NO129573B - - Google Patents

Description

Analogous process for the production of 2-(thienyl-3'-amino)-1,3-diazacycloalkenes with blood pressure-lowering action.

The object of the invention is an analog method

for the preparation of new 2-(thienyl-3<1->amino)-1,3-diazacycloalkenes with blood pressure-lowering action and with the general formula

where ■ ....■ ... ■ .....; ■>■:.■■:■■:-■■■■ Rj_> R206 R3 Denotes hydrogen, low molecular weight alkyl, halogen,; cyan or phenyl,

R2 and R^ together denote a trimethylene or tetramethylene chain, Z denotes a straight-chain or branched alkylene residue with

2-4 C atoms, of which 2-3 C atoms are in the ring as well as their acid addition salts.

The method used according to the invention is characterized in that one

a) reacts thienyl-3-isothiuronium salts, -thiourea compounds, -guanidines, -nitroguanidines or -cyanamides with

formula II

where R denotes the groups R^ denotes low molecular weight alkyl and X denotes an acid anion, preferably the anion of a hydrogen halide acid, with alkylenediamines of formula III

optionally in the form of their monosalts, or

b) ring-closing N-(3'-thienyl)-N'-aminoalkyl-thiourea compounds of formula IV

where A denotes oxygen or sulphur, or

c) reacts aminothiophenes of formula V

with 2-alkylmercapto-1,3-diazacycloalkenes of formula VI

preferably in the form of their salts,

and optionally halogenates prepared compounds where at least one of the residues R^, Ro or R^ denotes hydrogen, and/or transfers the products to acid addition salts with physiologically applicable acids..

a) Preparation of the new compounds of formula I according to method a) can be carried out by simple heating (0.5 - 3 hours)

of isothiuronium salts of formula IIa with alkylenediamines of formula

III at temperatures between 80 and 200°C. As an alkylenediamine, one can e.g. use ethylenediamine, 1,2-propylenediamine or 1,3-propyldiamine, 2,3^diaminobutane, 1,3-diaminobutane or 1,2-diamino-, butane. The reaction can also be carried out in a solvent at temperatures between 60 and 140°C. Solvents that contain polar groups, such as water or lower alcohols of the methanol, ethanol, n- and iso-propanol type, can be used above all. However, one must heat for a longer time in the presence of solvent (5 - 20 hours) and preferably work under pressure. In both cases, an excess of alkylenediamine (110 - 150%) is preferably used.

Isothiuronium salts with formula III are obtained in a known manner by heating corresponding thiourea compounds msd formula II with a lower alkyl halide or dialkyl sulfate in a solvent, e.g. a low alcohol. The thiourea compounds can also be prepared according to the method known in the literature (see Houben-WeylJ volume 9> page 887 et seq.) from the correspondingly substituted aminothiophenes.

Instead of isothiuronium salts, the thiourea compounds of formula II b can also be reacted directly together with alkylenediamines of general formula III, preferably in vacuum, by heating to temperatures between 100 and 200°C. An excess of 1,2-alkylenediamine is preferably used.

Likewise, the products can be prepared by the action of alkylenediamines of general formula III and their monosalts on thienyl-3-guanidines of formula 11c or their salts with inorganic or organic acids. In this case, the turnover can also take place both with and without solvent. The temperatures are between 100 and 200°C, preferably 130 to 150°C. Higher alcohols, nitrobenzene, etc. are used as solvents. Examples of inorganic salts are hydrochlorides, hydrobromides, hydroiodides, sulfates

and nitrates, organic salts may be benzene or toluene sulphonates.

Instead of thienyl-3-guanidines, one can also use

the corresponding nitroguanidines of formula Ild as starting materials, and reacting these with alkylenediamines of general formula III in suitable solvents such as e.g. ethanol, propanol, butanol or amyl alcohol. The starting substances can be prepared by reacting the corresponding aminothiophene with N-methyl-N-nitroso-N'-nitroguanidine according to the Journal of the American Chemical Society, volume 69, page 3028 (1947).

The reaction of thienyl-3-cyanamides of formula Ile with alkylenediamines or their monosalts is preferably carried out at temperatures between 50 and 200°C, especially 100 to 150°C, with or without solvent. It is an advantage to add an excess of alkylenediamine or alkylenediamine salt and to choose the solvent so that the reaction can take place in a homogeneous phase. Higher alcohols such as butanol, amyl alcohol or hexanol can be used as solvents, and suitable salts of alkylenediamines are e.g. the mono-hydroiodides or mono-p-toluene sulphonates.. Thienyl-3-cyanamides can also be prepared from corresponding thienyl-3-thiourea compounds and copper sulphate in alkaline solution.

b) The N-(3,-thienyl)-N'-(aminoalkyl)-thiourea compounds or urea compounds of formula IV, which are starting materials for

the method according to b), is prepared as indicated in Journal of Organic Chemistry, volume 24, page 8l8 (1959) by reaction of correspondingly substituted thienyl-3-isocyanates or -isothiocyanates with alkylenediamines of formula III. The ring closure takes place by heating to temperatures between 150 and 200°C in the presence or without solvent, preferably working under an inert gas atmosphere, e.g. nitrogen.

c) The reaction of 3-amino-thiophenes of formula V with alkyl-mercapto-1,3-diazacycloalkenes of formula VI can likewise take place

with or without solvent. However, one must choose a sufficiently high temperature so that alkyl mercaptans can be removed from the reaction solution. Generally, temperatures between 70 and 200°C are used. A higher boiling point can be used as a solvent

ethers, alcohols such as methanol, ethanol, propanol, saturated cyclic hydrocarbons such as cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene and chlorinated hydrocarbons such as chloro- and dichlorobenzene.

The alkylmercapto-1,3-diazacycloalkenes of general formula VI, which are used in the form of their salts, for example the hydro-iodides, can, as is known, be prepared by alkylation of the corresponding alkylenthiourea compounds according to Organic Syntheses III, page 394.

If desired, compounds of formula I in which at least one of the substituents R-p Rg or R^ denotes hydrogen can be halogenated. One then arrives at compounds where R-^ and/or R ? and/or R^ denotes one or more halogen atoms. As a halogenating agent, elemental bromine, chlorine, sulfuryl chloride, N-chlorosuccinimide, bromosuccinimide, 1,3-dichloro-5,5-dimethylydantoin or iodine monochloride can be used. Depending on the halogenating agents, ether, methylene chloride, chloroform, carbon tetrachloride, carbon disulphide, glacial acetic acid, nitrobenzene, thionyl chloride or sulfuryl chloride are then used as solvents, at temperatures between 0°C and the solvent's boiling point, possibly with the addition of catalysts such as e.g. aluminum chloride or iron III chloride.

The compounds of general formula I can be transferred by usual methods to corresponding acid addition salts. Inorganic or organic acids can be used, e.g. acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, citric acid, tartaric acid, ascorbic acid, oxyethanesulfonic acid, hydrochloric acid or hydrobromic acid.

Compounds produced according to the invention constitute, both in free form and in the form of their salts, valuable therapeutic agents with interesting pharmacological properties, particularly blood pressure-lowering action. They can be processed using the usual auxiliaries and carriers into all usual forms of preparation for pharmaceutical purposes.

The examples below shall further illustrate the invention:

Example 1.

a) 2-(thienyl-3'-amino)-1.3-diazacyclopentene-(2)

30>0 6 3'-thienyl-S-methyl-isothiouronium hydroiodide (melting point 113 - 115°C), prepared from N-3-thienylthiourea (melting point 185 - 187°C) and methyl iodide in absolute methanol, shaken together with 10.8 ml of ethylenediamine and 125 ml of methanol for 20 hours at 100°G in an autoclave. After cooling, the methanol is distilled off under vacuum, the residue is dissolved in dilute hydrochloric acid, insoluble material is filtered off and the aqueous hydrochloric acid phase is shaken several times with methylene chloride. The water phase is then filtered on activated charcoal and made alkaline while cooling with concentrated caustic soda. The precipitated base is filtered off, 'dried and recrystallized from benzene (melting point 155 ~ 156°^)• From the free base, the hydrochloride of 2-(3'-thienylamino)-1,3~diazacyclopentene-(2) is obtained with ethereal hydrochloric acid , which is recrystallized from isopropanol/petroleum ether (melting point 187 - 188°C).

Analogously, you get:

b) 2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2) (melting point 156 - 158°C, hydrochloride (melting point 200 - 202°C). c) 2-(4' -methylthienyl-3'-amino)-1,3-diaza-4-methyl-cyclopentene-(2) (m.p. 172 - 173°C), the hydrochloride: m.p. 132 - 133°C. d) 2-(4'-chlorothienyl-3'-amino)-lj3~diazacyclopentene-(2) (melting point 174 - 175°C), the hydrochloride: melting point 205°C.

e) 2-(2',4'-dimethylthienyl-3'-amino)-1,3-diazacyclopentene* (2). ;f) 2-(2',4,-dichlorothienyl-3,-amino)-1,3-diazacyclopentene-(2), ■ decomposition temperature for the hydrochloride from 295°C« ;g ) 2-( 2! -chloro- 4'-methylthienyl-3''-amino)-1,'3-diazacyclopentene-(2), m.p. 1529C, the hydrochloride: melting point 228 - 229°C.: ;h) 2-(5'.-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2). ;i) 2-(4',5'-dimethylthienyl-3'-amino)-ly3-diazacyclopentene-(2). ;k). 2-(4'-ethyl-5,-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2). ;1) 2-(5'-phenylthienyl-3'-amino)-1,3-diazacyclopentene-(2)." ;m) 2-(4',5'-tetramethylenethienyl-3'-amino)-1 ,3-diazacyclopentene-(2).n)2-(4'-phenyl-5'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).;o)2-(2i chloro-4'-methylthienyl-3'-amino )!-1;, 3-dlaza-4-methylcyclopentene-(2), hydrochloride salt: melting point 168 - 169° C. ;p ) 2-( 2' , 5' - dichloro-4'-methylthienyl-3'-amino )-1^ 3-diaza;cyclopentene-(2). ;hydrochloride salt : melting point 167 — 168°C. q) 2^(2'-chlorotleny 1-3''- amino )-1, 3-diaza'cyclo'pentene-( 2 ), hydrochloride salt: melting point 181 - 182°C.. ;r) 2-( 2' -io'd-4' -methylthienyl-3' -amino ) -l;,"3-diazacyclopenteh-( 2 ),: ;HCl salt: melting point 215 - 216 C. ;s ) 2-(2', 5''"diiodo-4'-methylthienyl-3'-amino' )-1,3-diazacyclopentene-(2),;hydrochloride salt: melting point 204 - 2050C. Example 2. ' .... 2-(4'-methylthienyl-3'-amino)-1,3Ldiaza-4-methylcyclopentene -( 2). ;31> 3 g of 4'-methylthienyl-3'-S-methyl-isothiouronium-hydro-iodide-, (melting point. 119 - 120°C), prepared from 4 -methythienyl-3-" thiourea (melting point 158 - 159°C) and methyl iodide in absolute methanol, are heated with 8.2 g of -1-,2-diaminopropane for 1 hour at 130 - 150°C. A strong development of methyl mercaptan occurs. ■ After cooling, the residue is treated with dilute hydrochloric acid, where insoluble material is removed, the acidic solution is shaken several times with methylene chloride and filtered on activated charcoal. It is then adjusted alkaline with concentrated caustic soda under ice cooling. The precipitated base is filtered off, washed with a small amount of ice water, dried and recrystallized from isopropanol (melting point 173 - 174°c)' The hydrochloride is obtained with ethereal hydrochloric acid from the base, and this melts at 132 - 133°C (from isopropanol/petroleum ether) . "Analogously to example 2, the compounds listed" under example-1 can be prepared. ;Example 3. ■ .l... ;a ) 2- 2' , 5' - dibromo- 4' - methylthienyl- 3' - amino )-1.:3-diazacyclopentene-(2); 1.8 g of 2-(4'-methylthienyl-3r'-amino)-1,3-diazacyclopentene-(2) is dissolved in 15 ml of glacial acetic acid and added dropwise under, stirring at .. room temperature a solution of 1.02 ml of bromine in 15 ml of glacial acetic acid.. Then stirring continues for 20 minutes, the suspension is poured into 50 ml of ice water and the solution is made alkaline under ice cooling. The precipitated base is filtered off, washed with ice water, dried and transferred to the hydrochloride with ethereal hydrochloric acid. After recrystallization from isopropanol/ether, 2-(2',5'-dibromo-4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2) melts at 224-225° C. In the same way as under example 3, the following compounds can be prepared: b) 2-(2',5'-dibromothienyl-3'-aminoJ-1,3-diazacyclopentene-(2 ). ;c) 2-(2',5'-dibromo-4'-chlorothienyl-3'-amino)-1,3-diazacyclopentene-(2). d) 2-(2'-bromo-4', 5' -dimethylthienyl-3'-amino)-1,3-diazacyclopentene-(2). e) 2-(2-L bromo-4'-ethyl-5'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2). f) 2-(2',5'-dibromothienyl-3'-amino)-1,3-diazacyclohexene-(2). Example 4. ;a ) 2-(2'-chloro-4'-methyl-thienyl-3'-amino)-1,■ 3-diazacyclopentene-(2.) ;10 g 2-(4'-methyl- thienyl-3'-amino)-1,3-diazacyclopentene-(2) is dissolved in 125 ml of chloroform and a solution of 7>5 ml of sulfuryl chloride in 15 ml of chloroform is added dropwise at 0°C. It is heated for two hours at the boiling point. After cooling, the chloroform and excess sulfuryl chloride are distilled off in vacuum. The residue is dissolved in dilute hydrochloric acid, the hydrochloric acid phase is shaken out several times with methylene chloride and filtered on activated charcoal. The acidic solution is made alkaline under ice-cooling with 6-N caustic soda and the base is extracted with methylene chloride. The methylene chloride layer is dried, the solvent is distilled off in vacuo, the residue is dissolved in a lot of ether and the hydrochloride is precipitated with ethereal hydrochloric acid, then recrystallized from isopropanol/petroleum ether and then melts at 228 - 229°C. The melting point of the free base is 152°C (from methylcyclohexane/benzene). In a similar manner, one obtains:, ;b) 2-(2',4'-dichlorothienyl-3'-amino)-1,3-diazacyclopentene-(2), decomposition point for the hydrochloride from 295°C. ;c) 2-(2'-chloro-5'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2). ;d ) 2-(2'-chloro-4,5-dimethylthienyl-3'-amino)-1,3-diazacyclopentene-(2)-. - ;e ) 2-(2',-chloro-4'-ethyl-5'-methylthienyl-3'-amino )-1,3-diazacyclopentene-(2 j. ;f) 2-(2'-chloro— 4'-methylthienyl-3-'-amino)-1,3-diazacyclohexene-(2), the melting point of the hydrochloride is 208 - 209°C. g) 2-(2'-chloro-4',5'-tetamethylenethienyl-3'-amino)-1,3-diazacyclopentene-(2). h) 2-(2'-chloro-4'-methylthienyl-3'-amino)-1,3-diaza-4-methylcyclopentene-(2), the melting point of the hydrochloride is 168 - 169°C. ;i) 2-(2'-chlorothienyl-3'-amino)-1,3-diazacyclopentene-(2), the melting point of the hydrochloride is 181 - 182°C. ;k) 2-(2'-chloro-4'-ethylthienyl-3'-amino)-1,3-diazacyclopentene-(2 ). Example 5»; a) 2-(4'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2); 7.9 g 4'-methylthienyl-3'-S-methylisothiouronium hydroiodide; (melting point 119 - 120°C), preparation see example 2, is shaken together with 2.1 g of 1,3-diaminopropane and 25 ml of methanol for 20 hours at 100°C in an autoclave. The preparation takes place in the same way as stated in example 1. The free base melts at 166 - 167°C recrystallized from isopropanol, the hydrochloride melts at 154 - 155°C - In an analogous way you get: ;b) 2 -(4'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2). ;c) 2-(thienyl~3'-amino)-1,3-diazacyclohexene-(2). ;d) 2-(4'-chlorothienyl-3'-amino)-1,3-diazacyclohexene-(2 ). ;e) 2-(2',4'-dimethylthienyl-3'-amino)-1,3-diazacyclohexene-(2). ;f) 2-(2',4'-dichlorothienyl-3'-amino)-1,3-diazacyclohexene-(2). ;g) 2-(5'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2). ;h) 2-(4',5'-dimethylthienyl-3'-amino)-1,3-diazacyclohexene-(2). ;i) 2-(4'-ethyl-5<*->methylthienyl-3'-amino)-1,3-diazacyclohexene-(2).

k) 2-(5'-phenylthienyl-3'-amino)-1,3-diazacyclohexene-(2).

1) 2-(4'>5'-tetramethylenethienyl-3'-amino)-1,3-diazacyclohexene-(2).

m) 2-(4'-phenyl-5'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2). Example 6.

a) 2-(3'-.iodo-4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

1.8 g of 2-(4'-methylthienyl-3'-imino)-1,3-diazacyclopentene-(2.) is dissolved in 30 ml of glacial acetic acid and a solution of 1'.63 g of iodine monochloride in 17 ml of glacial acetic acid is added dropwise at room temperature . Then 75 ml of water is added, heated to 80<r>G in the course of .20 minutes

and let the mixture stand at that temperature until the iodine color disappears. After cooling, activated carbon is added, filtered and made alkaline with caustic soda while cooling, per solid residue is dissolved in ether, acidified with ethereal hydrochloric acid, the solvent is evaporated, and the residue is boiled with acetone and filtered. The hydrochloride of 2-( 2 (-iodo-4'-methylthienyl-3'-amino)-1,3,-diazacyclopentene-(2) melts, recrystallized from ethanol/diisopropyl ether, at 215-216°C.

On. analogous way - you get:

b) 2-(2'-iodothienyl-3.'-amino)-1,3-diazacyclopentene-.(2). ,

c) 2-(2'-iodo-4'-methylthienyl-3'-amino)-1,3-diaza-4-methylcyclopentene-(2).

d) 2-(2'-iodo-4'-chlorothienyl-3.'.-amino)-1,.3-diazacyclopentene-(2).

e) 2-(2'-iodo-4'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2).

f) 2-(2'-iodo-5'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

g) 2-(2,'-iodo-4'>5'-dimethylthienyl-3'-amino)-1,3-diazacyclopentene-(2). h) 2-(2'-iodo-4',5'-tetramethylenethienyl-3'-amino)-1,3-diazacyclopentene-(2 ).. i) 2-(2'-iodo-4',5' -tetramethylenethienyl-3'-amino.)-1,3-diazacyclohexene-(2). k) If in example 6a: 3j25 € iodine monochloride is used, the product is obtained: 2-(2',5'-diiodo-4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

Analogously, you get: (Melting point for the hydrochloride salt

is 204 - 205°C) ...........

1) 2-(2',5'-diiodothienyl73,'-amino)-1,3-diazacyclopentene-(.2.).

m) 2-(2',5'-diiodo-4<->methylthienyl-3'-amino)-1,3-diaza-4-methylcyclo-

n) 2-(2',5'-diiodo-4'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2). o) 2-(2',5'-diiodo-4'-chlorothienyl-3'-amino)-1,3-diazacyclopentene-(2).. p ) 2-( 2' ,5.'-diiodo-4 ('-chlorothienyl-3'-amino.)-1,3-diazacyclohexene-(2 ). q ) 2-(2' , 5'-diiodo-4'-chlorothienyl-3'-amino-no-)-1,3-diaza-4-methylcyclopentene-(2)..■

Example 7. r. ;:' -1 . ;

a) 2-(2'.V-dichloro-4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2). 5 g of hydrochloride of 2-(4'-methylthienyl-3-'-amino)-1,,3-diazacyclopentene (2) is suspended in; 10 ml of benzene is added dropwise to 5 ml of sulphuryl chloride. It is then heated to boiling for 2 hours, the benzene is distilled off, the residue is "boiled/heated" with acetone and filtered.

after recrystallization from ethanol/diisopropyl ether, the hydrochloride of 2-(2',5'-dichloro-4-methylthienyi-3'-amino)-1,3-diazacyclopentene-(2) melts at 167-168°C.

Analogously, you get:

b) 2-(2',5,-dichlorothienyl-3'-amino)-1,3-diazacyclopentene-(2).

c ) 2-(2',4',5'-trichlorothienyl-3'-amino)-1,3-diazacyclopentene-(2).

d) 2-(2',5'-dichlorothienyl-3'-amino)-1,3-diaza-4-methylcyclopentene-(2). e) 2-(2',5'-dichloro-4'-methylthienyl-3'-amino)-1,3-diazacyclohexene-(2). f) 2-(2',5'-dichloro-4'-methylthienyl-3'-amino)-1,3-diaza-4-methylcyclopentene-(2).

g) 2-(2',5'-dichlorothienyl-3'-amino)-1,3-diazacyclohexene-(2).

h) 2-(2',4',5'-trichlorothienyl-3'-amino)-1,3-diaza-4-methylcyclopentene-(2).

i) 2-(2',4',5'-trichlorothienyl-3'-amino)-1,3-diazacyclohexene-(2 ). Example 8.

2-(4'-methylthienyl-3'-amino)-1.3-diazacyclopentene-(2).

2.4 g of 4-methylthienyl-3-guanidine (melting point of the hydrochloride 201 - 202°C) and 4 g of ethylenediamine-mono-p-toluenesulfonate are heated in 25 ml of ethanol for 48 hours at the boiling point. The solvent is distilled off in a vacuum, the residue is added to diluted caustic soda and extracted several times with methylene chloride. After drying over sodium sulphate, the solvent is evaporated and the solid residue is distilled off after trituration with ether. With ethereal hydrochloric acid, the hydrochloride of 2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2)- is obtained from the free base, which melts at 200 - 202°G.

In an analogous way, the compounds indicated under example 1 can also be prepared.

Example Q.

2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

Dissolve 2.2 g of N-(4-methylthienyl-3)-N'-(aminoethyl)-thiourea (melting point 128 - 129°C) in 25 ml of ethanol, add 4 g of lead II oxide and shake for 4 hours in an autoclave at 100°C. The formed lead sulphide is filtered off and the ethanol is distilled off. The residue is dissolved in dilute hydrochloric acid, filtered through activated carbon and the acidic solution is made alkaline under ice-cooling with caustic soda. The free base is filtered off and dried. Melting point after recrystallization from isopropanol I56 - 158°C. The melting point of the hydrochloride is 200 202°C.

In an analogous way, the compounds listed under example 1 can also be prepared.

Example 10»

2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

2.6 g of 4-methylthienyl-3-nitroguanidine (melting point 188 - 189°C) and 0.85 g of ethylenediamine are heated for 24 hours in 50 ml of ethanol at the boiling point. After distilling off the solvent in vacuo, the oily residue is brought to crystallization with a small amount of water, and filtered off. To prepare the hydrochloride, the base is taken up in methylene chloride, filtered through activated charcoal and ethereal hydrochloric acid is added. After evaporation of the solvent, the oily residue crystallizes on treatment with acetone. Melting point 200 - 202°C, from isopropanol.

Analogous to example 10, the compounds listed under example 1 can also be prepared.

Example 11.

2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

3.1 g of mono-p-toluenesulfonate of ethylenediamine are dissolved

in 20 ml of amyl alcohol. A solution of 1 g of 4-methylthienyl-3-cyanamide (melting point 97 - 98°C) is added dropwise to the boiling solution.

in 20 ml of amyl alcohol and heated for a further 5 hours while boiling. After cooling, insoluble substances are filtered off, the residue is washed with ether and the filtrate is evaporated in vacuo. The residue is dissolved in dilute hydrochloric acid, filtered through activated carbon and the free base is precipitated with caustic soda under ice cooling. The base melts after recrystallization from isopropanol at 156 - 158°C. The melting point of the hydrochloride is 200 - 202°C.

Example 12.

2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2).

1.8 g of 4-methyl-3-aminothiophene hydrochloride is heated with 1.4 g of 2-methylmercapto-1,3-diazacyclopentene-(2) for 20 hours at 60 - 70°C. Then dissolve in dilute hydrochloric acid, filter with

activated carbon and made alkaline with 5 N caustic soda. The precipitated base is extracted with methylene chloride. For further purification, chromatography is performed over an aluminum oxide column. 0.05 g of 2-(4'-methylthienyl-3'-amino)-1,3-diazacyclopentene-(2) of melting point 156 - 158°G (from isopropanol) is thus obtained. Melting point of the hydrochloride 200 - 202°C:

Claims (1)

Analogous process for the preparation of 2-(3'-thienyl-amino)-1,3-diazacycloalkene-(2 )-derivatives with blood pressure-lowering action and with general formula where R^, R£ and R^ denote hydrogen, low molecular weight alkyl, halogen, cyan or phenyl, Rg and R^ together form a tri- or tetramethylene chain, Z denotes a straight-chain or branched alkylene residue with 2-4 C atoms, of which 2-3 C atoms are in the ring, as well as their acid addition salts, characterized by a) reacting thienyl-3-isothiuronium salts, -thiourea compounds, -guanidines, -nitroguanidines or -cyanamides with formula II where R can denote the groups R^ denotes low molecular weight alkyl and X denotes an acid anion, preferably the acid anion of a hydrohalic acid, with alkylenediamines of formula III optionally in the form of their monosalts, or b) ring-closing N-(y-thienyl)-N'-aminoalkyl-thiourea compounds of formula IV where A denotes oxygen or sulphur, or c) reacts with aminothiophenes of formula V with 2-alkylmercapto-1,3-diazacycloalkenes of formula VI preferably in the form of their salts, optionally halogenates prepared compounds where at least one of the groups R^, Rg or R^ denotes hydrogen, and/or transfers the products to acid addition salts by means of physiologically acceptable acids.