DK144035B - ANALOGY PROCEDURE FOR PREPARING 2- (THIENYL-3-AMINO) -1,3-DIAZACYCLOPENTENES - Google Patents

Description

i 14/1035 o

This invention relates to an analogous process for the preparation of novel 2- (thienyl-3'-amino) -1,3-diazacyclopentenes of the general formula o-N-CHR 4

5 R2 -, - rm-C I

R3j [1.Rl Nft-CH2 1 2 7 hyor R, R and R means hydrogen, methyl, chloro, bromo 4 or iodo, and R means hydrogen or methyl, or acid addition salts thereof with physiologically acceptable acids.

The analogous process of the invention is characterized in that a) thienyl-3-isothiuronium salts, thioureas, guanidines, nitroguanidines or cyanamides of formula IX, R , HX (a), 25

.S

-c ^ (to),

^ NH

(c), -C ^ T (d) in NH NHNOg or -CN (e), U

ISLAND

2

R ~ represents low molecular alkyl and X represents an acid anion, preferably a halide ion, reacted with alkylene diamines of formula III

Wherein R is as defined above, optionally in the form of their monosalts, or b) N- (3'-thienyl) -Ν'-aminoalkyl (thio) urea] g of formula IV, R 2

c) aminothiophenes of formula V

20 r 2 -, - r-NH? R3 I LrI2 (V)

R_vns> R

13 wherein R -R is as defined above, is reacted with 2-alkyl mercapto-1,3-diazacyclopentenes of formula VI, A-CHR 4 R 5 -S-C in (VI)

\ NH_CH

Wherein R and R are as defined above, preferably 3Q in the form of their salts, or d) aminothiophenes of formula V are reacted with bis- (2-oxo-1,3-diaza-cyclopentyl) -phosphine chlorides of formula VII, CHR - CH "CHR - CH_ II 2 SII 2 35 HN NP- * N NH (VII) \ c / '' \ c / n Cl" oo 144036 4 3

ISLAND

wherein R is as defined above, or e) thiophene-3-isocyanide dihalides of formula VIII, 2aL 5 R -._ -N = C _ s | - \ Hal r3 - (^ (VIII) 13 where R - R is as defined above and Hal represents a chlorine or bromine atom, reacted with alkylendlamines of formula III and to form compounds in which at least one of the groups R, R, or R represent a hydrogen atom, if desired, to be halogenated and then, if desired, the compounds prepared by physiologically acceptable acids are converted into acid addition salts.

a) The preparation of the compounds of formula I according to process a) can be carried out by simply heating (1 / 2-3 hours) of the isothiuronium salts of formula Ila 20 with alkylene diamines of formula III to temperatures between 80 and 200 ° C. However, the reaction can also be carried out in the presence of a solvent at temperatures between 60 and 140 ° C.

In particular, solvents containing polar groups, e.g. water or low alcohols such as methanol, ethanol, n- and isopropanol. Admittedly, in the presence of a solvent, it must be heated for an extended period (5-20 hours) and preferably pressurized. In both cases, it is appropriate to use an excess (110-150%) of alkylenediamine.

The isothiuronium salts of formula IIa are prepared in known manner by heating the corresponding thioureas of formula IIb together with a low alkyl halide or dialkyl sulfate in a solvent, e.g. a low alcohol. The thioureas can also be prepared according to methods known in the literature (see: Houben-Weyl, Vol. 9, page 887 et seq.) From the corresponding substituted aminothiophenes.

Instead of the thiuronium salts, one can also directly heat the thioureas of formula IIb together with the alkylene diamines of the general formula III, preferably in vacuo, to temperatures between 100 and 200 ° C. Preferably, an excess of alkylenediamine is also used.

The compounds of the invention may also be provided by the action of alkylene diamines of general formula III or their monosalts on thienyl-3-guanidines of formula

Ile or their salts with inorganic or organic acids. Also, the reaction can be carried out both with and without solvents. The required temperatures are between 100 and 200 ° C, preferably between 130 and 150 ° C. As the solvent, higher alcohols, nitrobenzene, etc. are used. Examples of inorganic salts are hydrochlorides, hydrobromides, hydroiodides, sulphates and nitrates, to which the organic salts are benzene or toluene sulphonates.

Instead of thienyl-3-guanidines, the corresponding nitroguanidines of formula Ild can also be used as starting materials and heat them with alkylene diamines of general formula III in suitable solvents, e.g. ethanol, propanol, butanol or amyl alcohol. The starting products can be obtained by reacting a corresponding amino-thiophene with N-methyl-N-nitroso-N'-nitroguanidine after

Journal of the American Chemical Society J59, 3028 (1947).

The reaction of thienyl-3-cyanamides of formula Ile with alkylene diamines or their mono salts is preferably carried out at temperatures between 50 and 200 ° C, especially 100 25 to 150 ° C, in the presence or absence of a solvent.

Thus, it is advantageous to work with an excess of alkylenediamine or its salts and to select the solvent so that the reaction can take place in a homogeneous phase. As the solvent comes higher alcohols, e.g.

30 butanol, amyl alcohol or hexanol in speech. Suitable salts of alkylenediamines are e.g. monohydroiodides or mono-β - toluene sulfonates. The thienyl-3-cyanamides can be prepared from the corresponding thienyl-3-thioureas and copper sulfate in alkaline solution.

B) The N- (3'-thienyl) -N '- (aminoalkyl) - (thio) urea of formula IV, which serve as starting products for the process of b), is prepared by analogy to the Journal of Organic Chemistry 24: 818 (1959) by reacting the corresponding substituted thienyl-3-isocyanates or 5

ISLAND

1A6D36 isothiocyanates with alkylene diamines of formula III. The ring closure is then carried out by heating to temperatures between 150 and 200 ° C in the presence or absence of a solvent, thereby preferably being operated using a protective gas atmosphere, e.g. nitrogen.

c) The reaction of 3-amino-thiophenes of formula V with 2-alkylmercapto-1,3-diazacyclopentenes of formula VI can also be carried out in the presence or absence of a solvent. However, a sufficiently high temperature must be chosen to remove the alkyl mercaptan from the reaction mixture. In general, temperatures are between 70 and 200 ° C. As the solvent, the following are considered: higher boiling ethers, alcohols such as methanol, ethanol and propanol, saturated cyclic hydrocarbons such as cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, chlorinated hydrocarbons such as chloro and dichlorobenzene.

The required alkyl mercapto-1,3-diazacyclopenzenes of the general formula VI used in the form of their salts, e.g. in the form of hydroiodides, can be prepared in the known manner by alkylation of the corresponding alkylene thioureas according to Organic Syntheses III, page 394.

d) A further process for providing the compounds of general formula I consists in heating 25 bis (2-oxo-1,3-diazacyclopentyl) phosphine chlorides of formula VII with aminothiophenes of formula V in an inert organic solvent, f. eg. xylene or mesitylene, for temperatures between ca. 100 and 180 ° C. The starting materials of formula VII can be obtained in known manner by reacting 30 of the corresponding substituted 1,3-diazacyclopentanones- (2) with phosphorus pentachloride in chloroform at temperatures between 20 and 40 ° C (cf. Bull. Soc. Chim. France, 1961, page 2114).

e) Thiophene-3-isocyanide dihalides of formula VIII are also suitable for the preparation of the present invention.

35 binders. The reaction with the alkylene diamines of formula III

thereby best takes place in an organic solvent at temperatures between Q '-' C and the boiling point of the solvent used. As solvent can be used: dioxane, alcohols, e.g. methanol, ethanol, propanol or butanol, ketones, aromatic hydrocarbons, e.g. benzene, toluene, xylene and halogenated aliphatic or aromatic hydrocarbons. In this reaction, 2 moles of hydrogen halide per ml are formed. mole of isocyanide dihalide. This hydrogen halide can be bonded either by excess alkylenediamine, by potassium 5 or sodium carbonate or by tertiary amines, e.g. trimethylamine, triethylamine, tributylamine or Ν, Ν-dimethylcyclohexylamine.

Finally, compounds of formula I wherein at least 12 of one of the substituents R, R or R may be hydrogen, can be 1?

10 halogenes. Thereby, compounds are provided wherein R, R

and / or R represents one or more halogen atoms. As a halogenating agent, elemental bromine, chlorine, sulfuryl chloride, N-chlorosuccinimide, bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin and iodine monochloride are thus discussed.

Accordingly, depending on the halogenating agents, ether, methylene chloride, chloroform, tetrachloromethane, carbon disulfide, glacial acetic acid, nitrobenzene, thionyl chloride and sulfuryl chloride can be worked at temperatures between 0 ° C and the boiling point of the solvent, optionally under the addition of catalysts. eg. aluminum chloride or ferric chloride.

The compounds of general formula I can be converted to the corresponding acid addition salts. For salt formation, inorganic and organic acids are considered, e.g. acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, citric acid, aceturic acid, ascorbic acid, oxyethanesulfonic acid, hydrochloric acid and hydrobromic acid.

The compounds of the present invention are both in free form and in the form of their salts valuable therapeutic agents 30 with interesting pharmacological, especially blood pressure lowering properties. They can be processed with the usual auxiliaries and carriers for all pharmaceutical forms used for pharmaceutical purposes.

From Danish Patent Specification No. 108,364, nearly 35 related phenylamino-1,3-diazacyclopentener- (2) is known, which is just as having a blood pressure lowering effect. However, the compounds of the invention have a more advantageous relationship between toxicity and therapeutic effect than these known compounds, as can be seen in Comparative Experiments 1 and 2, discussed below.

0 144035 7

The following examples are intended to illustrate in detail the process of the invention:

Example 1 a) 2- (Thienyl-31-amino) -1,3-diazacyclopentene (2) 30.0 g of 3'-thienyl-5-methyl * isothiouronium hydroiodide (mp 113-115 ° C), which is obtained from N-3-thienyl-thiourea (m.p. 185-187 ° C) and methyl iodide in absolute methanol, is shaken in an autoclave with 10.8 ml of ethylenediamine 10 and 125 ml of methanol for 20 hours at 100 ° C. After cooling, the methanol is distilled in vacuo, the residue is dissolved in dilute hydrochloric acid, the insoluble components are filtered off and the aqueous hydrochloric acid phase is shaken several times with methylene chloride. The aqueous phase is then filtered with charcoal and made alkaline with concentrated sodium hydroxide solution under cooling. The precipitated base is filtered off on a soot filter, dried and recrystallized from benzene (mp 155-156 ° C).

From the free base is obtained with the ethereal hydrochloric acid the hydrochloride of 2- (3r-thienylamino) -1,3-diazacyclopentene- (2), which is crystallized by isopropanol / petroleum ether (mp 187-188 ° C).

Analogously obtained: b) 2- (4 '-Methylthienyl-3' -amino) -1,3-diazacyclopentene- (2) (mp 156-158 ° C); hydrochloride (m.p. 200-202 ° C). C) 2- (4'-Methylthienyl-3'-amino) -1,3-diaza-4-methyl-cyclopentene- (2) (mp 172-173 ° C); hydrochloride (mp 132-133 ° C).

d) 2- (4'-Chloro-thienyl-3'-amino) -1,3-diazacyclopenten- (2) (mp 174-175 ° C); hydrochloride (m.p. 205 ° C).

E) 2- (2 ', 4'-Dimethylthienyl-3'-amino) -1,3-diazacyclopenten- (2), melting point of the hydrochloride 210-215 ° C (decomposition).

f) 2- (2 ', 4'-Dichlorothienyl-3'-amino) -1,3-diazacyclopenten- (2), point of destruction of the hydrochloride from 295 ° C.

g) 2- (2'-Chloro-4'-methyl-thienyl-3'-amino) -1,3-diazacyclopentene

35 - (2) (mp 152 ° C); hydrochloride (mp 228-229 ° C) L

h) 2- (2'-Chloro-4'-methylthienyl-3'-amino) -1,3-diaza-4-methyl-cyclopenten- (2); hydrochloride melting point 168-169 ° C.

I) 2- (21,5'-Dichloro-4'-methylthienyl-3'-amino) -1,3-diaza-cyclopenten- (2); hydrochloric! mp 167-168 ° C. k) 2- (2'-Chloro-thienyl-3'-amino) -1,3-diazacyclopenten- (2); hydrochloride melting point 181-182 ° C.

1) 2- (2'-Iodine-4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2) hydrochloride mp 215-216 ° C. m) 2- (2 ', 5'-Diiodo-4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2); hydrochloride melting point 204-205 ° C.

Example 2 2- (4'-Methylthienyl-3'-amino) -1,3-diaza-4-methyl-cyclopenten- (2) 31.1 g of 4'-methylthienyl-3'-S-methyl-isothiouronium - hydroiodide (m.p. 119-120 ° C) obtained from 4-methyl-15-thienyl-3-thiourea (m.p. 158-159 ° C) and methyl iodide in absolute methanol is heated to 130-150 ° C for one hour. together with 8.2 g of 1,2-diaminopropane. Thereby a strong development of methyl mercaptan is observed. After cooling, the residue is treated with dilute hydrochloric acid, filtered from insoluble constituents and the acidic solution is shaken several times with methylene chloride and filtered with charcoal. The solution is then made alkaline with concentrated sodium hydroxide solution under ice-cooling. The precipitated base is suctioned off, washed with a little ice water, dried and recrystallized from isopropanol (mp 25 173-174 ° C). The hydrochloride can be obtained from the base with ethereal hydrochloric acid and melts at 132-133 ° C (of isopropanol / petroleum ether).

Example 3 a) 2- (2 ', 5'-Dibromo-4'-methylthienyl-3'-amino) -1,3- -diazacyclopenten- (2) 1.8 g 2- (4'-methylthienyl-3 (-amino) -1,3-diazacyclopentene (2) is dissolved in 15 ml of glacial acetic acid, to which is added dropwise, at room temperature, a solution of 1.02 ml of bromine 35 in 15 ml of glacial acetic acid. The mixture is stirred for another 20 minutes, the suspension is poured into 50 ml of ice water and the resulting solution is made alkaline under ice-cooling. The precipitated base is suctioned off, washed with ice water, dried and transferred to the hydrochloride with ethereal hydrochloric acid. After recrystallization from isopropanol / ether, the resulting 2- (2 ', 5'-dibromo-4'-methylthienyl-3'-amino) -1,3-diazacyclopentene (2) melts at 224-225 ° C. .

Example 4 a) 2- (2'-Chloro-4'-methylthienyl-3'-amino) -1,3- -diazacyclopenten- (2) 10 g of 2- (4'-methylthienyl-3'-amino) Dissolve -1,3-diazacyclopentene (2) in 125 ml of chloroform and add dropwise at 0 ° C a solution of 7.5 ml of sulfuryl chloride in 15 ml of chloroform. Then heat to boiling for 2 hours and after cooling, chloroform and excess sulfuryl chloride are distilled off in vacuo. The residue is dissolved in dilute hydrochloric acid, the hydrochloric acid phase is shaken several times with methylene chloride and then filtered over charcoal. The acidic solution is made basic with 6N sodium hydroxide solution under ice-cooling and the base is immediately extracted with methylene chloride. The methylene chloride layer is dried, the solvent is distilled off in vacuo, the residue is dissolved in much ether and the hydrochloride is precipitated with ethereal hydrochloric acid. The hydrochloride is recrystallized from isopropanol / petroleum ether and melts at 228-229 ° C. The melting point of the free base is 152 ° C (of methylcyclohexane / benzene).

Analogously available:

b) 2- (2 ', 4'-Dichloro-thienyl-3'-amino) -1,3-diazacyclopenten- (2), point of destruction of the hydrochloride from 295 ° C

C) 2- (2, -Chloro-4-methylthienyl-3'-amino) -1,3-diaza-4-methyl-cyclopenten- (2); hydrochloride melting point 168-169 ° C.

d) 2- (2, -Chlorothienyl-3'-amino) -1,3-diazacyclopenten- (2); hydrochloride melting point 181-182 ° C

U /, 035 o o

Example 5 a) 2- (21-Solo-4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2) - 1.8 g of 2- (4'-methylthienyl-3'-amino) ) - 1,3-Diazacyclo-5-pentene- (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 and heated to 80 ° C over 20 minutes and the solution is allowed to maintain this temperature until the iodine color disappears. After cooling 10, activated charcoal is filtered and made alkaline with sodium hydroxide solution under cooling. The solid residue is dissolved in ether, acidified with ethereal hydrochloric acid, the solvents are suctioned off, the solid is boiled with acetone and then suctioned off. The hydrochloride of 2- (2'-iodo-4'-methylthienyl-15 -3'-amino) -1,3-diazacyclopentene (2) recrystallized from ethanol / diisopropyl ether melts at 215-216 ° C.

b) Analogously obtained using 3.25 g of iodine monochloride 2- (2 ', 5'-diiodo-4'-methylthienyl-3'-amino) -1,3-diazacyclopentene (2) with a melting point at 142-146 ° C (m.p. 20 of hydrochloride 204-205 ° C).

Example 6 a) 2- (2 ', 5'-Dichloro-4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2) 5 g hydrochloride of 2- (4'-methylthienyl-3 (-amino) - 1,3-diazacyclopentene- (2) is suspended in 10 ml of benzene and 5 ml of sulfuryl chloride are added dropwise. The mixture is then heated to boiling for 2 hours, the benzene is distilled off, the residue is boiled with acetone and extracted. After recrystallization from ethano 1 / diisopropyl ether, the hydrochloride of 2- (2 ', 5' - -dichloro-4-methylthienyl-3'-amino) -1,3-diazacyclopentene-35 - (2) melts at 167-168 ° C.

144035 11 o

Example 7 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2) 2.4 g of 4-methylthienyl-3-guanidine (hydrochloride mp 201-202 ° C) and 4 g of ethylenediamine The mono-pT'toluene sulfonate is heated to boiling in 25 ml of ethanol for 48 hours.

The solvent is distilled off in vacuo, diluted sodium hydroxide solution is added to the residue and extracted several times with methylene chloride. After drying with sodium sulfate, the solvent is suctioned off and the solid residue is suctioned off after grating with ether. From the free base is obtained the ethereal hydrochloric acid hydrochloride of 2- (41-methylthienyl-3 1-amino) -1,3-diazacyclopenten- (2), which melts at 200-202 ° C.

Example 8 2- (4'-methylthlenyl-3'-amino) -1,3-dlazacyclopenten- (2) 2.2 g N- (4-methylthienyl-3) -Ν '- (aminoethyl) -thiourea (mp 128-129 ° C) is dissolved in 25 ml of ethanol, 4 g of lead II oxide is added and shaken in autoclave for 4 hours at 20 ° C. The resulting lead sulfide is filtered off and the ethanol is distilled off. The residue is dissolved in dilute hydrochloric acid, filtered with activated charcoal and the acidic solution made alkaline with sodium hydroxide solution under cooling. The free base is aspirated and dried. Melting point after recrystallization from isopropanol 156-158 ° C. Hydrochloride melting point 200-202 ° C.

Example 9 2- (4 '-methylthienyl-3' -amino) -1,3-diazacyclopentene (2) 2.6 g of 4-methylthienyl-3-nitroguanidine (mp 188-189 ° C) and 0 85 g of ethylenediamine are heated to boil in 50 ml of ethanol for 24 hours. After distilling off the solvent in vacuo, the oily residue 35 is crystallized with a little water and suctioned off. To prepare the hydrochloride, the base is dissolved in methylene chloride, filtered with activated carbon and ethereal hydrochloric acid added. The oily residue obtained after evaporation of the solvent crystallizes on acetone treatment. Melting point 200-202 ° C of isopropanol.

12 0 144035

Example 10 2- (4'-Methylthienyl-3'-amino) -1,3-diazacyclopentene (2) 3.1 g of mono-p-toluenesulfonate of ethylenediamine is dissolved in 20 ml of amyl alcohol. To the boiling solution, drizzle a solution of 1 g of 4-methyl-thienyl-3-cyanamide (mp 97-98 ° C) in 20 ml of amyl alcohol and heat to boiling for another 5 hours. After cooling, the insoluble material is filtered off, the residue is washed with ether and the filtrate is evaporated in vacuo. The residue is dissolved in dilute hydrochloric acid, the solution is filtered with activated charcoal and the free base is precipitated with sodium hydroxide solution under cooling. The base is recrystallized from isopropanol and melts at 156-168 ° C. The melting point of the hydrochloride is 200-202 ° C.

EksempelH

2- (4'-Methylthienyl-3'-amino) -1,3-diazacyclopentene (2) - 1.8 g of 4-Methyl-3-aminothiophene hydrochloride is heated together with 1.4 g of 2-methyl -mercapto-1,3-diazacyclopentene (2) for 20 hours at 60-70 ° C. The mixture is then dissolved in dilute hydrochloric acid, filtered with activated charcoal and the filtrate is basified with 5N sodium hydroxide solution. The precipitated base is extracted with methylene chloride. For further purification, chromatograph on an alumina column. There is thus obtained 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopenten- (2) having a melting point of 156-158 ° C (from isopropanol). Melting point of hydrochloride 200-202 ° C.

Example 12 2- (4'-Methylthienyl-3-amino) -1,3-diazacyclopentene (2) 5.1 g of Ν, Ν'-bis (imidazolidinyl-2-one) ~ phosphoryl chloride is emulsified with 11 5 g of 4-methyl-3-aminothiophene in 100 ml of xylene with stirring and heated for 4 hours under reflux. After distilling off the solvent, the residual aminothiophene is removed by steam distillation. The residue is stirred intensively in 120 ml of dilute hydrochloric acid. From the filtrate, the base is precipitated with 2N sodium hydroxide solution and then extracted with chloroform.

After drying the chloroform solution, the solvent is evaporated and the residue is crystallized by rinsing with ether. After filtration of the crystals, these are recrystallized from methylcyclohexane and then, if desired, from a little isopropanol. 2- (4'-methylthienyl-3-amino) -1,3-diazacyclopentene- (2) is obtained, mp 156-158 ° C. The hydrochloride melts at 200-202 ° C.

10

Example 13 2- (2 ', 5'-Dichloro-thienyl-3-amino) -1,3-diazacyclopenten- (2) 13 g of 4-Methyl-3-formylamino-thiophene is added portionwise with stirring and cooling. with ice water to 50 ml of freshly distilled thionyl chloride and stir for 15 minutes. Then, 36 ml of sulfuryl chloride is slowly added with stirring and cooling, the temperature of the solution being below 5 ° C. Then the reaction mixture is stirred for 1 hour at 0 ° C, for 1 hour at room temperature and for 5 hours at 60 ° C. The reaction solution is then evaporated under reduced pressure, and after the addition of 150 ml of toluene is evaporated again. The brown oily residue is dissolved in 100 ml of toluene and cooled to 0 ° C. Then, a solution of 5 g of ethylene diamine in 50 ml of toluene is slowly added with stirring and cooling. The reaction mixture is then warmed to room temperature and then stirred for 1 hour at 30 ° C. After distilling off the toluene under reduced pressure, the residue is stirred in 100 ml of 1 N hydrochloric acid and the undissolved material is filtered off.

To the acidic solution is then added sodium hydroxide solution to basic reaction and sometimes extracted with methylene chloride. After evaporation of the methylene chloride, the residue is dissolved in 150 ml of methanol and placed on a silica gel column. The product is developed with a mixture of 300 ml of methanol with concentrated ammonia in the ratio of 9.5: 0.5. There is thus obtained 2- (2 ', 5'-dichloro-thienyl-3-a-mino) -1,3-diazacyclopenten- (2). The hydrochloride melts at 167-168 ° C.

14 0 144035

The beneficial effect of the compounds of this invention over the compound Clonidine is. known from Danish Patent Specification No. 108,364, appears from the comparative experiments discussed below.

15: 1 * 4035

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P> φ -ΗΡΡΦ P ^ -115 Qj ιβΗΦΦΡ Ά PA J3pgig®>! P 0 Ad o + j a m g p h o -gy «« i “ί s ° P Λ! Ρ ΟΦ-PSi P 2 Pd> now PQ CXI & I0101P u H> -a M a> A L> 144035 16 0

Comparative Experiment 2.

In rats in Eviparr anesthesia, the blood pressure lowering effect is measured after injection into the lateral ventricle of the brain (J.F. Hayden, L.D. Johnson and R.P. Maickel, Life Sciences 1509 (1966)).

The blood pressure lowering effect of the compound of the invention is about as great as that of Clonidin. However, the acute toxicity of Clonidine is substantially greater than the acute toxicity of the compound of the invention.

Table II

15 -----

Toxx-

Blood pressure lowering in the rat site

Active compound Dose in pg Number of Blood Pressure Mean DL ^ -g i-v. animal rats —— —— rats are a before after difference

Compound 2 2 127.5 120 7.5 5Q

prepared 4 2 127.5 91.5 31 mg / kg according to Example 8 2 123.5 82.5 41 lf.

2 5 130 113 17 29 25 Clonidine 4 5 128 105 23 mg / kg 8 5 135 105 30

Mouse i.v.

30

Compound 1 1 155 100 55 40 prepared 2.5 1 120 58 72 mg / kg of Ex.

ie.

Clonidine 1 1 132 85 47 17.6 mg / kg 35

Claims (3)

1Λ A 03 Β 0 Patent claims. Analogous Process for Preparation of 2- (Thienyl-3'-Amino) -1,3-Diazacyclopentener- (2) of Formula 5 2 SR η-rNH-C 2 NH-CEL · (I) 10 3 1 12 3 wherein R, R and R are hydrogen, methyl, chlorine, bromine or iodine, and R4 is hydrogen or methyl, or acid addition salts thereof with physiologically acceptable acids, characterized in that a) thienyl-3-isothiuronium salts, thioureas, guanidines, nitroguanidines or cyanamides of formula II, R2 -, - p NH-R I (IX) 3 1 1 RR Wherein R represents the groups <NH, HX (a) SR5 -C (b) Xnh2 35 ^ NH -C (c) Nsnh2 014 ~ 35 (NH) cf (cl) ^ ΝΗΝO2 and X is an acid anion, preferably a halide ion, reacted with alkylenediamines of formula in H2N-CHR4-CH2-NH2 (III) 4 wherein R is as defined above, optionally in the form of their monosalts, or b) N- (3) (-thienyl) -N'-aminoalkyl (thio) ureas of formula IV, R2 -, - rNH-C-NH-CHR4-CH_-NHO 3. AR-1 JLr 25 wherein R 1 -R 4 has the above meaning and A means an oxy gene or sulfur atom is closed to ring, or c) aminothiophenes of formula V R2 -] - pNH "J Ιχ eVe 1 3 wherein R - R is as defined above, reacted with 2-alkyl mercapto-1,3-diazacyclopentenes of formula VI