FI73671B - FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT VAERDEFULLT TETRATZOLDERIVAT. - Google Patents

Description

1 73671

Method for the preparation of a pharmacologically valuable tetrazole derivative - Förfarande för framställning av pharmacologiskt Värdefullt tetrazoiderivat

The present invention relates to a process for the preparation of a tetrazole derivative of formula (Ia),

N - N

\ K

N (A) i-B-CON (Ia) |

In R 1, R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or phenyl; A is sulfur or C 1 -C 6 alkylthio; 1 is 0 or 1; B is C 1 -C 6 alkylene; and R 1, which may be the same or different, are hydrogen, C 1 -C 8 alkyl, C 3 -C 22 cycloalkyl, phenyl, C 3 -C 22 cycloalkyl-C 1 -C 6 alkyl, phenyl-C 1 -C 6 alkyl, hydroxy-C C 1 -C 6 alkyl, a heterocyclic group selected from pyridyl, pyrimidinyl, tetrahydropyranyl, thioazolyl, thienyl and furyl, or C 1 -C 6 alkyl substituted with said heterocyclic group, or r 3 and R 4 may be taken together with the nitrogen atom to which they are attached , forms a piperidinone, piperazino or morpholinone, which may be substituted by C 1 -C 6 alkyl or C 1 -C 6 alkanoyl; said cycloalkyl, phenyl and phenyl-C 1 -C 6 alkyl may have one or two substituents on the cycloalkyl or phenyl ring selected from the group consisting of C 2 -C 8 alkoxy, C 1 -C 6 alkyl, halogen, N, N-di (C 2 -C 8 alkyl); alkyl) amino, nitro, aminosulfonyl, hydroxy and C 1 -C 6 alkanoyloxy; provided that when 1 is 0 and R 1 - is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or phenyl, one of the two substituents R 1 and R 4 is not hydrogen, methyl, ethyl or benzyl and the other substituent is not hydrogen 2 73671 or ethyl, and R 3 and r 4 together with the nitrogen atom to which they are attached do not form morpholino or a pharmaceutically acceptable salt thereof.

The compounds of the present invention have prophylactic or therapeutic activities against peptic and / or duodenal ulcers, in particular stress obstructions and indomethacin-induced ulcers, while having fewer side effects such as central nervous system activities, anticholinergic activity and gastric emptying activity. These compounds are thus useful drugs for the treatment of such externalities. The compounds also have anti-inflammatory activity and are useful as anti-inflammatory drugs.

The compounds of the present invention can be prepared by the method described in the following Reaction Scheme I:

Reaction Scheme I

- r3 + HN ^ N “N ^ X. p4 n «i i k i; I i rmi N (A) β— £ QQj_j Amido bond formation- reaction R1 M | i! N N i J I * r3 NNn / NA! 0-B-CON <^ [la] i “X? 4 'R1 where R% R ^, r \ A, 3 and £ have the same meaning as above.

Il 3 73671

The process shown in Reaction Scheme I is carried out by carrying out an amido bond formation reaction between a carboxylic acid (11) and an amine (111).

Instead of the carboxylic acid (11), a compound having an activated carboxyl group can be used in the above-mentioned method. In addition, instead of the amine / 111 /, a compound having an activated amino group can be used. The amido bond formation reaction includes all conventional methods, such as (i) the mixed acid anhydride method, i. a process in which a carboxylic acid (11) is reacted with an alkyl halocarbocayylate to give a mixed acid anhydride which is reacted with an amine (111); (ii) the active ester method, i. a process for converting a carboxylic acid (111) into an active ester, for example a p-nitrophenyl ester, an N-hydroxysuccinimide ester or an N-hydroxybenzotriazole ester, after which the active ester is reacted with an amine (111); (iii) the carbodiimide method, i.e. a process in which a carboxylic acid (11) is condensed with an amine (111) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (iv) the carboxylic acid halide process, i.e. a method in which a halide compound of a carboxylic acid (111) is reacted with an amine (111); (v) a process in which a carboxylic acid (11) is converted into an acid addition compound using a dehydrating agent such as acetic anhydride, after which the obtained acid anhydride is reacted with an amine (III); and (vi) a process in which a carboxylic acid (11) is converted to an ester with a lower alcohol and the resulting ester is reacted with an amine (111) at high pressures and high temperature. Of these methods, the mixed acid anhydride method and the carboxylic acid halide method are preferred.

Alkyl halogen gene carboxylates used in the mixed acid anhydride method include, for example, methyl chloroformate, methyl bromate formate, ethyl chloroformate, ethyl bromoformate. isobutyl chloroformate and the like. The mixed acid anhydride can be prepared by the generally known Schotten-Baumann reaction and can be used in the subsequent reaction without isolating the amine / 111 / from the reaction mixture. The Schotten-Baumann1 reaction can be performed in the presence of a basic compound. These basic compounds include all compounds commonly used in the Schotten-Baumann reaction, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo / 4.3.0 / -nonsen-5 (DEN), 1,5-diazabicyclo / 5. 4. O / undecene-5 (D3U), 1,4-diazabicyclo / 2.2.2 / octane (DABCO) or the like, "3 inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or the like. The reaction is usually carried out * at a temperature of -2D to 100 ° C, preferably 10 to 50 ° C, for about 5 minutes to about 10 hours.

The mixed acid anhydride process is usually carried out in a suitable solvent. These solvents include all solvents normally used in this process, for example halogenated hydrocarbons such as methylene chloride, chloroform or alkyl chloroethane, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dimethoxyethane, esters such as methyl ethyl acetate, esters such as methyl , such as dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide and the like. The carboxylic acid (11), alkyl halocarboxylate and amine (111) are usually used in such an amount that the alkyl halocarboxylate and amine (111) are each at least equal to the molar amount of the carboxylic acid (11), preferably 1 to 1.5 moles per 1 mole of carboxylic acid (11). /.

Il: 5 73071

The carboxylic acid halide method is carried out by reacting a carboxylic acid (11) with a halogenating agent to give a carboxylic acid (11) halide compound.

The obtained carboxylic acid halide is then reacted with the amine (111) after the halide is first isolated and purified from the reaction mixture. The reaction can also be carried out without isolating the halide.

The reaction of the carboxylic acid (11) and the halogenating agent is carried out in the presence or absence of a solvent. These solvents include all solvents which do not adversely affect the reaction, for example aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as dioxane, tetrahydrofuran or diethyl ether such as aproethyl ether, aproethyl ether, aproethyl ether, apro or dimethyl sulfoxide and the like. Haggenes include any conventional halogenating agents that can convert a carboxyl group to a hydroxy group halogen, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, and the like.

The ratio of the amounts of carboxylic acid (11) and halogenating agent is not critical, but when the reaction is carried out without a solvent, the latter, i. acid / 11 / is used in large excess. When the reaction is carried out in the presence of a solvent, the latter is used in an amount equivalent to or more than the former compound, preferably 2 to 4 moles per 1 mole of the former compound. Also, the reaction temperature and reaction time are not critical, but the reaction is usually carried out between room temperature and 100 ° C, preferably between 5G and B0 ° C, for 30 minutes to 6 hours.

The reaction of the carboxylic acid halide with the amine (111) is usually carried out in the presence of a dehydrohalogenating agent. The halogenation is usually not a basic compound. Basic compounds used as dehydrohalogenating agents include all conventional compounds, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, organometallic carbonate or sodium carbonate, such as sodium or potassium, alkali metals such as sodium or potassium, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo / 4.3.0 / noneene-5 (D3N), 1,5-azabicyclo / 5.A.3 / undecene-5 (DBU) or 1, 4-diazab-cycl / 2.2.2 / octane (DAEC 0) / or equivalent. A large excess of amine (111) can be used instead of a dehydrohalogenating agent. The reaction may be carried out in the presence or absence of a solvent. Solvents include any inert solvent which does not adversely affect the reaction, for example, halogenated hydrocarbons such as chloroform, methylene chloride or carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran or dioxane, aromatic or xylene, esters such as methyl acetate or ethyl acetate, aprotic polar solvents such as N, N-dimethylformamide, dimethyl? ulfexide or hexamethyl "phosphoric acid triamide, or the like.

The ratio of the amounts of carboxylic acid halide to mine (111) is not critical, but when the reaction is carried out without a solvent, the latter compound, i. amine / 111 / is usually used in large excess. When the reaction is carried out in the presence of a solvent, the latter compound is usually used relative to the former compound in the amount of valence tq ^. more, preferably 1-2 moles per mole of the previous compound. Also, the reaction temperature and reaction time are not critical, but the reaction is usually carried out at -30 to 100 ° C, preferably 0 to 5 ° C, for 30 minutes to 12 hours.

h II: 7 73671

Compounds (1) having an acidic group can be converted into a salt with a pharmaceutically acceptable basic compound. Basic compounds include a metal hydroxide such as sodium hydroxide or potassium hydroxide, alkali metal alcoholates such as sodium ethylate or potassium ethylate or the like. Compounds (1) having a basic group can also be converted into a salt with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids are hydrochloric acid or hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid or benzoic acid.

The compounds obtained in the above methods can be easily isolated from the reaction mixture and purified by conventional methods. For example, isolation can be performed by precipitation, extraction, recrystallization, distillation, column chromatography, chute plate chromatography, and the like.

The compounds of the invention (1) or pharmaceutically acceptable salts thereof are useful in the treatment of peptic and duodenal vaginas. They are usually used as conventional pharmaceutical preparations. The pharmaceutical preparations can be made using conventional diluents and carriers, such as filter aids, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants or the like. The preparations may be in various forms such as tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solution, suspension, etc.) and the like. Tablets may be prepared using conventional carriers such as excipients (e.g. lactose, sucrose, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, pure syrup, aqueous solution, aqueous solution of starches, aqueous solution of gelatin, in carboxymethylcellulose - it 11 s: <ks, merylcellulose, potassium esat. , sodium hydrogen carbonate, calcium carbonate, polycyloxyol sorbitan fatty acid esters, sodium auryl sulfate, monoglyceryl stearate, starches, lactose, etc.), ), a wetting agent (e.g. glycerin, starches, etc., a sorbent (e.g., starches, lactose, kaolin, pentonite, colloidal silica, etc.), can be used. ta '(e.g., purified talc, stearic acid scavengers, boric acid, polyethylene glycol, etc.) and the like. The tablets may be in the form of sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, bilayer or multilayer tablets, and the like. Pills may be prepared using conventional carriers such as excipients (e.g., glucose, lactose, starches, cocoa butter, hardened vegetable oils, kaolin, talc, etc.), binders, e.g., gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrants, e.g. agar, etc.) and the like. Suppositories may be prepared using conventional cantilever, such as cocoa butter, higher alcohols or their esters, gelatin, semisynthetic glycerides or the like.

When the active compounds are prepared for injection, the solution or suspension containing the active compounds is sterilized and rendered isotonic with blood. Injectable, emulsion or suspension injections may be prepared using conventional dilute aspirates such as water, ethylene glycol, propylene glycol, ethoxylated isostearyl alcohol, polynxystearyl alcohol, polyoxyethylene. 5,73671 nisorbitaene fatty acid esters or the like. The injection preparation can be made isotonic by adding a sufficient amount of nitrile chloride, glucose, glycerin or the like, and optionally, conventional solvents, buffers, analgesics, colorants, preservatives, perfumes, favors, sweeteners and other drugs can be added to the preparation.

The antifouling preparations of the present invention may contain the active compounds in very different amounts. They usually contain from about 1 to 70% by weight, preferably from 5 to 50% by weight, of the active compounds of the present invention, based on the total amount of preparations.

The route of administration of the anti-external preparations of the present invention is not limited. The appropriate route of administration will depend on the form of the preparations, the age, sex and other condition of the patients to be treated, the severity of the disease and the like. Tablets, pills, solutions, suspensions, emulsions, granules and capsules are usually administered orally. Injections are usually administered alone intravenously or optionally in combination with a suitable excipient such as glucose or amino acids, or may be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally.

In addition, the dosage of the active compounds of the invention may vary depending on the mode of administration, the age, sex or other condition of the patients to be treated, the severity of the disease or the like. It is usually in the range of 0.6 to 50 mg / kg body weight per day. The antiperspirant preparations preferably contain the active compounds of the present invention in a unit dose of 10 to 100 mg.

U.S. Patent 4,044,144 contains a few tetratol derivatives of the formula: 10 7367 1 M -: ANHCO-C;

On the other hand, the compounds of the invention have a chemical structure which differs from the tetrazole derivative of U.S. Pat. No. 4,044,144 in that the compound of formula (I) has a group - (A) 1-3 between the group -CONR 3 R 4.

The compounds prepared by the method of the invention have completely different pharmacological activities (antiulcer activity) than the compounds of U.S. Pat. No. 4,144,144 (anti-allergic activity).

The compounds of T7S Patent 3,743,646 have an anti-inflammatory effect which differs from the antiulcer activity of the compounds of formula (I).

DE patent 1,570,183 contains a few tetrazole derivatives of the formula ϋ 3> = / /

R3 N

B

The compounds of the formula (I) differ from the compounds of DE 16 70 183 in the substituent - (A) '- 3-CONR3r4, as well as in their antichoesterester activity.

Pharmacological test:

The pharmacological activities of the compounds (I) were tested by the Shay rat gate ligation method (cf. H. Shay et al., Gastroenterol., Vol. 5, page 43, 19845), which is the most popular method: 11: ^ 7 f Π / 06 /: method , in which gastric fluid secretion inhibitory activity is tested. The test was performed using male Wistar rats weighing approximately 170 g and fasted for 24 hours.

Test compounds were administered subcutaneously 30 minutes before gastric pertussis ligation. Gastric fluid volume, total acidity, and pepsin activity were measured 4 hours after Ligation. For comparison, saline was administered instead of the test compound. The inhibition ratio (? Ό) of the test compounds was calculated when the inhibitory activities of the control were considered zero (G). The results are shown in Table 1 below.

In the following table, the inhibition ratio ('n) was estimated as follows: +: 10 - less than 50% • «-r-: more than 50 15

The test compounds were as follows: N, N-diethyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl} thio-butamide 2. N-ethyl-N-alkylhexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 3. N-ethyl-N'-cyclohexyl-5- (1-methyl-2,3,4-tetrazole-5-yl) -yl} thiovaleramide 4. N-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeride 5. N, N-diethyl-5- (1 -cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide Γ Ο 7 / Π / β was 6, N-γ; 2,3,3-Tetrazol-5-yl) -thio-b-thyramide 7, N- (4- (N, N'-cisyl) -1'-cinino; -methyl-1,2,3,4-terazol-5-yl-N, ethyl-N- (2-hydroxycyclohexyl) - 4- (2-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide 9. N-ethyl-N-phenyl-4- (1H-methyl-1,2,3,4-tetrazol-5-yl) t io-butyratide 1 C. Nc * ty I i - M- (2-pyridyl) -4- (lr? e ty y 1-2, 1,3,4-1 etra t sol-5 - yyii) thio - fa utyranic: i.

21. N-cyclohexyl-1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (i-methyl) -1,2,3,4-ta; n-N-cetyl-3- [1- (4-3-phenylphenyl) -1,2,3,4-tetrazol-5-yl] methylthiopropanismide 13 Nfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyl-14] 2- (3-bromophenyl} -5- (2-piperidinocarbonyl) - 1,2,3,4-tetrazole tl 13 73671

Table i l ------------------ "? -----! -; - 1; Test test: Dose | Inhibition ratio i ϊ disie (mg / kg, j. —.................. · ------------ j] n: c 5.2 i Total gastric Pepsin and volume of acidity activities-i j il ti jj; “ii * | i

j i! loo ++ .. ++ ++ I

j 2 f 100 ++ ++ ++ i? i loo ++ | + + l ä! 10D (+ ί + + f; i] ·: 5 i 1G GI + ί + + (: {f I 6 f 100 i + I + + i | 7 * ien j ++ I + + | [> 3 (ICC | + j + j + ί LP 100 '++ j + ++' \ 5 i \ l ί 10 I 100 j + l + | +] l 11 | 100 ί + ί + I + ί f 12 {100 I + I + f + [l 13 i 100 + I + j + 1

1 14! loo I - t -! - I

- indicates ineffective Acute toxicity;

Test compounds were administered orally to male Wiscar rats and the lethal dose (LD50) was measured. The results are shown in Table 2.

• · * n 7 s n * fob! !

Table 2 'Tested y h d i s t n *>:? .. 0-.n (mc, / kg, p. C.);

I h 50C

1 o> Elf. r l ”-'jL * f 3> 5C0 i i I 4> 500 | i. . i 2> 500 f; 6 and 500 |

, J

7> c. n r · 3 ’> s n n? 9 '> 5 0 Π 1

i S

; io '-o: · II> 5CO! 12 0 5CO j; 13 S: 5 G G * t ·

The compounds of the present invention and their illumination are illustrated by the following examples and examples, without being limited to the n> a rivet.

Comparative Example 1 N-methyl-cyclohexylamine (26 ml) is added to ethyl acetate (ml) and 4-chlorobutyryl chloride (25 ml) and toluene ion are added over a period of 20 minutes with stirring. (33.5 ml), keeping the internal temperature on ice by cooling to 10-20 ° C.

The mixture is further stirred at room temperature for 1 hour.

After the reaction, water is added to the reaction mixture. The organic layer is separated and washed successively with water, saturated aqueous potassium carbonate solution, 10-p r o s e n 11 i s e11a aqueous sucrose and water, followed by.

k u i v a t a a n let water !! n r. Sodium sulfate 11 in 7 3671 is filtered off and the mother liquor is concentrated and distilled under reduced pressure to give N-methyl-N-cyclohexyl-4-chlorobutyramide (41.5 g), b.p. 133-136 ° C / 2mmHg.

Comparative Example 2 N-ethyl-cyclohexylamine (2.6 g) is dissolved in dry benzene (20 ml). Chloroacetyl chloride (2.6 g) and triethylamine (2.4 g) are added dropwise to the solution with stirring and 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 into ice water and extracted with ether. The ether layer was washed with aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is distilled off, after which the residue obtained is distilled off under reduced pressure to give N-ethyl-N-cyclohexyl-chloroacetamide (3 g), b.p. 118-120 ° C / C, 2 mmHg.

Comparative Examples 3 and 4

In Comparative Example 2 ', the following compounds are prepared in a fluted manner.

N-ethyl-N-cyclohexyl-4-chlorobutyramide, b.p. 120-13 ° C / 1.5 mmHg N-ethyl-N-cyclohexyl-3-chloropropionamide, b.p.

103-110 ° C / 0.15 mmHg

Comparative Example 5

Thionyl chloride (10 ml) is added to monomethyl adipate (6 g) and the mixture is refluxed for 1 hour. Excess r thionyl chloride is distilled off and benzene is added to the residue. The thionyl chloride is then removed from the tis-;. o ο · o pis ^ sti.

- nk. "? ·? - ..trusted '; ~:. nn; sr. 1i r;' D u n. *.) and water (15 mi., 4, v; jr -t ... unk n rh o ηε n; 1 i 3 (5.2 g '.

udei .., u j.-tc c. k _ c ".. os; e .i?!: Fn iion under ice-cooling and stirring to this mixture. The mixture is stirred under ice-cooling for 1 hour and 11 hours at room temperature for 2 hours. The acetone is distilled off, water is added to the residue and the mixture is extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and dried over sodium phase 1. The chloroform is distilled off to give methylphenyl adipinamate '' O n \ \ '- · * r ΡΠ nl NMR; 01.-F' - 1,? 0 '4K, ->) "η, ϋ? - 2.50 (4H, n), 1.62 (5 h, -s). £, SC -", ~ 0 (5η (n), H, 55 (1H , 1 year s / V3 comparative examples 6, ~ s 7

As described in Comparative Example 5, the following compounds are obtained.

Methyl N-cyclohexylacyl? Format, light brown prisms (recrystallized from methanol-water), m.p. ·

72 - ~ hcZ

; F'v.ä; v .. t -i - / v i- r ~ - r t, I pass r: not °, kp. 136

Comparative Example 2 A solution of 10-ororent variable me tv over amine (46.5 mL) is dissolved in acetone (300 mL). Potassium carbonate (45.6 ml) and water (ICO ml) are added to the solution, and chloroacetyl chloride (14.3 ml) is added dropwise to the solution under stirring under ice-cooling for 4 a. The mixture is stirred under ice-cooling for 1 h and further for 2 hours in room II; • At a temperature of 7,73671. Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The chloroform is distilled off and the residue is distilled under reduced pressure to give N-methyl-chloroacetamide (15.5 g), a colorless liquid, b.p. 107-109 ° C / 27 mmHg.

Comparative Example 9 N-methyl-chloroacetamide (10.8 g) is dissolved in benzene (10 ° C) and phosphorus pentachloride (10.8 g) is added below 15 ° C with stirring. The mixture is stirred for 1 hour at room temperature and then allowed to stand overnight. The mixture is slowly refluxed for 2 hours. The reaction mixture is concentrated and ice water is added. The mixture is extracted with chloroform. The chloroform layer was washed with water, dilute aqueous sodium hydroxide solution and water, dried over magnesium sulfate, and chloroform was distilled off. The resulting residue was subjected to column chromatography (Wakogel C-200, manufactured by Wako Pure Chemical Industry, eluting with chloroform: methanol = 50: 1, v / v) to give isolated 1-methyl-5-chloromethyl-1,2,3,4-tetrazole ( 8.5 g).

Example 1 4- (1-Methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (2 g) is dissolved in dry tetrahydrofuran (30 ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture with stirring and ice-cooling. The mixture is stirred at room temperature for 30 minutes. Diethylamine (G, 9 g) is further added dropwise to the mixture at room temperature, and the mixture is stirred for 2 hours. The mixture is concentrated under reduced pressure and the residue obtained is purified by flash chromatography (Kieselgel '60, manufactured by Merck & Co.).

is 73671

Elution with n-benzane-ethyl acetate (1: 1) gives N, N-diacyl-4- (i-methyl-1,2,3,4-terazol-5-yl) thio-butyramide (1.4 g), a colorless liquid, my; * = 1.5227 L / n NMR: δ 3 1.04 <3K, t, J = 7Hz), 1.12 (3H, t, 3 = 7Hz), 1.90 - 2.70 (4H, m ), 3.00 - 3.60 (6H, m), 3.88 (3H, s)

Elemental analysis, C ^ qH ^^ N ^ OS:

Calculated (%): 0.46.67; H, 7.44; N, 27.21

Found (8): C, 46f7S; H, 7.51; N, 27.29

Examples 2-5

The following compounds are obtained from the starting materials as described in Example 1.

(2) N-ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetazol-17,5 5-yl) thio-butyramide, colorless liquid, n * * = 1.5327 NMRs δ CDCl 3 o, 90 - 1.40 (3H, m), 1.20 - 2.00 (10H, ppm '' 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- (2,6-yl) thio-butyramide, pale yellow liquid, n = 1.5534 NM S: C> 3.12 (3H, t, O = 7Hz), 1.70 - 2 , 40 (4H, m), 3.32 (2H, t, O = 7Hz), 3.74 (2H, q, J = 14Hz, 7Hz), 3.90 (3Hf s), 7.00 - 7.60 (5H, m) (4) 5- (3-morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71-73 ° C.

(5) 5- [3- (4-acetylpiperaidinocarbonyl) propylthio] -1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from naphtha-acetone). mp.

- 9i, 5 ° o.

h 73671 19

Example 6 4- (1-Methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (45 mils) is dissolved in tetrahydrofuran (5 ml) and DBU (50 mmol) is added. . Isobutyl chloroformate (50 mmol) is added dropwise to the mixture with stirring and ice-cooling.

The mixture is stirred at room temperature for 30 minutes.

2- (3,4-Dimethoxyphenyl) -ethylamine (54 mmol) is added dropwise to the mixture, and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the resulting residue is extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After distilling off the chloroform, the residue is subjected to flash chromatography (Wakogel 0-200, chloroform as eluent) to isolate N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-1,2,3,4- tetrazol-5-yl) thio-butyramide (yield: 41%), recrystallized from hexane-chloroform, colorless flakes, m.p. 70.5-71.5 ° C.

Elemental analysis, ^ 26 ^ 23 ^ 5 ^ 3 ^ 1

Calculated (? I): 0.52.59; H, 6.34; N, 19.16: Found (S): 0.52.51; H, 6.16; N, 19.10

Examples 7-58

The following compounds are prepared from the starting materials as described in Example 6.

(7) N-Hexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio- *

butyramide, colorless flakes (recrystallized from hexane-ether), m.p. 41-42 ° C

20 7 3 6 7 1

(8) N-cyclohexyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 116.5-117.5 ° C

(9) N-cyclooctyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramine, colorless liquid, n = 1.5323

(10) N-cyclododecanyl-4- (1-methyl-1,2,3,4-tetrazol-yl) thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 115-120 ° C

(11) N-butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n-t = 1.5198 (12) N- (2 -hydroxyethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramycam, colorless liquid, f = 1,5350 (13) N-ethyl-N-benzyl -4- (1-methyl-1,2,3,4-tetrazol-19-yl] thio-butyramide, colorless liquid, n = 1.5596 (14) N'-butyl-N-cyclohexyl-4- (1-methyl -1,2,3,4-19-tetrazac-5-yl) thio-butyrimide, colorless liquid, nj = 1.5222 (15) N, N-dibutyl-4- (1-methyl-1,2,3 , 4-tetrazol-5-yl] thio-butyramide, colorless liquid, n * = 1.5049 (16) N, N-dibenzyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl)

1 Q

yl) thio-butyramide, colorless liquid, n = 1.5773 (17) N, N-diisopropyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio -butyramide, colorless liquid, n ^ '= 1,5111 (18) N, N-dicyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles ( hexane), t

mp. 91-92 ° C

II: 2i 73671

(19) N-Benzyl-N-tert-butyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl'thio-butyramide, colorless needles (hexane), sr. S6,5 - S7,5 ° C

(20) N-cyclohexyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n = R = 1.5470 (21) N-methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n N 6 - 1,5706 (22) N-Benzyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (2-methyl-1,2,3,4-tetrazol-5-yl) thio -butyramide, colorless liquid, = 1,5659 (23) N- [2- (3,4-dimethoxyphenyl) ethyl] -N- (2-hydroxyethyl) -4- (1-methyl-1,2,3 (4-Tetrazol-5-yl) thio-butyrcyram-14 5 amide, colorless liquid, n - * = 1.5372 (24) N, N-dihexyl-4- (i-methyl-1,2,3,4 -tetrazol-5-yl) -7 5 thio-butyramide, colorless liquid, njij = 1,5011 (25) N-ethyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl ethyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, 14 colorless liquid, n-1.5451

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

(27) N-ethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n = 1.5319 (28) N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 65-6 6 ° 2 22 7 3 6 7 1 (29) N-hexyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyrimoyl, colorless liquid , n'S =:., 5132 (30) N-cyclohexyl -> - (2-hydroxyethyl) -4- (i-methyl-2,3,3-tetrazol-5-yl) thio-butyramide, colorless liquid, u ς n ^? ' = 1,5372 (31) N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (hexane-ethyl acetate),

mp. iC6 - 107 C

(32) N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-

yyii) thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95-96 ° C

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

(34) N- (2-pyrimidyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide? colorless granules (hexane-ethyl acetate), m.p. 108 -: .10c2

(35) N-furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 71 - 7 3 0 C

(36) N- (4-aminosulphenylphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (methanol), mp 169.5- 170.5 ° C

(37) N- [4- (N, X-Dimethylamino) phenyl] -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless prisms (hexane-ethyl acetate) , sp. 144 DEG-147 DEG C.

(38) N- (2-methyl-3-chlorophenyl) -4- (1-methyl-1,2,3,4-tetrazin-5-yl) thio-butyramide, colorless needles (hexanes-ethyl acetate), m.p. 104.5-105.5 ° C

(3F) N- (4-nitrophenyl) -4- (1-methyl-1,2,3,4-tetrazole)

5-yl) tert-butyramide, colorless needles (ethyl acetate), m.p. 194-195 ° C

(40) N- (2-methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazole-

5-yl) thio-butyramide, colorless needles (hexane-ethyl acetate) m.p. 79.5 ° C

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

• S

(42) N-ethyl-N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyrimide, colorless liquid, , 5623 (43) N-ethyl-N- (3-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramoyl, colorless liquid, nj = 1.5618 (44) NI-ethyl-N-cycloert 11-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid , n = 1.5384 - (45) N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, no. x = 1.5293 (46) N-isapropyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, nj5 = 1.5232 (47) ) N-ethyl-N- (4-hydroxycyclohexyl) -4- (i-methyl-1,2,3,4-strrazol-5-yl) thio-butyramide, colorless liquid, n * = 1.5363 ^ / O 6 / i ' 46) N-style-X- (2-hydroicyclohexyl) -4- (1-methyl-

1,2,3,4-Tetrazol-5-yl-10-butyramide, colorless needles (hexarethyl acetate). mp. 132-133 ° C

(49) N-ethyl-N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n "" = 1.5218 (50) N, N-Dipropyl-4- (1-methyl-1,2,3,4-tetrazal-5-yl) tic-hutyramide, colorless liquid, nj = 1,515.1 (51) N-butyl-N-phenyl- 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, nj = 1.5509 (52) N-methyl-N-cyclohexyl-4- (i- methyl-1,2,3,4-tetrazol-3-yl) thio-butyramide, pale yellow liquid MMR: 6CC1 4.100 - 2.00 (10H, broad), 1.80 - 2.70 (4H, m ), 2.73 (3H; d, O = 6Hz), 3.23 (2H, t, J = 6Hz), 3.85 (3H, s), 3.20 - 4.50 (1H, m) (53) Ν, Ν-Dimethyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl) thio-batyramide, colorless liquid, H1 = 1.5327 ( 54) N-ethyl-Ni-cyclool-ethyl-4- (1-methyl-1,2,3,4-tetrazc-5-yl) 12 o-phenylurea: colorless liquid, = 1.5309

(55) 5- [3- (4-methylpiperazinecarbonyl) propylthio] -1-methyl-1,2,3,4-tert-methyl, colorless flakes (hexane-ethyl acetate), m.p. 5-6 ° C

(56) 5- (3-piperidinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, colorless liquid, = 1.5310 (57) N-ethyl-N-cycloethyl-4- (1- methyl-1,2,3,4-tetrazol-1 g of 5-yl) thio-butyramide, colorless liquid, = 1.5290 l! 25 7 3 6 71

Example 59 4- (1-Phenyl-1,2,3,4-dihydro-2-5-yl) -butyric acid (45 ml 1 in cel, li. (5G ml) and 03U (50 mmol) is added dropwise, isobutyl chloroformate (50 mmol) is added dropwise to the mixture with stirring and cooling on ice, the mixture is stirred for 30 minutes at room temperature, N-ethylcyclohexylamine (54 mmol) is added dropwise and the mixture is further stirred. At room temperature for 2 hours, the solvent is distilled off under reduced pressure, after which the residue is extracted with chloroform. C-200, chloroform as eluent) to isolate N-ethyl-N-cyclohexyl-4- (i-phenyl-1,2,3,4-tetrazole-5 -yl) thio-8-butyramide (yield; 43 5o), colorless liquid, n ^ = 1.5590.

Elemental analysis, C .:

Calculated (S): C, 61.10; H *, 29.; N, 18.75 Found (»); 0,61,28; H, 7.38; »\ !, 18.86

Example 59

By acting in the same way as in the example; 58 except using K ', N'-diethylamine instead of N-ethyl-N-cyclohexylamine to give N, N-diallyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n ~ 3 = 1.5592.

f 2 6

Example <2 7 3 6 71 2 - 1 - n e i y y 1 i -1, 2, 1,4 - i 3; r? so 1 - 5 - yy 1 i) thioacetic acid (45 ~ i λ 2 ·. "icc 1 ia 'is dissolved in tetrahydrofuran (50 ml) and then D32 i 5C ~ i11 imoo 1 is added.) Isobutyl chloroformate (5G) is added dropwise to the mixture. millimoles) with stirring and ice-cooling, and the mixture is stirred for 30 minutes at room temperature, N-ethyl-N-cyclohexylamine is added dropwise and, under ice-cooling, to the mixture, which is then stirred for a further 2 hours at room temperature. washed with 5-orcent aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and oat rum <aot * c in ky-cetethyl of transport 1.1 to 11a and dried over chloroform of chloroform. distill DC-S J3 J ran n us pv .. copper? or? tc ora fc id an n (Wakogel C-200, el uoint wave benzse5nl, chloroform = 4: 1, v / v) to isolate 'v ~ 5ty yi iNs yklohe xyl-2- (1-methyl, 3,4-Letra <.sc ± -5-yl) ^ 0_ase.;: amj_cj ^ a (yield: 52%)> which is crystallized from ethyl ester petroleum ether, white prisms, m.p. . $ 5 _ 7 '° q,

Elemental analysis, C

i. 2 1 1 "ς V» "

Calculated (5S): C, 50.56; μ> 7 47. K, 24.71 Found (? -.): C, 50.75; H, 7f55; N, 24.73

Esime rk i t 6j :: 6 2

In Example 60 Figure -'- U ΐε iavgiia the following compounds are prepared from the starting materials in question.

(61) N-ethyl-N-cyclohexyl-3- (i-methyl-1,2,3,4-cetrazol-5-yl), thio-pr> Cp ^ G_, jjs: rij_c |; j_> pale yellow liquid , n ^ 6 = 1.5273

i, j

f

II

27,73671 (62) N-ethyl-N-cyclohexyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) thiovaleramide, pale yellow liquid, 25 Πρ = 1.5227 Example 63 4 - (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (45 mmol) is dissolved in tetrahydrofuran (50 ml) and DBU (50 mmol) is added. Isobutyl chloroformate is added dropwise to the mixture while stirring and cooling on ice. The mixture is stirred at room temperature for 30 minutes. N-ethyl-cyclohexylamine (54 mmol) is added dropwise to the mixture, and the mixture is further stirred for 2 hours at room temperature. The solvent is distilled off under reduced pressure, and the residue is extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The chloroform is distilled off and the residue obtained is subjected to column chromatography (Wakogel C-200, eluent benzene: chloroform = 4: 1, v / v) to isolate N-ethyl-N-cyclohexyl-4- (i-cyclohexyl-1,2,3 , 4-tetrazol-5-yl) thiobutyramide 18 (yield: 47 μl), colorless liquid, = 1.5290.

Elemental analysis, C ^ gHj ^ N ^ OS:

Lask. (S): C, 60.12; H, 8.76; N, 18.45

Found (S): C, 59.95; H, 8.62; N, 18.55

Example 64 4- (1-Methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (45 mmol) and N-methylmorpholine (50 mmol) are added to methylene chloride (50 ml). Methyl chloroformate (50 mmol) is added dropwise to the mixture while stirring and maintaining the internal temperature at 10 to 20 ° C on ice; 73671

· 'Ähd νtt änäli li. The mixture of this person is stirred at 3C

Wi> W

minutes at room temperature. To the mixture is added 2-; notckr 1 sv, <1 oh? K3vy 1; 1 s' iinis (34 moles) and the mixture is impacted with r * · *?.? 'Idrr ..: · in lilac for 4 hours. After the reaction: e a <·· ;. i o s s- r k c s?. n more water. The organic layer is separated and passed sequentially with sodium hydroxide with dilute aqueous solution, dilute hydrochloric acid and water and dried over sodium sulfate. The inorganic materials are filtered off and the emaiiucs are concentrated. The residue obtained is subjected to column chromatography (Wakogel C-200), eluting with amine as n: rene: «<„ oroform = 4: 1, v / v), to give isolates \ (4-nsto: <5isy <Ixexyl). .i) -4- (i-methyl-1,2,3,4-tenrazol-5-yl) -cio-butyramide (yield: 43 Ϊ), colorless liquid, -V "· = 1.5263 ..

A1k u a i n e s n? 1v v s 1, C ,, U0, N! _C_S; '2 5 5 2

Lask. (K): 1.52.51; 7 7.7 ?; N ', 25.55 Found (J5): C, 52.56? ri, 7.71; N, 23.63

Example 65 4 - '(1-Methyl-1,2,3,4-tetrazol-5-yl) tic-volpic acid (45 r: lilmoclis) and pyridiline (5G moles) are added to the "ethshycro" ururar and then added dropwise and while stirring the methyl oromoformate (50 moles) by maintaining the internal temperature at 5 to 15 ° C under ice-cooling, and the mixture is stirred for 1 hour at room temperature. The reaction mixture is stirred for a further 3 hours. After the reaction, the pigs are dissolved under reduced pressure and the residue is dissolved in chloroform. The K1 or of layer is washed successively with dilute aqueous solution of sodium hydroxide, dark hydrochloric acid and water and dried over sodium sulfate. 200, as eluent Benzene i: k ler o äo rrr i ~ 6: 1, V / V) to isolate

II

29 7 3671 N- (4-methylcyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide (yield: 45 SS).

Elemental analysis, C ^ H ^^ OS: task. (K): C, 52.50; H, 7.79; N, 23.55 Found (K): C, 52.31; H, 7.65; N, 23.80

Example 66 4- (1-Methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (45 mmol) is dissolved in tetrahydrofuran (50 ml) and DB'J (50 mmol) is added. Isobutyl chloroformate (50 mmol) is added dropwise to the mixture while stirring and cooling on ice. The mixture is stirred for 30 minutes at room temperature. 4- (N, N-Dimethylamino) cyclohexylamine (54 mmol) is added dropwise to the mixture, and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure, and the resulting residue is extracted with chloroform. The chloroform layer was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The chloroform is distilled off and the residue obtained is chromatographed on a silica gel column (Wakogel C-200, eluting with benzene: chloroform = 4: 1, v / v) to give N- (4- (N, N-dimethylamino) cyclohexyl). 4- (1-methyl-1,2,3,4-tetrazol-5-yl Hiobutyramide (yield: 47 SS).

Elemental analysis, C, .H „.N, OS: 14 Zo 6

Lask. (SS): 0.51.51; H, 8.03; N, 25.74 Found (S): 0.51.60; H, 6.22; N, 26.05

Example 67 4- [1- (2-Methoxycyclohexyl) -1,2,3,4-tetrazol-5-yl] thiobutyric acid (45 mmol) is dissolved in tetrahydrofuran (50 ml) and DBU (50 mmol) is added to the solution.

9 ^ ·) ^ 71 f ^ w ·

Isobutyl chloroformate a (5 C rn i 11 imcc A r / oa - a 11 s is added dropwise to the mixture with stirring and cooling in ice and a mixture of sn cc 13 for 30 minutes. Seo / 33? Λ iin "" lr. ti. ···: nr \ - etvyii - syk 1 thins 1 amine {5 L r.iil limo. a; and 3 orsoso is further timed for 2 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is extracted with klcrcfom. The chloroform layer is washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogenerate solution and saturated aqueous sodium chloride solution and dried on ice, - water, n ali a r. Atr iumsu 1 phase 11ε, chloro-f crmin tis 1 k ken get tujä dose pylvaskrcnato- r> vnf ^ icy 3 Π (lv Γ: · 'n Q p ** 2-220. Γ 1' 1 oini *. ';: · ΐ Ί p OPG Hont S 0 0 Π 2 l '<1 ovofor rn j. ~: 1 j V / V1 ^ i "c 11 o ir' rn £ d ^ τι ncris 2 ^ 11 y 3 N - ethyl-N-sv '< lchei <cyyii-4 ~ / l - (? - retocyclohexyl) -1,1,1,4 -1 e i n s t t s 1 - 5 -> "/ 1 i / 1 i o b u t y r a m i d i a (yield: 43 O '\ / 0, *

Elemental analysis, C „_ H _r N. 3 „S: iJ ti; z

Las. (° C: 52.55; H, 3f51; N, 17.10 Found {%]: 1.33.23; . c, 34: N, 17.23

Example 6S

4- [1- (4-Ethylphenyl); - 1,2,3,4-tetrazol-5-yl] thioic acid (45 ml) is dissolved in tetrahydrofuran (50 ml) and diluted with Dili (5G). To the mixture i: si - "r. · ..: · *: er, i; r. ·. i; - yli ikori formate (51 niliinocl i '5) with the same stirring and cooling on ice and the mixture is stirred at room temperature 30 minutes.

N - e t y y 11 - s y k 1 o h e k e y y 1: r- m m i i n i a (50 millimoles) are added dropwise to the mixture, which is further screened for 2 hours at room temperature. The solvent is distilled off under reduced pressure and the residue s a ε t u is removed from the bone with k Icr of em. K1 o r o f o r m i k e r r o s washed 5-present 'εε 1 · a v-ε: ;; .with another aqueous hydrochloric acid, solid ur.hydrogen ksrbcnasöin saturated with water-1 i i: o k s e 11 a j a o o i: i u r k I c r i c 1 m saturated aqueous solution 5P n: 'j. k C C “i’ (·. j. r> r f- L r- ·; - '' 7 Π S 2 ~ j. 'J ΠS U 1 f 3 c. t i 11 3,

II

31 73671

The chloroform is distilled off and the residue obtained is subjected to flash chromatography (Wakogel C-200, eluting with benzene: chloroform r 4: 1, v / v) to give isolated N-8-ethyl-N-cyclohexyl-4- [1- (4-ethylphenyl) -1,2,3,4-triacyc-5-yl / thio-butyramide (yield: 43%), colorless liquid 19, nQ = 1.5533.

Elemental analysis, ^ £ 1 ^ 31 ^ 5 ^^ 5

Lask. (S): C, 62.81; H, 7.78; N, 17.44 Found (S): C, 63.05; H, 7.84; N, 17.81

Example 69 5- (1-Phenyl-1,2,3,4-tetrazol-5-yl) valeric acid (2.5 g) is dissolved in dimethylformamide (5D ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise with stirring and ice-cooling to this mixture, which is stirred for 30 minutes at room temperature. Diethylamine (0.9 g) is added to the mixture with stirring at room temperature and stirred for 2 hours. Dimethylformamide is distilled off under reduced pressure, after which acetone is added to the obtained residue, and the insoluble matter is separated by filtration. The mother liquor is concentrated and then purified by column chromatography (Kieselgei 60, Merck 4 Co.). Elution with chloroform gives N, N-diethyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide (1.2 g), colorless liquid, = 1.53 ° C.

Elemental analysis, ^ i6 ^ 23 ^ 5 ^:

Lask. (K): C, 56.40; H, 6.63; N, 21.92 Found (S): C, 56.69; H, 6.80; N, 21.71

Example 70 5- (1-Cyclohexyl-1,2,3,4-tetrazol-5-yl) valeric acid (2.5 g) is dissolved in tetrahydrofuran (50 ml), and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture while stirring and cooling on ice and stirring at room temperature for 30 minutes. N-Ethyl-cyclohexylamine (1.5 g) is added dropwise at room temperature to the mixture, which is further stirred for 2 hours, letrahydrofuran is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The chloroform is distilled off and the residue obtained is subjected to column chromatography (silicon gel 60, manufactured by Merck & Co., eluting with chloroform) to give N-ethyl-N-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5- yy1i) -valeramide (2.6 g), colorless liquid, n; δ = 1.4970.

Elemental analysis, ^ £ 0 ^ 35 ^ 5 ^ 1

Lask. (K): C, 66.44; H, 5.76: N, 19.37 Found (%): C, 66.78; H, 9.56; N, 19.52;

Example 71 5- (1-Methyl-1,2,3,4-tetrazol-5-yl) valeric acid (1.3 g) is dissolved in dimethylformamide (50 ml) and triethylamine (1.1 3) is added. Isobutyl chloroformate (1.5 g) is added dropwise to the mixture while stirring and cooling on ice, and the mixture is stirred for 30 minutes at room temperature. Diethylamine (0.9 g) is added dropwise at room temperature with stirring to the mixture, which is stirred for 2 hours. Dimethylformamide is distilled off under reduced pressure and the residue is purified by flash chromatography (Wakogel C-200). Elute with benzene-chloroform (1: 1) and distill the eluate under reduced pressure to give N, N-diethyl-5- (i-methyl-1,2,3,4-tetrazol-5-yl) valeramide (0.7 g). , colorless liquid, b.p. 190-2 ° C, (bath temperature) / 0.07 mmHg, n = 5 = 1.4907.

Elemental analysis, C ,, H91N_0: il 33 7 3 6 71

Lask. (S): 0.55.20; H, 8.85; H, 29.27 Found (S): C, 55.48; H, 8.98; N, 29.34

Examples 72 to 76

As described in Example 71, the following compounds are prepared from the appropriate starting materials.

(72) N, N-Diethyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n = 1.4970 (73) N, N- diethyl_5_ (i> 2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n “= 1.4867 (74) N-ethyl-N-cyclohexyl-5- (1-methyl-1,2,3 , 4- and 8-tetrazol-5-yl) valeramide, colorless liquid, mp 1.5085

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

(76) 1H-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valericide, white prisms (ether),. mp. 73-75 ° C.

Example 77 3- (1-Methyl-1,2,3,4-tetrazol-5-yl) methylthiopropionic acid (2 g) is dissolved in tetrahydrofuran (50 ml) and triethylamine (1.1 g) is added to the solution. Isobutyl chloroformate (1.5 g) is added dropwise with stirring and ice-cooling to the mixture, which is stirred for 30 minutes at room temperature. Diethylamine (0.9 g) is added dropwise to the mixture with stirring at the same temperature, and the mixture is stirred for a further 3 hours. The solvent is distilled off, after which the residue obtained is obtained by silica gel chromatography (silica gel 60, manufactured by 34 7 3 6 7 1

Merck & Co., eluting with chloroform: methanol = 50: 1, v / v) to isolate N, N-diethyl-3- (1-methyl-1,2,5,4-etrazol-5-yl) methylthio -propionamide (1.5 2 "g), colorless liquid, so-called 1.5200.

Elemental analysis, C H, J, 0S: j.ϋ y task. (¾): 0.46.67; H, 7.44: N, 27.21 Found (X): 0.46.85; H, 7.61; N, 27.39

Examples 78 to 80

As described in Example 77, the following compounds are prepared using the appropriate starting materials.

(78) N, N-Diethyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-propionamide, colorless needles (recrystallized from ether), m.p. 5S - 59 ° C

(79) N, N-Diethyl-3- [1- (4-ethylphenyl) -1,2,3,4-tetrazol-95-yl) / methylthiopropionamide, colorless liquid, n ~ = 1 , 5499 (80) N-ethyl-N'-cyclohexyl.Li-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionic acid, pale yellow liquid, nf = 1.5277

Example 31

Thionyl chloride (10 ml) is added to 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyric acid (2 g) and the mixture is refluxed for 1 hour. Excess thionyl chloride is distilled off under reduced pressure, after which dry benzene is added to the residue and the remaining small amount of thionyl chloride is removed as an azeotrope of benzene. The residue is dissolved in dry ozenene (50 ml) and N-methylcyclohexylamine (2.8 g) is added dropwise with stirring and ice-cooling. The mixture is stirred for 1 hour at room temperature and added to the reaction mixture

II

35 7 36 7 1 benzene. The mixture is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution, and dried over sodium sulfate. After distilling off benzene, the residue is subjected to column chromatography (Wakogel C-200) eluting with a column of benzene-chloroform (4: 1, v / v) to give N-methyl-N-cyclohexyl-4- (1-methyl-1,2,3, 4-Tetrazol-5-yl) thio-butyramide (2.3 g), pale yellow liquid.

NMR: δ $ 1.00 - 2.00 (10 H, broad), 1.80 - 2.70 (4 H, m), 2.73 (3H, d, J = 6 Hz), 3.28 ( 2H, t. J = 0Hz), 3.85 (3H, s), 3.20 - 4.50 (1H, m)

Elemental analysis, C ,, HOTNc0S: task. (?): C, 2.5 2.5; H, 7.79; N, 23.55 Found (K): C, 52.65; H, 7.83; N, 23.51

Examples 82-100

By the method described in Example 81, the following compounds are obtained.

(82) N-ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, = 1.5327 (83) Ethyl N-phenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, pale yellow liquid, n 3 b = 1,553

(84) 5- (3-morpholinocarbonylpropylthio) -1-methyl-1,2,3,4-tetrazole, white needles (recrystallized from petroleum ether-ethanol), m.p. 71-73 ° C

(85) 5- [3- (4-Acetyl-piperazinocarbonyl) -propylthio] -1-methyl-1,2,3,4-tetrazole, white crystalline powder (recrystallized from ligroin-acetone), m.p.

90-91.5 ° C

35 7 36 7 1 (85) - [2- (3,4-Dimethoxyphenylethyl) -4- (1-methyl-1,2,3,4-tetrastal-5-yl) thio-butyramide, colorless flakes ( recrystallized from hexane-ethyl acetate), m.p.

70.5-71.53C

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

5-yiiii) thio-butyramide, colorless liquid, m.p. = 1.535 ° C

(88) N-ethyl-N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-19-yl) thio-butyramide, colorless liquid, nQ = 1.5596 (8?) N '-cyclohexyl-N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (i-neyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, nj = 1.5470 (9C) N-methyl-N- (2-enienylmethyl) -4- (i-methyl-1,2,3,4-tetrazal-5-yl) thio-butyramide, colorless liquid, n ä r 1.5706

(91) N- (2-pyridyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (hexane-ethyl acetate), m.p. 95-9 ° C

(92) N-Furfuryl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -

thio-butyramyci, colorless flakes (hexane-ethyl acetate)., m.p. 71-73 ° C

(3S, 4R, 4'- (dipetyl-3x, amino) phenyl) -4- (1-methyl-

1.2.3.4-tetrazol-5-yl) thio-butyramide, colorless prisms (hexane-ethyl acetate), m.p. 144-147 ° C

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

(95) N-Methyl-N- (2-tetrahydropyranyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) tic-butyridine, colorless liquid, n · "· 1 · ' '- i; rn II.

37 7 3 6 71 (96) N-N-cyclobexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n = 1, 5293 (97) N-ethyl: N- (4-hydroxycyclohexyl) -4- (i-methyl-1,2,3,4-entrol-5-ylthioethyramide), colorless liquid, n * = 1 , 5363 (93) N-ethyl-N- (2-acetyloxycyclohexyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl] thio-butyramide, colorless liquid, "D '---- (99) 5 - (3-thioidinecarbonylpropyl) -1-methyl-1,2,3,4-2 2 tetrazole, colorless liquid, n = 1.5310 (10) (N) -ethyl-N-cyclohexyl-4- (1- phenyl-1,2,3,4-p-tetrathol-5-yl) thio-butyramide, colorless liquid, n - = 1.5590.

Example 101

Thionyl chloride (10 ml) is added to 5- (1-phenyl-1,2,3,4-tetrazol-5-yl] valenic acid (1.8 g) and the mixture is refluxed for 1 hour, the excess thionyl chloride is distilled off under reduced pressure, after which dry benzene is added to the residue. and the remaining small amount of thionyl chloride is removed as an azeotrope of benzene, the residue obtained is taken up in dry pyridine (50 ml) and N, N-diethylamine (1.5 g) is added dropwise to the solution under cooling and stirring under ice-stirring. The mixture is washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. re ° yv .1 i -1. 2, 3 '-1 etrats o- 5 - yy 1 i) va 1 eramidia (T.' n '· -a e- ! v n ne * '“' n *" - "1 'n 3.

73671

Adult analysis, C ,, Hr-N ^ C: »_; y ('<v \, r * r“ t “f ^. -' O * 4. 'o" 7 ο Λ _, Z. Wa, 5 / - S_ * r O - jt <1 »; *«>. <«A s .C e ** · cr> - ·;>, (v \, ^ <· txo,. '-? *? Q, \ · Ovti “ac- - ^ '' - - ·« - · * t '·?' · '-> - s /> t ^ _

Examples 102 to 10 4

The following compounds are obtained by the method described in Example 101.

{1C, N-methyl-N'-cyclohexyl-5- (1-cyclohexyl-1,2,3,4-tetrazol-1'-yl] valeramide, white crystalline powder

Q

(recrystallized from ether), m.p. 92-95 ° C-ethyl-N-cycloxymethyl- (5- (i-methyl-1,2,5,4- "1 g terrazol-5-yl)) carving amide, colorless liquid, n = 1.5085 L> (104} N-ethyl-N-cyclohexyl-5- (1-enyl-1,2,3,4-tetrazol-5-yl) valeramide, white orismoja (ether), _ _ “7 * 7 -r C * - * o

Sp i / J * "iJ w

Example 105 4- (i-Methyl-1,2,3,4-tetraisol-5-yl) thiobutyric acid (2c) and N-ethyl-N-cyclohexylamine (1.4 g) are added in dioxane (20 ml). To a mixed solvent of methylene chloride (20 ml) and to the solution is added dropwise, with stirring, N, N '- uis / k 1 one · <· nyy .. irbodiimide (2.1 g) at 10 - 2 0 0 0 solution in ethyl chloride (5 ml). At the same time, cool the outside with ice. After the addition of the solution, stirring is continued at the same temperature for 5 hours. The crystals separated from the reaction mixture are separated by filtration and the filtrate is concentrated under reduced pressure. The residue obtained is dissolved in methylene chloride (100 ml). The organic layer is washed with 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, and the like. kur vitaan natriums ui aa account. The solvent is removed under reduced pressure and a residue is obtained. 39 7 36 7 1 is chromatographed (Wakogei C-200) without eluting the column with chloroform to give N-ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide (0.8 g), colorless nests, n £ 7.5 = 1.5327

Elemental analysis, C14H25N50S:

Lask. (8): C, 53.99; H, 8.09; N, 22.49 Found (S): C, 54.12; H, 8.14; N, 22.56

Examples 106 to 115

The following compounds are obtained by the method described in Example 105.

(1fl6) N-ethyl-N-phenyl-4- (1-methyl-1,2 ', 3,4-tetrazol-5-yl) thiohutyramide, pale yellow liquid, n = 1.5534 (107) 5- (3-morfolinokarbonyylipropyylitio) -l-methyl-

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

(108) N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-

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

(109) N-ethyl-N-benzyl-4- (1-methyl-1,2,3,4-tetrazol-19-yl) thio-butyramide, colorless liquid, n = 1.5596 (110) N -methyl-N- (2-thienylmethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n = 1.5706

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

t (112) N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-1H-tetrazol-5-yl) thio-butyramide, colorless liquid, n * = 1.5293 7 3671 (.1..7] λ - ° type 1y <c re k 3y y 1 i-4 - ί I- f eny y li -1,2,3,4-

1B

t s t r ε t s c I - 5 - y y I i) t i c - b u t y r a m i d i, colorless liquid, n ^ =; ", ε, Τ- (114; - ο t y y 1: - X - s y <_ c -; e <s y y 1 _ - 5 - (i - s y k 1 o h e k s y y 1 i - 1,2,3,4 -

tetrsiscl-5-yy li.) vsiers-niöi, white crystalline powder (ester), m.p. 31-95 ° C

(115) N-ethyl-N-cyclohexyl-5- (i-phenyl-1,2,3,4-tetrahydro-5-yl) vooramide, white prisms (ether).

mp. - - eg e r k k i 1J. Dissolve 6 p - n 1 trophenyl 4 - (1 - methyl 1 - 1,2,3,4 - 1 stratol - 5 - yl) thiobutyrate (1.2 g) in dimethylformamide ( 4 C rl) and amine (1 g) (2.0 g) is added. The reaction mixture is allowed to stand at room temperature overnight and then concentrated under reduced pressure.

The resulting residue was collected on a column (Wakogel C-200) on a column of benzene-chloroform 11a (4: 1, v / v) and boiled. again from hexane-ethyl acetate to give N-cyclohexyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide (1.8 g), colorless needles, m.p. 116.5 - 117.5 ° C

Elemental analysis, C, 0 H,. N c 0 S: L ^ s k. :: 1, 3 Ci. . · - 6 ·, "., 47;, 7 1

Found (1): 0.50.35; -, 7.37; H, 24.65

Examples 117-125

By the method described in Example 116, the following compounds are obtained.

(177) Ne ty 1 i - N - ny k 1 oh ek Cause 3. i-4- (i-mey y 1 i -1,2,3,4-te trats o1-5-y y1i) 15 o -butylamide, colorless liquid, 17, 5 _, rT7.

rrj - li 41 73671 (118) N-ethyl-n-phenyl-4- (1-methyl-1,2,3,4-tetrazol-26,5-yl) thio-butyramide, pale yellow liquid, n = 1 , 5534 (119) N- [2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-

1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 70.5-71.5 ° C

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

(121) N-ethyl-N-cyclohexylmethyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, = 1,5293 (122) N-ethyl- N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, white prisms (ether),

mp. 73-75 ° C

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

Example 124

Methyl 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thiobutyrate (1.4 g), sodium ethylate (0.5 g) and N-ethylcyclohexylamine (5 ml) are added. to ethanol (50 ml) and the mixture is reacted in an autoclave at 140-150 ° C at 110 atmospheres for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (200 ml). The solution is washed with 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was subjected to column chromatography (Wakogel C-200) eluting with chloroform to give N-ethyl-N-cyclohexyl-4- (1-methyl-1,2,3,4 -tetrazol-5-yl) thio-butyramide (0.6 g), colorless liquid, n 7.5 = 1.5327

D

Elemental analysis, C ^ Hgs ^ OS

Calculated (%) C 53.99; H 8.09; N 22.49

Found (%) C 54.19; H 8.21; N 22.68

Examples 125-127

The following compounds are obtained by the method described in Example 124.

(125) Ν-Γ2- (3,4-dimethoxyphenyl) ethyl] -4- (1-methyl-

1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless flakes (hexane-ethyl acetate), m.p. 70.5-71.5 ° C

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

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

Examples 128-133

The following compounds are obtained by the method described in Examples 71 and 777.

{128) N-hexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless needles (ethyl acetate-hexane), m.p. 80.5-82.5 ° C

11 43 7 3 6 71

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

(130) N-ethyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) butyramide, colorless needles (ether),

Sp. 77.5-80 ° C

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

(132) N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -

valeramide, colorless needles (ethyl acetate-hexane), m.p. 100-102 ° C

(133) N-methyl-N-cyclohexyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless oily substance, n2i = 1,5396

D

Examples 134-182

The following compounds were prepared according to the procedures described in Examples 6 and 81: (134) N-Ethyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) -methylthio-propionamide, colorless flakes (hexane ethyl acetate), m.p. 61.5-62.5 ° C.

(135) N-Ethyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methylthio-propionamide, pale yellow liquid, n2? = 1.5253

D

(136) N-ethyl-3- (1-isopropyl-1,2,3,4-tetrazol-5-yl; '-)' methylthio-oropionamide, colorless liquid, n22 = 1.5179

D

44 7 3 6 71 (137) N-ethyl-3- (1-butyl-1,2,3,4-tetrazol-5-yl) methyl

thio-oropionamide, pale yellow liquid, n1 ^ = 1.5149 ‘D

(138) N-ethyl-3- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless needles (hexane-ethyl acetate), m.p. 131-132 ° C.

(139) N-ethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless needles (hexane-ethyl acetate), m.p. 88-89.5 ° C.

(140) N-ethyl-3- [1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl] methylthiopropionamide, colorless needles (hexane-ethyl acetate), m.p. 88-89.5 ° C.

{141) N, N-Diethyl-3- (1-Bytyl-1,2,3,4-tetrazol-5-yl) -methyl-thiopropionamide, red-brown liquid, n ^ 6 = 1.5107 (142) N, N-Diethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) -methylthiopropionamide, yellow-brown liquid, n = 6 = 1.5625

D

(143) N-ethyl-4- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methyl-thio-butyramide, pale yellow liquid, n ^ 6 = 1.5224 (144) N-ethyl- 2- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methylthioacetamide, pale yellow liquid, n 2 = 1.5305.

D

(145) N-Ethyl-2- (1-ethyl-1,2,3,4-tetrazol-5-yl) -ethylthioacetamide, pale yellow liquid, n 2 = 1.5274.

D

(146) N-ethyl-2- (1-ethyl-1,2,3,4-tetrazol-5-yl) -propylthioacetamide, pale yellow liquid, n23 = 1.5210.

D

11 45 7 3 671 (147) N, N-Diethyl-4- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methylthiobutyramyl, pale yellow liquid, n2 = 1.5128

D

(148) N-Methyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methylthiopropionamide, colorless liquid, n2 = 1.5320.

D

(149) N-Butyl-3- (1-ethyl-1,2,3,4-tetrazol-5-yl) -methylthio-oropionamide, pale yellow liquid, n21- = 1.5111.

D

(150) N-methyl-N- (2-thienylmethyl) -3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless liquid, n22 = 1.5697.

D

(151) N- (2-thiazolyl) -3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, pale yellow prisms (hexane-ethyl acetate), m.p. 113-114 ° C.

(152) N, N-Diethyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) -thiobutyramide, colorless liquid, n · · ® = 1.5592.

D

(153) N, N-Diethyl-4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, n 2 O = 1.5237.

D

(154) N-Pentyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide, colorless crystals (hexane-ether)

Sp. 67.5-68.5 ° C.

(155) N- (4-methoxyphenyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless crystals (ethanol) M.p. 148-150.5 ° C.

(156) N-butyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless crystals (ethyl acetate-hexane),

Sp. 71-73 ° C.

46 73671 (157) N- (2-thiacyl-4- (i-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide, colorless crystals (methanol),

Sp. 175-176.5 ° C.

(158) N- (methoxyphenyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless crystals (hexane-ethyl acetate) M.p. 122.5-124 ° C.

(159) N- (3-methoxyphenyl-4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless crystals (hexane-ethyl acetate) mp 122.5-124 ° C .

(160) N-methylpropyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless liquid, = 1.5066.

D

(161) N-butyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thiobutyramide, colorless liquid, η 2 = 2.5 = 1.5590.

D

(162) N-Butyl-3- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-propionamide, colorless crystals (ethyl acetate-hexane)

Sp. 80.5-82.5 ° C.

(163) N-butyl-5- (1-methyl-1,2,3,4-tetrazol-5-yl) -thiovaleramide, colorless crystals (ethyl) M.p. 53.5-55 ° C.

(164) N-ethyl-N-cyclohexyl-5- [1- (4-methoxyphenyl) -1,2,3,4-tetrazol-5-yl] -valeramide, colorless liquid, n16 = 1.5343.

D

(165) N-ethyl-N-phenyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless liquid, n = 1.5640.

D

(166) N-ethyl-N-cyclohexyl-5- [1- (4-acetyloxyphenyl) -1,2,3,4-tetrazol-5-yl] valeramide, white powdery crystals (ethyl acetate-hexane), m.p. 88-90 ° C.

11 47 7 3 6 71 (167) N-ethyl-N-cyclohexyl-5- [1- (4-hydroxyphenyl) -1,2,3,4-tetrazol-5-yl] valeramide, colorless granules (ethanol), m.p. 131.5-183 ° C.

(168) N-ethyl-N-cyclohexyl-5 - [- 1- (4-ethylphenyl) -1,2,3,4-tetrazol-5-yl] valeramide, colorless needles (ethyl acetate-hexane) M.p. 54-55.5 ° C.

(169) N-ethyl-N-cyclohexyl-5- (1-butyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n20.5- 1.5013.

D

(170) 5- [3- (4-methylpiperazinylcarbonyl) propyl] -1-phenyl-1,2,3,4-tetrazole, pale yellow needles (ethyl acetate-hexane) M.p. 62-64 ° C.

(171) N-ethyl-N-cyclohexyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) propionamide, colorless prisms (ethanol),

Sp. 137-138 ° C.

(172) 5- [4- (4-methylpiperazinylcarbonyl) butyl (J-phenyl-1,2,3,4-tetrazole, pale yellow liquid, n15.5 = 1.5543.

P

(173) N- (4-methoxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetraol-5-yl) valeramide, colorless needles (hexane-ethyl acetate) M.p. 89-90.5 ° C.

(174) N-ethyl-N- (2-hydroxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n * 6 = 1.5501.

D

(175) N, N-Dipropyl-4- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless liquid, n--5.5 = 1.5311.

D

48 73671 (176) N-methyl-N- (2-furylmethyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, η 2, δ = 1.5490.

D

'177) N-ethyl-N-cyclooctyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, coloring liquid, n * ® »5 = 1.5418.

D

(178) N-ethyl-N- (4-hydroxycyclohexyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n15-5.5505.

D

(179) N-ethyl-N-cyclopentyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless liquid, n 2 O = 1.5446.

D

(180) N- (2-thiazolyl) -5- (1-phenyl-1,2,3,4-tetrazol-5-yl) -valeramide, colorless needles (ethanol), m.p. 166-168 ° C.

(181) N-ethyl-5- (1-phenyl-1,2,3,4-tetrazol-5-yl) valeramide, colorless flakes (ethyl acetate-hexane),

Sp. 60-61.5 ° C.

(182) N, N-Diethyl-3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, tan liquid, n26 = 1.5625.

D

Example 133 To 3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropylic acid (20 g) was added thionyl chloride (30 ml), and the mixture was stirred at 50 ° C for 3 minutes. Excess thionyl chloride was separated by distillation as well as by azeotropic distillation with benzene.

Separately, 25% aqueous ammonia (20 ml) and potassium carbonate (12.8 g) were dissolved in aqueous acetone I. A.c 7 3 671 1 * 50 ml - 30 ml ;. To this solution was added dropwise the acid chloride described above in acetone (30 ml) with stirring and ice-cooling, and the mixture was stirred for 2 hours. The acetone was then separated by distillation, the aqueous phase was saturated with sodium chloride and extracted with chloroform. The chloroform solution was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate to give 3- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide (9.2 g) as colored flakes. .

M.p., 74-76 ° C.

Examples 184-728

The following compounds were prepared as described in Examples 6 and 183: (184) 3- (1-phenyl-1,2,3,4-tetrazol-5-yl) methylthio-

propionamide, colorless prisms {recrystallized from ethyl acetate) M.p. 91-92 ° C

(135) 3- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless needles (recrystallized from ethanol) M.p. 137-1,4t (186) 4- (1-methyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless prisms (recrystallized from ethanol),

Sp. 90-92 ° C

(187) 3- (1-butyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, colorless flakes (recrystallized from ethyl acetate) M.p. 79-01 ° C

(188) 3- (1-methyl-1,2,3,4-tetrazol-5-yl) methylthiopropionamide, white granules (recrystallized from ethanol) M.p. 105.5 - 10'-C

7 3 6 71 (139) 4- (1-ethyl-1,2,3,4-tetrazol-5-yl) methylthio-

butyramide, colorless prisms (recrystallized from ethyl acetate-hexane) M.p. 73-75 ° C

(190) 4- (1-phenyl-1,2,3,4-tetrazol-5-yl) thio-butyramide, colorless needles (recrystallized from ethyl acetate-hexane) M.p. 115-116.5 ° C

(191) N- (2-phenylethyl) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thio-butyramide, colorless needles (recrystallized from ethyl acetate-hexane) M.p. 58.5-60 ° C

Claims (2)

A process for the preparation of a tetrazole derivative of formula (Ia), N-N. R3 Il /. N U_ (A) i-B-CON (Ia) \ R «In R 1 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl or phenyl? A is sulfur or C1-C5 alkylenethio; 1 is 0 or 1? B is C 1 -C 6 alkylene; R 3 and R 4, which may be the same or different, are hydrogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, phenyl, C 3 -C 12 cycloalkyl-C 1 -C 6 alkyl, phenyl-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl alkyl, a heterocyclic group selected from pyridyl, pyrimidinyl, tetrahydropyranyl, thioazolyl, thienyl and furyl, or C 1 -C 6 alkyl substituted with said heterocyclic group, or R 3 and R 4 together with the nitrogen atom to which they are attached may form piperidinone, piperazine or morpholinone which may be substituted by C 1 -C 6 alkyl or C 1 -C 6 alkanoyl; said cycloalkyl, phenyl and phenyl-C 1 -C 6 alkyl may have one or two substituents on the cycloalkyl or phenyl ring selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl, halogen, NFN-di (C 1 -C 6 alkyl); alkyl) amino, nitro, aminosulfonyl, hydroxy and C 1 -C 6 alkanoyloxy? provided that when 1 is 0 and R 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or phenyl, one of the two substituents R 3 and R 4 is not hydrogen, methyl, ethyl or benzyl and the other substituent is not hydrogen or ethyl, and R3 and R4 together with the nitrogen atom to which they are attached do not form morpholino or a pharmaceutically acceptable salt thereof, characterized in that the carboxylic acid compound of formula (II) 52 7 3 6 71 N -? Li NT _ (AJi-B-COOH (II) R 1 wherein R 1, h, 1 and R are as defined above, or a reactive derivative thereof is reacted with at least an equivalent molar amount of an amine of formula (III) R 3 HN (III) wherein r 3 and are as defined above above, or with its reactive derivative II 53 7 3 6 71 1. Frequency of the tetrazole compound of formula (Ia) N-N I I N I R3 (Ia) \ / N (A) 1-B-CON | X R4 R1 is R1, C1-C8 alkyl, C8-C8 cycloalkyl or phenyl; A is selected from C 1 -C 6 alkylthio; 1 is 0 or 1; B is C 1 -C 6 alkylene; R 3 and R 2 are fused or substituted by C 1 -C 8 alkyl, C 3 -C 12 cycloalkyl, phenyl, C 3-3 cycloalkyl (C 1 -C 6) alkyl, phenyl (C 1 -C 6) alkyl, hydroxy (C 1 -C 6) alkyl, en heterocyclic group, preferably pyridyl, pyrimidinyl, tetrahydropyranyl, thioazolyl, thienyl and furyl, or C 1-4 alkyl substituted with some heterocyclic group, or R 3 and R 6 the same is a quaternary atom, a mixture of piperidinone, piperazinone or morpholinone, a sorbent substituent with C 1 -C 6 alkyl or C 1 -C 6 alkanoyl, a cycloalkylene, phenyl and phenyl (C 1 -C 6) alkylene cycloalkyl or the phenyl ring may be substituted or substituted with C 1-6 C 1-4 alkoxy, C 1-4 alkyl, halogen. N, N-di (C 1 -C 6) alkylamino, nitro, aninosulfenyl, hydroxy and C 1 -C 6 alknaoyloxy, fertzate, n 1 to 0 and R 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl or phenyl the substituents R3 and the like: are methyl, ethyl or benzyl or benzyl and the other substituents are ethyl, and R3 and R are the same as those used in the form of a morpholine or a pharmaceutically acceptable site, kännetecknad av att en carboxyisyraförening med formuleln (II)