FI57412B - REFERENCE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ACID 2- (THIENYL-3'-AMINO) -1,3-DIAZASYCLOPENTEN- (2) -FOERENINGAR OCH DERAS SYRAADDITIONSSALTER - Google Patents

Description

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Patent- och ragittentyralaan Amekan utl * fd och uti.> Krift * n pubikwnd JU. 04. ου (32) (33) (31) Privilege claimed —B «| <rd prtorltet l6.08.69

Federal Republic of Germany-Förbundsrepubliken

Tyskland (DE) P 19UI76I.9 (71) Hoechst Aktiengesellschaft, 6230 Frankfurt / Main 80, Postfach 80 03 20,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Robert Rippel, Hofheim / Taunus, Heinrich Ruschig, Bad Soden / Taunus,

Ernst Lindner, Frankfurt / Main, Manfred Schorr, Frankfurt / Main,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7U) Oy Kolster Ab (5U) Process for the preparation of new therapeutically useful 2- (thienyl-3'-amino) -1,3-diazacyclopentene (2) compounds and their acid addition salts The present invention relates to a process for the preparation of new therapeutically useful 2- (thienyl-3'-amino) -1,3-diazacyclopenten- (2) -forations and derivatives of the present invention. -amino) -1,3-diazacyclopentene- (2) compounds of formula

^ N CHRU

R2 -T "NH" CC 1

1 H NH-CH 2 I

r3 2 57412 in which represents a hydrogen, chlorine, bromine or iodine atom or a methyl group, Rg represents a hydrogen or chlorine atom or a methyl group, represents a hydrogen, chlorine, bromine or iodine atom, and is a hydrogen atom or a methyl group and acid addition salts thereof.

The process according to the invention is characterized in that a) a thienyl-3-isothiuronium salt of the formula r 2 -T-r-™-cs "·" ΧΓ ^ R 3 r, in which R 1, R 8 and R 2 are as defined above and R 1, is a lower alkyl group and X is an acid anion, or b) a thienyl-3-thiourea of the formula R 2 -I-if-NH'cC 111 wherein R 1, R 8 and R 2 are as defined above, or c) thienyl-3-guanidine of formula

R "-N-n-RH-C

I IV

wherein R 1, R 8 and R 2 are as defined above, or 3,57412 d) thienyl-3-nitroguanidine of formula

^ NH

R 7 -i-NH-C 1 I NHNO 2 R 3 / R 2 · R 2 wherein R 1, R 2 and R 2 are as defined above, or e) thienyl-3-cyanamide of the formula

R2 —- Γ NH-CN

/ \ Jk VI

V s R 1 wherein R 1, R 2 and R 2 are as defined above is reacted with an alkylenediamine of formula

H2N-CHR4-CH2-NH2 VII

wherein R 4 is as defined above, and which is optionally in the form of a mono-salt, or f) heating an N- (3'-thienyl) -N'-aminoalkylthiourea of formula R, -Π-1-NH-C- NH-CHR-CH9-NH9

1 I £ * 1 1 VIII

wherein A is an oxygen or sulfur atom, and R 1, R 6, R 2 and R 2 are as defined above, or g) an aminothiophene of the formula R 9 "T-T" NH 9

IX

* 57412 wherein R1, R2 and R8 are as defined above, is reacted with 2-alkylmercapto-1,3-diazacycloalkene of formula

= N-CHR

Rc-S-C | X

^ nh-ch2 where R1 and R1. or h) reacting an aminothiophene of formula IX with bis- (2-oxo-1,3-diazacycloalkyl) -phosphine chloride of the formula R 1 H-CH 2 O / CH 2 -CHR

HN / N-P-N 2 .NH XI

N C 'r.

»Cl n 0 o wherein R 1 is as defined above, or i) a thiophene-3-isocyanide dihalide of formula

Vt-f N * C

^ Hal XII

wherein R 1, R 2 and R 8 are as defined above, and Hal is chlorine or bromine, is reacted with an alkylenediamine of formula VII, followed by halogenation and / or conversion of the resulting compound in which at least one of R 2 and R 8 is hydrogen, if desired. as an acid addition salt by reacting it with a pharmaceutically acceptable acid.

The preparation of the novel compounds of the formula I can be carried out according to embodiment a) simply by heating (1/2 to 3 hours) the isothiouranium salts of the formula II with the alkylenediamines of the formula VII at a temperature of 80 to 200 ° C. Suitable alkylenediamines are, for example, ethylenediamine, 1,2-propylenediamine or 1,3-propylenediamine. However, the reaction can also be carried out in the presence of a solvent at a temperature between 60 and 140 ° C. As solvents, it is possible in particular to use those which contain polar groups such as water or low-molecular-weight alcohols, e.g. methanol, ethanol, n-propanol and iso-propanol. However, in the presence of solvents, it is necessary to heat for longer periods (5 to 20 hours) and preferably at elevated pressure. In both cases, an excess (110-150%) of alkylenediamine is suitably used.

The isothiuronium salts of the formula II are prepared in a known manner by heating the corresponding thiol ureas of the formula III with a lower alkyl halide or dialkyl sulfate in a solvent, e.g. a lower alcohol. Thioureas can likewise be prepared from correspondingly substituted aminothiophenes by methods known from the literature (Houben-Weyl, Vol. 9, p. 887).

Instead of the isothiouronium salts, the thioureas of the formula III can also be heated directly together with the alkylenediamines of the general formula VII, preferably in vacuo at temperatures between 100 and 200 ° C. In this case, too, an excess of 1,2-alkylenediamine is preferably used.

Likewise, the new compounds can also be obtained by reacting the alkylenediamines of the formula VII or their mono-salts with the thienyl-3-guanidines of the formula IV or their salts with inorganic or organic acids. Also in this case, the reaction can be carried out as well in the presence of solvents as in the absence of solvents. The required temperatures are 100 to 200 ° C, most preferably 130 to 150 ° C. Higher alcohols, nitrobenzene, etc. are used as solvents. Examples of inorganic acids include hydrochlorides, hydrobromides, hydroiodides, sulfates and nitrates; of the organic salts, benzene and toluene sulfonates are suitable.

Instead of thienyl-3-guanidines, the corresponding nitroguanidines of the formula V can also be used as starting materials and heated with the alkylenediamines of the general formula VII in suitable solvents, such as, for example, ethanol, propanol, butanol or amyl alcohol. The starting materials can be obtained by the reaction of the corresponding amino-thiophene with N-methyl-N-nitroso-N'-nitroguanidine as described in the Journal of the American Chemical Society, Vol. 69, p. 3028 (1947).

6 57412

The reaction between thienyl-3-cyanamides of the formula VI and alkylenediamines of the formula VII or their mono-salts can preferably be carried out at a temperature of 50 to 200 ° C, in particular 100 to 150 ° C, in the presence or absence of a solvent. In this case, it is preferable to use an excess of alkylenediamine or its salts and to select the solvent so that the reaction takes place in a homogeneous phase. Suitable solvents are higher alcohols, such as butanol, amyl alcohol or hexanol; suitable alkylenediamine salts are, for example, monohydroiodides or mono-p-toluenesulfonates. Thienyl 3-cyanamides can be prepared from the corresponding thienyl 3-thioureas and copper sulfate in alkaline solution.

The N-O'-thienylD-N'-CaminoalkylD-thio ureas of formula VIII or the ureas starting materials in process f) can be prepared according to the instructions given in the Journal of Organic Chemistry, Part 24, p. 818 (1959), by the reaction of the correspondingly substituted thienyl 3-isocyanates or isothiocyanates with the alkylenediamines of the formula VII. Ring closure is achieved by heating to temperatures between 150 and 200 ° C in the presence or absence of a solvent; then it is preferable to work in a shielding gas atmosphere, e.g. nitrogen.

The reaction of 3-amino-thiophenes of formula IX with alkyl mercapto-1,3-diazacycloalkenes of formula X can likewise be carried out in the presence or absence of a solvent. However, a temperature high enough to remove the alkyl mercaptan from the reaction mixture must be selected. Usually work at temperatures between 70 and 20 ° C. Suitable solvents are high-boiling ethers, alcohols such as methanol, ethanol and propanol, saturated cyclic hydrocarbons such as cyclohexane, and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorinated hydrocarbons such as chlorinated hydrocarbons such as chlorine.

The required alkyl mercapto-1,3-diazacycloalkenes of the general formula X, which are used in the form of their salts, e.g. hydroiodides, can be prepared in a known manner by alkylation of the corresponding alkylene thioureas, cf. Organic Syntheses III, pp. 394.

7 57412

Another embodiment for the preparation of compounds of general formula I is the heating of bis- (2-oxo-1,3-diazacycloalkenyl) -phosphine chlorides of formula XI with aminothiophenes of formula IX in an inert organic solvent such as xylene or mesitylene at about 100-200 ° C. C temperatures. The starting materials of the formula XI can be obtained in a known manner by the reaction of correspondingly substituted 1,3-diazacycloalkanones- (2) with phosphorus pentachloride in chloroform at temperatures between 20 and 40 ° C (cf. Bull. Soc. Chim. France, 1969, p. 2114).

Thiophene-3-isocyanide dihalides of formula XII are also suitable for the preparation of new compounds. The reaction with the alkylenediamines of the formula VII is then best carried out in an organic solvent at a temperature between 0 ° C and the boiling point of the solvent used. As the solvent, dioxane, alcohols such as, for example, methanol, ethanol, propanol or butanol, ketones, aromatic hydrocarbons such as benzene, toluene, xylene and halogenated aliphatic or aromatic hydrocarbons can be used. These reactions yield 2 moles of hydrogen halide per mole of isocyanide dihalogen, which can be coupled with additional alkylenediamine, potassium or sodium carbonate, or tertiary amines such as trimethylamine, triethylamine, tributylamine, N, N-dimethylamine.

If desired, compounds of the formula I in which at least one of the substituents R 1, R 2 or R 1 represents hydrogen, halogenate. Thus, compounds are obtained in which R1 and / or R2 and / or R3 represent one or more halogen atoms. Suitable halogenating agents are elemental chlorine, bromine, sulfuryl chloride, N-chlorosuccinimide, bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin and iodine monochloride. In this case, depending on the halogenating agent, work in ether, methylene chloride, chloroform, carbon tetrachloride, carbon disulphide, glacial acetic acid, nitrobenzene, thionyl chloride or sulfuryl chloride to 0 [deg.] C. chloride.

8 57412

The compounds of formula I can be converted into the corresponding acid addition salts by conventional methods. Suitable salt forms are inorganic and organic acids, e.g. acetic acid, lactic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, ascorbic acid, oxyethanesulfonic acid, hydrochloric acid or hydrochloric acid.

The compounds according to the invention, both in their free form and in the form of their salts, are valuable drugs which have interesting pharmacological, in particular antihypertensive, properties. They can be obtained with the aid of customary carriers for formulations used for all pharmaceutical purposes.

Pharmacological experiments and their results A. The antihypertensive effect of the compounds according to the invention and the reference compound (clonidine = 2- (2 ', 6'-dichlorophenyl) -amino-1,3-diazacyclopentene- (2)) was determined. Rats and mice (under Evipan® anesthesia) were used as experimental animals. Test compounds were administered to the lateral ventricle of the brain (method described by Hayden, J.F., Jonson, L.D., and Maickel, R.P., Life Science, 1966, 1509.

The results are shown in the following table.

Table I

Antihypertensive effect Acute toxicity

lisity id Q

(mg / kg i.v.).

Examined Dose Animal Blood Pressure (Mean) Compound ^ .g / Number of Animals mm Hg

At the beginning At the end Separation 2- (2 ', lt'-dicloc-2 2 127.5 120 7.5 50 ritienyl-3'-, 5 η, amino) -1,3-diato- ^ 2 127.5 91.5 31 Sasyclopentene- 8 2 123.5 82.5 11 (2)

Clonidine 2 5 130 113 17 29 U 5 128 105 23 8 5 135 105 30 2- (2'-iodo-U * - 1 1 155 100 55 i + O, N-methylthienyl-3'-amino) -1,3- di- 2'5 1 120 58 72 azacyclopentene- (2)

Clonidine 1 1 132 85 1 * 7 17.6 ^

As experimental animal rat YV) „, M,

As an experimental animal hiin 9 57412

As shown in Table I, the compounds of the invention have as good an antihypertensive effect as the reference substance and have a lower acute toxicity.

B. The antihypertensive effect of the compounds of the invention and the blood compound (clonidine) was determined. Elevated blood pressure was obtained by constricting the renal arteries of the experimental animal (rat). Blood pressure was measured with a recording meter in mild ether anesthesia (Lindner, E., Arzneimittelforschung 16, 1966, 628). The results are shown in the following table.

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Although it can be seen from Table II, the known compound has a 2-3 times stronger effect than the new compound, but the known compound causes circulatory deterioration and eye damage (corneal opacification), and is also quite toxic. As shown in Table II, the toxicity of the new compounds is only about 6-fold that of the known compound.

The compounds prepared according to the invention, which are not shown in Tables I and II, also have corresponding valuable and surprising properties.

The following examples further illustrate the invention:

Example 1 a) 2- (Thienyl-3'-amino) -1,3-diazacyclopentene- (2) 30.0 g of S'-thienyl-S-methylisothiouronium hydroiodide (m.p. 113-H5 ° C) obtained From N-3-thienylthiourea (m.p. 185-187 ° C) and methyl iodide in absolute methanol, shake in an autoclave for 20 hours at 100 ° C with 10.8 ml of ethylenediamine and 125 ml of methanol. After cooling, the methanol is distilled off in vacuo, the residue is dissolved in hydrochloric acid, separated from the insoluble by filtration, and the aqueous hydrochloric acid phase is shaken several times with methylene chloride. The aqueous phase is then filtered through carbon and made alkaline with concentrated sodium hydroxide solution while cooling. The precipitated base is filtered off with suction, dried and recrystallized from benzene (m.p. 155-156 ° C). The free base gives 2- (3'-thienylamino) -1,3-diazacyclopentene (2) with ethereal hydrochloric acid, which is recrystallized from isopropanol / petroleum ether (m.p. 18T-188 ° C).

In a similar manner there are obtained: b) 2- (N, -methylthienyl-3-amino) -1,3-diazacyclopentene- (2) (m.p. 156-158 ° C; hydrochloride m.p. 200-202 ° C), using as starting materials 1 + '- methylthienyl-3'-5-methylisothiouronium hydrochloride (m.p. 119-120 ° C) and ethylenediamine; c) 2- (1+'-methylthienyl-3 * -amino) -1,3-diaza-U-methylcyclopentene- (23) (m.p. 172-175 ° C; hydrochloride mp 132-133 ° C), from 1 '' - methylthienyl-3'-5-methylisothiouronium hydroiodide (m.p. 119-120 ° C) and 1,2-diaminopropane; d) 2- (1 +, - chlorothienyl-3'-amino) -1,3-diazacyclopentene (2) (m.p. 17 * + - 175 ° C; hydrochloride m.p. 205 ° C), starting from U'-chlorothienyl -1'-i-methylisothiuronium hydroiodide (m.p. 86-89 ° C) and ethylenediamine; e) 2- (2 +, 1 +'-dimethylthienyl-3'-amino) -1,3-diazacyclopentene- (2) (m.p. 210-215 ° C, as hydrochloride), starting from 2 ', U'-dimethyl- 3,5-methylisothiuronium hydroiodide (m.p. 180-190 ° C) and ethylenediamine; f) 2- (2 ', 1 +, - dichlorothienyl-3-amino) -1,3-diazacyclopentene- (2) (decomposition point of the hydrochloride from 295 ° C), starting from 2, U, -dichlorothienyl-3' methyl isothiuronium hydroiodide (m.p. 165-168 ° C) and ethylenediamine; g) 2- (2'-chloro-h'-methyl-thienyl-3'-amino) -1,3-diazacyclopentene- (2) (m.p. 152 ° C) (m.p. 228-299 ° C) , starting from 2'-chloro-1 + '- methylthienyl-3 * -5-methylisothiuronium hydroiodide (m.p. 157 DEG-160 DEG C.) and ethylenediamine;

12 5741 2 I

i; it, h) 2- (2'-chloro-N1-methylthienyl-3'-amino) -1,5-aza-N-diethylcyclopentene- (2) (m.p. 168-169 ° C of the hydrochloride), from 2 '-chloro-1'-methylthienyl, 3'-5'-methyl-isothiuronide: hydroiodide (m.p. 157-160 ° C) and 1,2-diaminoproparis-1, or (2-) N, N'-chloro-N-methylthienyl-5'-emino-1S-diazacyclopentene (2) (m.p. 177-168 ° C of the hydrochloride), starting from 2'-dichloro-N'-methylthienyl -3'-5-methylisothiuronurahydroiodide (m.p. 127-129 ° C) and ethylenediamine (2'-chlorothienyl-3 '-amino) -1,3-diazacyclopentene- (2) (hydrochloride m.p. 181) -82 ° C), starting from 2, -chlorothienyl-3'-5-methyl-isothiuronium hydrochloride (m.p. 13-137 ° C) and ethylenediamine (2-) 2 (2'-iodo-U'-methylthienyl). 3'-amino) -1,3-diazacyclopentene- (2) (hydrochloride m.p. 215-216 ° C), starting from 2, -iodo-4,4-methylthienyl-3'-5'-ethyl-isothiuronimidohydroiodide (m.p. 1 (9-15-15 ° C) and ethylenediamine (2-) 2- (2 ', 5'-diiodo-U'-methylthienyl-3'-amino) -1,3-diazate sacyclopentene- (2) (hydrochloride m.p. 20-120 ° C), starting from 2 ', 5, -diiodo-H'-methyl-thienyl-3'-5-methyl-isothiuronium hydrochloride (m.p. 175 DEG-18 DEG C.) and ethylenediamine.

Example 2 2- (U'-methylthienyl-3'-amino) -1,3-diaza-N-methylcyclopentene-12) 31.3 g of U'-methylethienyl-S'-S-methylisothiouronium hydroiodide ( m.p. 119-120 ° C) obtained from U-methylthienyl-3-thiourea (m.p. 158-159 ° C) and methyl iodide in anhydrous methanol is heated together with 8.2 g of 1,2-diaminopropane for one hour at 130-150 ° C, whereupon a large amount of methyl aeraptan is evolved. After cooling, the residue is treated with dilute hydrochloric acid, filtered off from insoluble matter, the acidic solution is shaken several times with methylene chloride and filtered through charcoal. It is then basified with concentrated sodium hydroxide solution while cooling with ice. The precipitated base is filtered off with suction, dried and crystallized from isopropanol (m.p. 173-17 ° C). The hydrochloride obtained from the base with ethereal hydrochloric acid melts at 132-133 ° C (isopropanol / petroleum ether).

Example 3 2- (2 *, 5'-Dichromo-1 * 1-methylthienyl-3'-amino) -1,3-diazacyclopentene- (2) 1.8 g of 2- (1 * '-methylthienyl-3' "amino) -1,3-diazacyclopentene- (2) is dissolved in 15 ml of glacial acetic acid and a solution of 1.02 ml of bromine in 15 ml of glacial acetic acid is added dropwise with stirring at room temperature. Stir for a further 20 minutes, add 50 ml of ice water to give a solution. The solution is made ulceration by cooling on the wall with ice, the precipitated base is filtered off with suction, washed with ice water, dried and converted into the hydrochloride with ethereal hydrochloric acid after crystallization from isopropanol / ether Kola 2- (2 ', 5' own methylthienyl-3'-amino) -1,3-diazacyclonentene- (2) at 22k-225 ° C.

13 5741 2

Example 4 2- (2'-Chloro-U'-methyl-thienyl-3'-amino) -1,3-diazacyclopentene- (2) 10 g of 2- (U'-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. Then keep for two hours at boiling point. After cooling, the 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 through carbon. The acidic solution is made under alkaline ice-cooling with 6N sodium hydroxide solution 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 a large amount of ether and the hydrochloride is precipitated with ether-hydrochloric acid and crystallized from isopropanol / petroleum ether, melting at 228-229 ° C. The free base m.p. is 152 ° C (crystallized from methylcyclohexane / benzene).

Example 5 2- (2'-Iodo-U'-methylthienyl-3'-amino) -1,3-diazacyclopentene- (2) 1.8 g of 2- (U'-methylthienyl-3'-amino) -1 The 3-diazacyclopentene (2) is mixed with 30 ml of glacial acetic acid and 1.63 g of iodine monochloride in 17 ml of glacial acetic acid are added dropwise at room temperature. Then add 75 ml of water, heat for 20 min. 80 ° C and left at this temperature until the color of the iodine disappears. After cooling, activated carbon is added, filtered and made alkaline with sodium hydroxide solution while cooling. The solid residue 1 "5741 2 is dissolved in ether, acidified with ether-hydrochloric acid, the solvent is removed, the residue is boiled in acetone and then filtered off with suction. 2- (2'-iodo-4'-methylthienyl-3'-amino) -1, 3-Diaza-cyclopentene (2) melts from ethanol / diisopropyl ether crystallized at 215-216 ° C.

Example 6 2- (2 ', 5'-Dichloro-4 * -methylenyl-3'-amino) -1,3-diazacyclopentene- (2) 5 g of 2- (4, -methylthienyl-3' -amino) -1,3-diazacyclopentene- (2) hydrochloride is suspended in 10 ml of benzene and 5 ml of sulfuryl chloride are added dropwise. It is then heated at reflux for 2 hours, the benzene is distilled off, the residue is boiled in acetone and filtered off with suction. After crystallization from ethanol / isopropyl ether, 2- (2 ', 5'-dichloro-4-methylthienyl-3'-amino) -1,3-diazacyclopentene (2) hydrochloride melts at 167-168 ° C.

Example 7 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopentene- (2) 2.4 g of 4-methylthienyl-3-guanidine (hydrochloride m.p.

201-202 ° C) and 4 g of ethylenediamine mono-p-toluenesulfonate are heated with 25 ml of ethanol at reflux for 48 hours. The solvent is distilled off in vacuo, dilute sodium hydroxide is added to the residue and extracted several times with methylene chloride. Dry over sodium sulfate and triturate the suction filtrate with ether and filter off the solid residue. Ether hydrochloric acid gives the free base hydrochloride of 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopentene (2), melting at 200-202 ° C.

Example 8 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopentene- (2) 2.2 g of N- (4-methylthienyl-3) -N '- (aminoethyl) thiourea ( mp 128-9 ° C) is dissolved in 25 ml of ethanol, 4 g of lead II oxide are added and shaken in an autoclave at 100 ° C for 4 hours. The resulting lead sulfide is filtered off and the ethanol is distilled off. The residue is dissolved in dilute hydrochloric acid, filtered with activated carbon and the acidic solution is made alkaline with sodium hydroxide solution while cooling. The free base is filtered off and dried. The melting point after crystallization from isopropanol is 156-158 ° C. Hydrochloridine m.p. is 200-202 ° C.

15 5741 2

Example 9 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopentene (2) 2.6 g of 4-methylthienyl-3-nitroguanidine (m.p. 188-189 ° C) and 0.85 g the ethylenediamine is heated at reflux in 50 ml of ethanol for 24 hours. After distilling off the solvent in vacuo, the oily residue is crystallized with a small amount of water and filtered off with suction. To prepare the hydrochloride, the base is dissolved in methylene chloride, filtered over activated carbon and ether-hydrochloric acid is added. After evaporation of the solvent, the oily residue crystallized on treatment with acetone. Sp. 200-202 ° C (from isopropanol).

Example 10 2- (4'-methylthienyl-3'-amino) -1,3-diazacyclopentene- (2) 3.1 g of ethylenediamine mono-p-toluenesulfonate are dissolved in 20 ml of amyl alcohol. To the boiling solution is added dropwise 1 g of 4-methylthienyl-3-cyanamide (m.p. 97-98 ° C) dissolved in 20 ml of amyl alcohol and further heated at reflux for 5 hours. After cooling, the precipitate formed is separated off, extracted with ether and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in dilute hydrochloric acid, filtered with activated carbon and the free base is precipitated with sodium hydroxide solution while cooling. The base melts at 156-8 ° C when crystallized from isopropanol. Hydrochloridine m.p. is 200-202 ° C.

Example 11 2- (4'-methylthienyl-31-amino) -1,3-diazacyclopentene- (2) 1.8 g of 4-methyl-3-aminothiophene hydrochloride and 1.4 g of 2-methylmercapto-1,3- diazacyclopentene (2) is heated at 60-70 ° C for 20 hours. Dilute hydrochloric acid is added to the mixture until a clear solution is obtained, filtered with activated carbon, and the filtrate is basified with 5N sodium hydroxide solution. The precipitated base is extracted into methylene chloride. Purify the extract by chromatography on alumina. 2- (4'-methylthienyl-31-amino) -1,3-diazacyclopentene- (2) is obtained; mp. 156-158 ° C (from isopropanol). Hydrochloridine m.p. 200-202 ° C.

Example 12 17.2 g of 4-methylthienyl-3-thiourea (m.p. 105-187 ° C) and Θ0 ml of methanol, 44.6 g of lead (II) oxide and Θ ml of ethylenediamine are heated in an autoclave for 4 hours at 100 ° C: while stirring.

The reaction mixture is then stripped of lead sulphide, the methanol solution is evaporated to half its volume and 5-n sodium hydroxide is added, whereupon 2- (4-methylthienyl-3'-amino) -1,3-diazacyclopentene (2) precipitates. Separate the product by filtration and dry it; yield 6 g; mp. 156-15 ° C (recrystallized from isopropanol).

16 5741 2

Example 13 2- (4R-Methylthienyl-3-amino) -1,3-diazacyclopentene- (2) 5.1 g of N, N'-bis- (imidazolidinyl-2-one) -phosphoryl chloride and 11.5 g of 4 -methyl-3-aminothiophene is emulsified in 100 ml of anhydrous xylene (stirred) and heated at reflux for 4 hours. The solvent is distilled off, and then the remaining aminothiophene is removed by steam distillation. Add 120 ml of hydrochloric acid to the residue and stir vigorously. Filter, add 2N sodium hydroxide solution to the filtrate until the solution is basic, and extract the precipitate formed into chloroform. Dry the chloroform solution, evaporate the solvent and add ether to the residue. Trituration causes the residue to crystallize. The precipitated base is filtered off and recrystallized from methylcyclohexane and, if desired, a small amount of isopropanol. There is obtained 2- (4'-methylthienyl-3-amino) -1,3-diazacyclopentene (2), m.p. 156-158 ° C; hydrochloride m.p.

200-202 ° C.

Example 14 2- (2 ', 5R-Dichlorothienyl-3-amino) -1,3-diazacyclopentene- (2) 13 g of 4-methyl-3-formylaminothiophene are added in small portions and, with stirring and cooling with ice water, to 50 ml. freshly charged thionyl chloride and stirred for 15 minutes. 36 ml of sulfuryl chloride are slowly added with stirring and cooling (temperature below 5 ° C). The mixture is stirred for 1 hour at 0 ° C, then for one hour at room temperature and finally for 5 hours at 60 ° C. Evaporate the reaction mixture under reduced pressure, add 150 ml of toluene and evaporate again. The brown oily residue is dissolved in 100 ml of toluene, and the mixture is cooled to 0 ° C. A solution of 5 g of ethylenediamine in 50 ml of toluene is added slowly, with stirring and cooling. Warm the thigh mixture to room temperature and then for an additional hour at 30 ° C. Distill off the toluene under reduced pressure, add 100 ml of 1N hydrochloric acid to the residue, stir vigorously and filter. The acidic filtrate is basified with sodium hydroxide solution and extracted into methylene chloride. Evaporate the methylene chloride, dissolve the residue in 150 ml of methanol and purify by chromatography (silica gel column; elution with a mixture of 300 ml of methanol and 16 ml of concentrated ammonia). The resulting 2- (2 ', 5'-dichlorothienyl-3-amino) -1,3-diazacyclopentene- (2) is converted to the hydrochloride; mp. 167-168 ° C.

Claims (3)

17 5741 Claim: A process for the preparation of new therapeutically useful 2- (thienyl-3'-amino) -1,3-diazacyclopentene (2) compounds of the formula ^ e-el®! * 'XX * 3 3 R1 wherein represents a hydrogen, chlorine, bromine or iodine atom or a methyl group, Rg represents a hydrogen or chlorine atom or a methyl group, R1 represents a hydrogen, chlorine, bromine or iodine atom, and R1 represents a hydrogen atom or a methyl group, and acid addition salts of these compounds characterized in that a) a thienyl-3-isothiuronium salt of the formula Vjj-ii— NH '<^ · “11 A1 ·,' wherein R1, R8 and R1 have the same meaning as above and R1, . is a lower alkyl group and X is an acid anion, or b) a thienyl-3-thiourea of the formula: wherein R 1, R 8 and R 2 are as defined above, or c) thienyl 3 "guanidine of formula S * R 3 R 1 IV 18 5741 2 wherein R 1, R 8 and are as defined above, or d) thienyl-3-nitroguanidine of formula ^ nh R c -T, -NH-C V AA R 3 R 1 wherein R 1, R 8 and R 2 are as defined above, or e) thienyl-3-cyanamide of the formula R 9-1-NH-CN VI ΑβΑ R 3 R 1 wherein R 1, R 8 and R 2 are as defined above. the same as above, reacted with an alkylenediamine of the formula HgN - CHR 1 - CH 2 --NH 2 VII wherein R 1 is as defined above and optionally in the form of a monosalt, or f) heating with N- (3, -thienyl) -N '-aminoalkylthiourea of the formula R 2 - NH - C - NH - CHR 2 - CH 2 -NH 8 VIII AsK 1 R 3 R 1 wherein A is an oxygen or sulfur atom, and R 1, R 2, R 2 and the same meanings as above, or g) an aminothiophene of the formula R 2 μ-pNH 2 XI n 2 S 2 R 3 R 1 19 5741 2 wherein R 1, R 8 and R 2 are as defined above is reacted with 2-alkyl-mercapto-1,3-diazacycloalkene of the formula -CHR 2 R c - S - CX 5 \ NH- CH 2 wherein R 1 and R 2 are as defined above, or h) the aminothiophene of formula IX is reacted with bis- (2-oxo-1,3-diazacycloalkyl) -phosphine chloride of the formula R 1 CH-CHO CH-CHR . I \ 0 / i XI - f - Nc / NH ί ^ 8 wherein R ^ is as defined above, or i) a thiophene-3-isocyanide dihalide of formula R2-j-rj-N-C XII / A, wherein R 1, R 2 and are as defined above, and Hal is a chlorine or bromine atom, is reacted with an alkylenediamine of formula VII, after which the resulting compound in which at least one of R 1, R 8 and R 2 is a hydrogen atom is, if desired, halogenated and / or is converted to an acid addition salt by reacting it with a pharmaceutically acceptable acid. 20 5741 2 For the preparation of a compound, therapeutically active compound 2- (thienyl-3'-amino) -1,3-diazacyclopenten-2 (2) -formation with the formula ^ X-CMU E, -r-τ-ΗΗ-CT I (I jl v K3 ^ 8 \ rär R ^ betecnar en väte-, chloro, brom- eller iodatom ellet methylen, R2 betecnar en väte- eller chlororatom ell methylyl, R ^ betecknar en väte-, chloro, Brom - in the case of iodine, and in the case of R 2, in the case of a methyl group, in the case of a compound having a radical salt, in which case a thienyl-3-isothiuronium salt of the formula Vjj-Tl- »HC --- II XX R3 Rx for R , Rg and R ^ betecnar decamma som tidigare och R ^ är en lägre alkylgrupp och X är en syranjon, eller b) en thienyl-3-thiourea with the formula S f E— nT-EH-C. , Rg and R ^ are selected from the group consisting of th), or c) that thienyl-3-guanidine is formulated with 41π ai 5741 2 for R ^, Rg and R ^ is given with the form of a compound, or d) that thienyl-3-nitroguanidine is formula Rp-nn - NH-C ^ NHNOg V R3 R1 to R1 Rg and R ^ betecknar decamma som tidigare, eller e) ett thienyl-3 ~ Cyanamidine with the formula R0 ~ * 5-— NH-CN li vi 3 R, wherein R1> Rg and R2 are selected from the group consisting of alkylenediamine with the formula HgN-CHR2-CH2-NHg VII and then selected from the group consisting of monosalt, or f) en N- (3'-thienyl) -N'-aminoalkyl-thiourea with the formula Rg-tn NH-C-HH-CHR2-CH2-NHg VIII ('IA h R a is a sugar or hydrogen atom, and R , Rg, R2 and R2 are selected from the group consisting of g) and aminothiophenes with the formula R2 and R8, R8 and R1 are selected from the group consisting of 2-alkylmercapto- 1,3-diazocycloalkene with the formula -CHRU r, - s - e I x \ ..: iH.