidone 15

Polyethylene Glycol ("Carbowax" ® 1500) 4.5

Polyethylene Glycol ("Carbowax" ® 6000) 45

Corn starch 30 Dry sodium lauryl sulfate 3 Dry magnesium stearate 3

Ethanol appropriate amount

The present compound, citric acid, lactose, dipotassium hydrogen phosphate, "Pluronic" ® F-68 and sodium lauryl sulfate are mixed and passed through a No. 60 sieve. The resulting mixture is granulated with an alcoholic solution containing polyvinylpyrrolidone, "Carbowax" ® 1500 and "Carbowax" ® 6000. The powdered mixture is formed, if desired, into a paste by the addition of alcohol. Corn starch is added to the wet mass and the mixture is continued until uniform granules are formed. The wet granules are passed through a sieve no.

10, placed on a tray and dried in an oven at 100 ° C for 12-14 hours. The dried granules are passed through a screen # 16, mixed with dry sodium lauryl sulfate and dry magnesium stearate, and then pressed to the desired shape.

The core tablets thus obtained are treated with varnish and talc is sprayed to prevent moisture absorption. About the resulting tablets are applied undercoating. The tablets are again sufficiently treated with varnish for oral administration. Additional sub-

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79 coating and smooth layers are applied around the tablets to make them round and smooth. Color layers are applied to give the tablets a desired color. After drying, a polish gives tablets with a homogeneous sheen.

Preparation 3.

Ingredients Amount of N-Ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide 5 g Polyethylene glycol (molecular weight 4000) 0.3 g

Sodium chloride 0.9 g

Folyoxyethylene sorbitan monooleate 0.4 g

Sodium metabisulphite 0.1 g

Methylparaben 0.18 g Porpylparaben 0.02 g

Distilled water for injection 100 ml

The parabens, sodium metabisulphite and sodium chloride mentioned above dissolved in ca. half the distilled water while stirring at 20 80 ° C. The resulting solution is cooled to 40 ° C and the above-mentioned compound, polyethylene glycol and polyoxyethylene sorbitan monooleate dissolved in the solution. The residual amount of distilled water was added to the solution to adjust the volume. The solution is sterilized by filtration with a suitable filter paper to prepare a preparation for injection.

Claims (10)

1. Analogous Process for the Preparation of 5-Aminocarbonylalkyl and 5-Aminocarbonylalkylthio-tetrazole Derivatives of General Formula Ia N-N I A Method according to claim 1, 20, characterized in that 1 is 0. DK 162047B A process according to claim 2, characterized in that R 1 and are the same or different and each represents g-alkyl or C 9 -C 10 cycloalkyl. Method according to Claim 1, 5, characterized in that 1 is 1. N-ethyl-N-cyclohexyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, N-ethyl-N-cyclohexyl-4- (1-cyclohexyl-1,2 3,4-tetrazol-5-yl) thiobutyramide, N-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, or Process according to claim 4, characterized in that A represents g-alkylthio. 5 XN X (A) and -B-CON <f. Ia * 1 XR4 ΈΓ where R 2 represents hydrogen; alkyl; cyclohexyl optionally substituted with C 1-4 alkoxy; or phenyl optionally substituted with C 1-4 alkyl; 10. represents sulfur or g-alkylthio; 1 is 0 or 1; - B represents g-alkylene; and are the same or different and each represents hydrogen; g-alkyl, C 5 -C 20 cycloalkyl, which is optionally substituted with a substituent selected from hydroxy, C 1-6 alkanoyloxy, C 1-6 alkoxy, C 1-4. alkyl and N, N-di (C 1-6 alkyl) amino; phenyl optionally substituted with one or two substituents selected from aminosulfonyl, N, N-di (C 1-6 alkyl) amino, C 1-6 alkyl, halogen, C 1-6 alkoxy and nitro; cyclohexyl-C ^ .g alkyl; phenyl - C 1-6 alkyl, wherein the phenyl ring is optionally substituted with C 1-6 alkoxy; hydroxy-alkyl; pyridyl; 2-furylmethyl; or 2-thienylmethyl, or R 2 and together with the nitrogen atom to which they are attached may form a heterocyclic group selected from piperidino, piperazino and morpholino, which may be optionally substituted with C ; 25 with the proviso that a) if 1 is 0 and rA · is hydrogen or C 1-6 alkyl then is too different from amino; b) if 1 is 0 and R 1 is n-butyl, then B does not denote methylene and NR 2 R 2 does not denote ethylamino; C) if 1 is 0, R 1 - represents phenyl and B represents methylene, then NR 1 R 2 is different from amino, methylamino and benzylamino; d) if 1 is 0, R 4 represents phenyl and B is ethyl methylene, then NR% 2 does not represent amino; E) if 1 is O, eA represents cyclohexyl and B represents ethyl one or methylethylene then does not represent amino; and f) if 1 is 0, R 1 represents cyclohexyl and B represents dimethyl methyl, then NR 1 general formula II nine NX (A) ^ - B ~ COOH II R1 10 wherein R * -, A, 1 and B are as defined above, or a reactive derivative thereof is reacted with an amine of general formula III / R ^ Wherein R R and R og have the meaning given above, or a reactive derivative thereof. Process according to claim 5, characterized in that R 1 and R 2 are the same or different and each represents C 1-6 alkyl or C 1-6 cycloalkyl. Process according to claim 1, characterized in that A denotes sulfur. Process according to claim 7, characterized in that one of the symbols R 1 and R 2 is hydrogen, and the other is selected from phenyl which is optionally substituted with one or two substituents selected from aminosulfonyl, N, N-di (C 1-6 alkyl) amino, C 1-4 alkyl, halogen, C 1-6 alkoxy and nitro; phenyl-C 1-6 alkyl, wherein the phenyl ring is optionally substituted with C 1-6 alkoxy; pyridyl; 2-furylmethyl or 2-thienylmethyl. Process according to claim 1, characterized in that N, N-dimethyl-4- (1-methyl-1,2,2,4,4-tetrazol-5-yl) thiobutyramide, N, N-diethylamide is prepared. 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, N-methyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5) yl) valeramide, N, N-diethyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, N-isopropyl-N-cyclohexyl-5- (1-phenyl-1,2,3) 4-tetrazol-5-yl) valeramide, N-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide, N-ethyl-N- (2 -hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, N-ethyl-N- (4-hydroxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, DK-162047B N-ethyl-N-cyclohexyl-3- ( 1-methyl-1,2,3,4-teCrazol-5-yl) thiopropionamide, N - ethyl-N-cyclohexyl-5- (1-methyl -1,2,3,4-tetrazol-5 yl) thiovaleramide, N, N-diethyl -4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, N-ethyl-N-cyclohexyl -5- (1-cyclohexyl -1,2,3,4-tetrazol-5-yl) valeramide.