IL26613A - 2-anilino-1,3-diaza-2-cyclopentene derivatives and their manufacture - Google Patents

Description

26613/2 2-Aailino-l, 3-diaza-2-cyclopentene derivatives and their manufacture C.H. BOBHRIMBR SOW C. 25298 This invention relates to novel derivatives of 2-anilino-1, 3-diazacyclopentene-( 2 ) having valuable physiological properties.

Certain 2-arylamino-l, 3-&iazacyclopentenes-(2 ) are known to be pharmacologically active. Thus, U.S. P. No. 2,899,426 (column 1) reports that substituted 2-naphthylamino-l , 3-diazacyclopentenes can have both hypertensive and hypotensive activity, but makes no mention of the pharmacological action of further 2-aryl-amino-1, 3-diazacyclopentenes-( 2 ) described in the said U.S. Patent, merely describing a vulcanisation-accelerating action for such compounds.

Furthermore, Belgian Patent Specification No. 623,305 reports that compounds of the formula H in which Ar is an aryl group which may have one or more substitu-ents, R is a hydrogen atom or a lower alkyl group and n the number 2 or 3, have valuable vaso-constrictory and piloerectory properties which make them appear suitable for example in shaving preparations.

Surprisingly it has now been found that a small group of the compounds covered by formula I above in Belgian Patent No. 623,305 have a very strong hypotensive activity and are superior even to trie nap thylamino-1, 3-diazacyclopentenes-(2 ) known as hypotensives from U.S. . No. 2,899,426. These compounds are derivatives of 2-anilino-l,3-diazacyclopentene-(2 ) which have two substituents in the benzene nucleus, one being a methyl or methoxy group and the other being a halogen atom or a substituent having a physiological behaviour similar to that of a halo en atom.

According to the invention, therefore, we provide compounds of the formula in which R represents a fluorine, chlorine, or bromine atom or 2 a methyl or methoxy group, and R represents a fluorine, j>, chlorine, or bromine atom or a trifluoromethyl ,—o ane^ methyl or methoxy group in the 3-, 4-, 5-, or 6-position of the 1 2 benzene ring, one of the groups R and R being a methyl o methoxy group, except that when ^ represents a chlorine atom, 2 2 R does not represent a 4- or b- methyl group, and when R represents a chlorine atom, R^ does not represent a methyl group, and their acid-addition salts.

Whereas acid addition salts in general may be useful for example in purifying a compound of the formula II, for medicinal purposes non-toxic acid addition salts must of course be used. By the term "non-toxic acid addition salts" we mean those salts the anionic moieties of which are physiologically compatible in the dosages at which the salts are administered.

Compounds of the formula II are not described in Belgian Patent No. 623,305. These compounds possess strong hypotensive activity. Furthermore, several of the compounds according to the invention have a sedative action which varies quantitatively from case to case but can generally be detected in the therapeutic range with doses having a hypotensive activity.

The following results were obtained during pharmacological examination of several of the compounds according to the Examination of the hypotensive effect: Rabbits under urethane narcosis served as experimental animals, their blood pressure being recorded directly from the Arteria caro is with a mercury manometer. The compounds were administered intravenously. The known hypotensive Guanethidine served as comparison substance.

Action of Dose applied LD50 s.c. therapeutic compound relative to Index = E1 R2 relative to G-uanethidine mg./kg. mouse H50: Guane hidine = 1 column 4. = 1 CH5 3-Br 117 0.00855 227.5 26,600 CH3 5-3? 42 0.0238 355 14,900 Br 4-CH, 24 0.0416 90 2,160 Guanethidine 1 1 470 470 The hypotensive activity of the substances according to the invention can surprisingly be proved not only on hypertonics but also on healthy experimental persons with normal blood pressure and also on hypotonics. Most of the hypotensive agents used therapeutically show, in contrast, no action at all in the two last-mentioned groups or they only act at an extreme overdose.

Particularly preferred compounds by virtue of their especially favourable · therapeutic properties are 2-( 2-methyl-3-bromoanilino )-l , 3-diazacyclopentene-( 2 ) ; 2-(2-methyl-5-fluoroanilino )-l, 3-diazacyclopentene-( 2 ) ; 2- ( -bromo-4-me hylanilino )-l , 3-diazacyclopentene-( 2 ) 2-( 2-bromo-5-methylanilino ) -1 , 3-diazac clopent ene- ( 2 ) 2-( 2-methyl-5-bromoanilino )-l , 3-diazacyclopentene-( 2 ) 2-( 2-methyl-5-chloroanilino )-l , 3-diazac clopentene-( 2 ) ; 2-( 2-chloro-5-methoxyanilino )-l, 3-diazacyclopentene-(2 ) ; 2- (2-chloro-3-methylanilino )-l, 3-diazacyclopentene-(2 ) ; - - - - ^ - - i - 2-( 2-methoxy-5-chloroanilino )-l, 3-diazacyclopentene-( 2 ) .

Compounds of the formula II are preferably used in the form of their physiologically compatible acid addition salts.

Suitable salts include those formed with inorganic or organic acids, such as hydrohalides , phosphates, oxalates, 8-chloro-theophyllinates , or salts with acid synthetic resins, e.g.

"Zeo-Karb 225". Moreover, therapeutic preparations containing compounds according to the invention can contain more than one active compound of formula II and, if desired, also other physiologically active substances, for example saluretics.

They can further contain other known fillers or carriers, extenders, disintegrating or binding agents, lubricants, thickeners or diluents, suspending agents or agents for achieving a depot effect, depending upon the desired mode of administration. Preferred forms of administration according to the invention include tablets, dragees, ampoules, powders, aqueous or oily emulsions, and depot forms.

Dosage units preferably contain 0.01 to 5 mg, more preferably 0.03 to 1.5 mg. , of active ingredient according to the invention.

The compounds according to the invention can be prepared by any convenient method. According to a further feature of the invention, we provide the followin processes for the preparation of compounds of the formula II which are in general the most convenient; 1) Reaction of an isothiuronium salt of the formula: wherein R 1 and R2 are as hereinbefore defined, R3 represents a lower alkyl group, and X represents an anion, with ethylene-diamine; HX preferably represents a hydrohalic acid.

The reaction can be carried out either without usin a solvent or with a solvent; upon addition of a solvent the reaction takes place more smoothly but longer reaction times then result.

The isothiuronium salt .of formula III required as 1 starting material can be prepared in conventional manner by heating a thiourea derivative (prepared from a correspondingly substituted aniline and ammonium thiocyanate - see Houben-Weyl, vol. 9, p. 887), with an alkylating agent, e.g., an alkyl halide or a dialkyl sulphate. 2) Reaction of a thiourea derivative of formula in which R 1 and R2 are as hereinbefore defined, with ethylene-diamine. In this modification the two reaction components are heated together, preferably in vacuo, an excess of ethylene-diamine being preferably used.

As already stated, the thiourea derivative of formula IV can be prepared from a correspondingly substituted aniline and ammonium thiocyanate. 3) Ring closure of a correspondingly substituted N-phenyl-N' (3-aminoethyl)-urea or -thiourea of formula 1 2 wherein R and R are as hereinbefore defined and Y represents The starting compounds required can be obtained by reaction of a disubstituted phenyl isocyanate or phenyl isothiocy-anate with ethylenediamine , analogously to the method of the Journal of Organic Chemistry, vol. 24, page 818 (1959). 4) Reaction of a substituted phenyl-nitroguanidine of the formula wherein R and R are as hereinbefore defined, with ethylene-diamine or a salt thereof.

This reaction is preferably carried out in the presence of a suitable solvent, and with heating to reflux temperature.

Nitroguanidines of the formula VI may be obtained by reaction of the correspondingly substituted anilines with N-methyl-N-nitroso-N'-nitroguanidine , preferably using a polar solvent at temperatures between room temperature and reflux temperature, according to the method of the Journal of the American Chemical Society, vol. 69, p.3028 (1947).

) Reaction of a substituted aniline of the formula wherein R 1 and R2 are as hereinbefore defined, with a 2-alkylthioimidazoline of the formula C-S-lower alkyl VIII.

- ^ H Here it is possible to work in the presence or absence of a solvent. It is important to choose a sufficiently high temperature range to split off the resulting mercaptan. The temperatures necessary for this purpose lie generally at 100-150°C. However, sometimes it may be necessary to heat the reaction mixture up to about 200 °C.

The 2-alkylthio-imidazolines used as starting materials can be obtained in known manner by alkylation of the corresponding ethylene thioureas (cf. Organic Syntheses III, p.394). 6) Heating a bis-( 2-oxo-l-imidazolidinyl )-chloro-phosphine oxide of the formula 0 I 1 j? - N ^NH IX C It 01 " 0 0 with a substituted aniline of the formula VII (hereinbefore defined) in the presence of a solvent, for example xylene, at about 110-180 °C.

The bis-(2-oxo-l-imidazolidinyl)-chlorophosphine oxide required in this reaction as a starting material may be obtained for example by reaction of a corresponding imidazoline-l-one, with phosphorus pentachloride in chloroform as solvent at a temperature of about 20-40°C (cf. Bull.Soc.Chim. France, 1961 p.2114 et seq. ) .

The following examples illustrate the invention: Example 1 2- ( 2-Methyl-5-bromoanilino ) -1 , 3-diazacyclopentene-( 2 ) 6.1 g. of N-( 2-methyl-5-bromophenyl )-iso t hiuronium hydriodide (0.016 mol) are refluxed with 1.6 ml. of ethylene diamine in e h lenediamine are then taken off in vacuo. The residue is taken up with a little methanol and the solution made alkaline wi 50$ potassium hydroxide. The imidazoline base which separates oi at first "becomes crystalline after ice-cooling, is filtered off with suction, and washed with water and petroleum ether, and dried. Yield: 2.5 g. After recrystallisation from "benzene/ petroleum ether ("boiling range 40-80°0), 1.2 g. of imidazoline base of m.pt. = 145°C (29.6$ of theory) are obtained.

After purification over charcoal an ethereal solution of the base is acidified with ethereal hydrogen chloride to yield 0.9 g. of the imidazoline hydrochloride of m.pt. = 194-196°C. Thin layer chromatogram: pure.

The following compounds can be prepared in analogous manner (same solvent, same reaction time, same working up): 2-(2-chloro-5-methylanilino)-l, 3-diazacyclopentet -(2 ) ; yield (base) 22.0$ of theory; m.pt. of the base: 187-190°C; m.pt. of the hydrochloride: 178-180°C; 2-(2-bromo-5-methylanilino)-l,3-diazacyclopentene-(2) ; yield 24$ t of hydrochloride: --2- , m.pt. of hydrochloride: 238-240°C; 2-(2-methyl-5-chloroanilino )-l, 3-diazacyclopentene-(2) ; yield of base: 34.9$ of theory; m.pt. of the base: 176-178°C; m.pt. of the hydrochloride: 181-182°0.

Example 2 2-(2-Methyl-5- luoroanilino )-l , 3-diazacyclopentane-( 2 ) 13 g. (0.08 mol) of 2-methyl-5-fluoroaniline hydrochloride are heated with 6.4 g. of ammonium thiocyanate (105$) in 110 ml. of chlorobenzene for 7.5 hours at 95-100°0. After cooling, the product is filtered off with suction and washed with water.

The crude substance is digested with 200 ml. of water, and 200 ml of petroleum ether are added; the mixture is thenmade alkaline sodium bicarbonate with aotte- and filtered0 with suction. 7.0 g. (0.038) mol of the resultin -fluoro-2-meth l hen l-isothiourea of m. t. = 119-122 °0 . are heated to "boiling in 40 ml. of methanol with 3 . 5 ml. of methyl iodide for 1. 5 hours. The mixture is then concentrated in vacuo and dried. The isothiuronium hydriodide remaining as residue in quantitative yield is refluxed in 40 ml. of methanol with 3. 8 ml. of ethylenediamine for 18 hours.

The solvent is then distilled off in vacuo, the residue dissolved in a little methanol, the solution made alkaline with 0 potassium hydroxide, cooled, and vigorously stirred with petroleum ether. The base is then filtered off with suction, washed with water, and dried. Yield: 5 .0 g. , i.e., a yield of 68.0% of theory. M.pt. = 119-121°C . After purifying over activated charcoal, the hydrochloride is precipitated from ethereal solution with ethereal hydrogen chloride and recrystallised from methanol/ether. M.pt, = 169-170°G . Thin layer chromatogram : pure.

Analogously to Example 2 there is obtained 2- ( 2-fluoro-4-methylanilino )-l, 3-diazacyclopentene- ( 2 ) in a yield of 59. 5 of theory; m.pt. (base) = 130-131°C Nitrate: m.pt. = 139°C 2-( 2-Methyl-4-fluoroanilino )-l, 3-diazocyclopentene-( 2 ) is obtained in analogous manner in a yield of 34.6% of theory, m.pt. (base) = 101-103 °C o Example 3 2- ( 2-Meth.yl-3-bromoanilino) -1 , 3-diazacyclopentene-( 2 ) By means of a Sandmeyer reaction there are obtained from 58.0 g. of 2-amino-6-nitro-toluene and cuprous bromide, 20 g. of 2-bromo-6-nitro-toluene ( = 24.4% of theory) which is hydrogenated with Raney nickel as catalyst under normal conditions, hydrogenation being discontinued upon uptake of the theoretical amount of H2> to yield 9.2 g. of 3-bromo-2-methyl-aniline (hydrochloride: m.pt. = 245 °C ) . 11.0 g. ( 0.05 mol) of 3-bromo-2-methyl-aniline hydrochloride are. then heated for about 7 hours with 4 g. of ammonium thiocyanate (105 ) in 100 ml. of chloroform at 95-100 °C. The mixture is then cooled and the product is filtered off with suction and washed with water and petroleum ether. The crude substance is digested with 100 ml. of water, 100 ml. of petroleum ether are added, the mixture is then made alkaline with soda, and filtered with suction. 3.2 g. (0.013 mol ; 26.3$ of theory) of the resulting 3-bromo-2-methyl-phenyl-isothiourea of m.pt. = 171°C are heated to boiling in 20 ml. of methanol with 1.2 ml. of methyl iodide for 1.5 hours. The reaction mixture is then concentrated in vacuo and dried. The isothiuronium salt (yield quantitative) remaining as residue is refluxed in 15 ml. of methanol with 1.3 ml. of ethylenediamine for 16 hours. The solvent is then distilled off in vacuo and the residue is dissolved in a little methanol; the solution is made alkaline with 50$ potassium hydroxide, cooled, and vigorously stirred with petroleum ether. The solid is filtered off with suction, washed and dried to yield 1.7 g. of 2-(2-methyl-3-bromo-anilino )-l, 3-diazacyclo-pentene-(2) of m.pt. 105-107°C. (this corresponds to a yield of 51.5$ of theory, calculated on the isothiuronium salt). The hydrochloride is obtained from an ethereal solution of the base by precipitation with ethereal hydrogen chloride, and after recrystallisation from methanol/ether has m.pt. of 210-211°C.

Thin layer chromatogram : pure.

Analysis : Calculated: C 41.34$ H 4.51$ N 14.46$ Found: 0 41.34$ H 4.79$ N 14.33$ By means of a Sandmeyer reaction there is obtained from 2-amino-3-nitro oluene and GuGl, and subsequent catalytic reduction analogously to the above working method, 2-chloro-3-methyl-aniline which is converted via intermediates 2-chloro-3-methyl- phenyl-isothiourea (m.pt. = 150-152°G) and 2-chloro-3-methyl-phenyl-S-methyl- isothiuronium hydriodide into 2-(2-chloro-3-meth 1anilino ) -1 , 3-diazacyclopentene-( 2 ) , as described in the above Examples 2 and 3» Yield 77$ of theory; m.pt. (base) = 159-161°C; hydrochloride m.pt. = 220°C; thin layer chromatogram: pure .

Example 4 2-( 2-Chloro-5-methoxyanilino )-l , 3-diacyclopentene-( 2 ) 37.5 g. (0,02 mol) of 4-chloro-3-nitroanisole are hydrogen-ated under normal conditions in methanol/tetrahydrofuran with Raney nickel as catalyst. After uptake of the calculated quantity of hydrogen (13=4 litres in 3.5 hours), hydrogenation is discontinued. The catalyst is filtered off and the clear filtrate is concentrated in vacuo to dryness. The residue is taken up with ether, the ethereal solution is purified by means of activated charcoal, and 3-amino-4-chloroanisole hydrochloride is precipitated by passing in dry HCl-gas, The solid is filtered off with suction and dried to yield 35°5 g. (= 91.5$ of theory). 35.5 g. (0.183 mol) of 3-amino-4-chloroanisole hydrochloride are heated for 6 hours with 14.6 g. (105$) of ammonium thiocyanate in 250 ml. of chlorobenzene at 95-100°Co The reaction mixture is cooled and the solid is filtered off with suction and washed with water and petroleum ether. The crude substance is digested with about 300 ml. of water, and 300 ml. of petroleum ether are added; the mixture is made alkaline with NagCO^ and filtered with suction. 17.0 g. (= 42,9$ of theory) of 2-chloro-5-methoxyphenyl-isothiourea of melting point 163-166 °0 are obtained. This is heated to boiling for 1.5 hours with 7.3 ml. of methyl iodide in 75 ml. of absolute methanol. The mixture is then concentrated in vacuo and dried. The residual isothiuronium hydriodide is refluxed in 75 ml. of methanol with 7.85 ml.0 of ethylene-diamine (150$) for 17 hours. The solvent is then distilled off in vacuo and the residue is dissolved in a little methanol; the solution is made alkaline with 50% potassium hydroxide, cooled, and stirred with petroleum ether. The solid component is filtered off with suction, washed with water, and dried. The crude base is recrystallised from benzene/petrol to yield: 15.0 g. (=85% of theory). M.pt. = 126-128°C.

An ethereal solution of the base is purified by means of activated charcoal and concentrated nitric acid is added thereto until the solution is acid to congo-red. 2-( 2-Chloro-5-methoxyanilino)-l*3 -diazacyclopentene-( 2 ) nitrate crystallises.

After recrystallisation from methanol/ethe , the compound, the thin layer chromatogram of which is uniform, melts at 177-178°C.

The following compounds can be obtained analogously to Example 4: 2-( 2-me thoxy-4-chloroanilino )-l, 3-diazacyclopentene-(2 ) yield: 63.2 of theory; m.pt. of the base: 136-138°C; m.pt. of the hydrochloride: 181°C; 2-(2-methoxy-5-chloroanilino )-l, 3-diazacyclopentene-( 2) yield: .3$ of theory; m.pt. of the base: 145-147°C; m.pt. of the nitrate: 140°G.

Example 5 2- ( 2-Bromo-3-methylanilino )-l , 5-diazacyclopentene-( 2 ) g. (0oll5 mol) of 2-bromo-3-methylaniline hydrochloride of m.pt. 211-212°C„ are heated with 9 g. of ammonium thiocyanate (105$) in 150,: ml. of chlorobenzene for 15 hours at 95-100°C.

The reaction mixture is cooled and the solid filtered off with suction and washed with water and petroleum ether. The crude 2-bromo-3-methylphenyl-isothiourea is digested with 150 ml. of water and 150 ml. of petroleum ether are added; the mixture is made alkaline with soda and filtered with suction. 3.5 g. 2- - -m t -is io e 234-238°C. are then heated to boiling in 15 ml. of absolute methanol for one and a half hours . The reaction mixture is then concentrated in vacuo and driedo The residual isoth.a_ronium salt (yield quantitative) is refluxed in 15 ml. of methanol with 1.54 ml. of ethylenediamine for 5 hours, the solvent and excess of ethylenediamine are distilled off in vacuo, and the residue is taken up with warming in a little methanol. The imidazoline base which separates thereby is filtered off with suction and converted in conventional manner into the hydrochloride. Yield: 0.2 g. of 2-( 2-bromo-3-methylanilino -l, 3-diazacyclopentene-( 2 ) hydrochloride of m.pt. 287-288°C.

Analogously to Example 5, the 2-(2-bromo-4-me h lanilino )-l,3-diazacyclopentene-(2) is obtained in a yield of 79»2 of theory- M.pt. of the base: 145-148°C<> (from benzene/ petroleum ether); m.pt. of the nitrate: 165-166°C.

The following Examples 6 to 10 illustrate pharmaceutical compositions according to the invention: Example 6 Tablets 2-( 2-Bromo-4-nie thylanilino)-!, 3-diazacyclo- pentene-(2) hydrochloride 0.3 mg.

Lactose 54.7 mg.

Maize starch 29.5 mg.

Soluble starch 4.0 mg.

Magnesium stearate 1.5 mg.

Example 7 Drop solution (1.0 mg. in 1 ml. = 20 drops) 2-(2-Chloro-5-methoxyanilino )-l , 3-diazacyclo- pentene-(2) hydrochloride 0.10 g.

Methyl ]D-hydroxybenzoate } 0.07 g.

Propyl p_-hydroxybenzoate 0.03 g.

Example 8 Ampoules 2-(2-Methyl-3-bromoanilino)-l,3-diazacyclopentene-(2) 0.05 mge NaCl 18.0 mg.

Distilled water ad 2 ml. Example 9 Suppositories 2-(2-C loro-3~metaylanilino )-l, 3-diazacyclo- pentene-(2) hydrochloride 0.7 mg.

Lactose 244.2 mg.

Suppository base ad 1.7 g.

Example 10 Tablets 2-( 2-Methyl-3-bromoanilino )-l, 3-diazacyclo- pentene-(2) hydrochloride 0.06 mg.

Lactose 54.8 mg.

Maize starch 29.7 mg.

Soluble starch 4.0 mg.

Magnesium s earate * 1.5 mg, 90.0 mg The compositions are prepared according to standard methods.

Claims (10)

1. HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is:- 1. Compounds of the formula in which R represents a fluorine, chlorine, or "bromine atom 2 or a methyl or methoxy group, and R represents a fluorine, chlorine or bromine atom or a tri luoromethyl,—oyano^ methyl or methoxy group in the 3-, 4-, 5- or 6-position of the "benzene 1 2 ring, one of the groups R and R "being a methyl or methoxy 1 ' 2 group, except that when R represents a chlorine atom, R does 2 not represent a 4- or 6- methyl group, and when R represents a chlorine atom, R1 does not represent a methyl group, and their acid-addition salts,

2. Non-toxic acid addition salts (as herein defined) of compounds as claimed in claim 1.

3. Salts as claimed in claim 2 formed with a hydrohalic acid, phosphoric acid, oxalic acid, 8-chlorotheophyllinic acid, or with a synthetic acidic resin.

4. 2-(k2--Methyl-3-hromoanilino )-l , 3-diazacyclopentene-(2 ) .

5. 2-( [2--Methyl-5-fluoroanilino )-1, 3-diazacyclopentene-( 2 ) .

6. 2-(k2--Bromo-4-methylanilino )-l , 3-diazacyclopentene-(2 ) .

7. 2-( ^2< -Bromo-5-methylanilino )-l , 3-diazacyclopentene-( 2 ) .

8. 2-( 2--Methyl-5-bromoanilino )-l , 3-diazacyclopentene-( 2 ) .

9. 2-( -Methyl-5-chloroanilino )-1, 3-diazacyclopentene-( 2) . 10. 2- -Chloro-5-methoxyanilino ) -l,3-diazacyclopentene-(2) . llo 2-( [2--Chloro-3-methylanilino)-1, 3-diazacyclopentene-(2 ) . 12. 2- [2--Ghloro-5-methylanilino )-l,3-diazacyclopentene-(2) . 13. 2- [2--Methoxy-4-chloroanilino ) -1, 3-diazacyclopentene-(2 ) . 1 . 2-(2-Methoxy-5-chloroanilino )-l, 3-diazacyclopentene-( 2 ) . 15. Acid addition salts of compounds as claimed in any of claims 4 to 14. 16. Non-toxic acid addition salts (as herein defined) of compounds as claimed in any of claims 4 to 14. 17. A process for the preparation of a compound as claimed in claim 1 which comprises reacting an i sothi ronium salt of the formula in which R and R are as defined in claim 1, R represents a lower alkyl group and X represents an anion, with ethylene-diamine. 18. A process as claimed in claim 17 in which HX is a hydro-halic' acid. 19. A process as claimed in claim 17 or claim 18 in which the reaction is effected in the presence of a solvent. 20. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a thiourea derivative of the formula in which R and R are as defined in claim 1, with ethylene diamine . 21. A process as claimed in claim 20 in which the reaction is effected in vacuo. 22. A process as claimed in claim 20 or claim 21 in which an excess of ethylene diamine is used, 23. A process for the preparation of a compound as claimed in claim 1 which comprises pyrolysing an N-( substituted phenyl)-N'-^-aminoethyl)-urea or -thiourea of the- formula in which R 1 and R2 are as defined in claim 1, and Y represents an oxygen or sulphur atom? whereby ring-closure occurs. 24. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a substituted phenyl-nitro uanidine of the formula in which R and R are as defined in claim 1, with ethylene-diamine or a salt thereof, 25 o A process as claimed in claim 24 in which the reaction is effected in the presence of a solvent. 26. A process as claimed in claim 25 in which the reaction is effected at the boiling temperature of the solvent. 27. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a substituted aniline of the formula in which R 1 and R2 are as defined in claim 1, with a 2-alkyl-thioimida oline of the formula HpC - II^ ' .0 - S - lower alk l VIII HpG - Nx H with elimination of alkylthiol, 28. A process as claimed in claim 27 in which the reaction is effected in the presence of a solvento 29. A process as claimed in claim 27 or claim 28 in which the reaction is effected at a temperature from 100-150°Co 30. A process for the preparation of a compound as claimed in claim 1 which comprises heating a bis-(2-oxo-l-imidazolidinyl)-chloro-phosphine oxide of the formula 0 with a substituted aniline of the formula in which R 1 and R2 are as defined in claim 1, at about 110-180°C, in the presence of a solvento 31. A process as claimed in claim 30 in which the solvent is xylene. 32. A process as claimed in any of claims 17 to 41 which also includes the step of converting the compound of the formula I into a non-toxic acid addition salt thereof o 33. A process for the preparation of a compound as claimed in claim 1, or an acid-addition salt thereof, substantially as herein described, 34. A process for the preparation of a compound as claimed as herein described with reference to any of Examples 1 to 5. 35. Compounds as claimed in claim 1 , and acid addition salts \ thereof, whenever prepared by a process as claimed in any of claims 17 to 34 o 36. Pharmaceutical compositions containing as active ingredient at least one compound or non-toxic acid addition salt thereof (as herein defined) as claimed in any of claims 1 to 14 , 16 and 35 together with a pharmaceutical carrier or excipiento 37. A composition as claimed in claim 3 containing also a saluretic . 38. A composition as claimed in claim 36 or claim 37 in the form of dosage uni s0 39. A composition as claimed in claim 38 in the form of tablets, dragees, depot forms, suppositories, or ampoules. 40. A composition as claimed in claim 38 or claim 39 containing from 0 - 01 to 5 mg, of active ingredient per dosage unit. 41. A composition as claimed in claim 40 containing from 0.03 to 1.5 mg. of active ingredient per dosage unit. 42. A composition as claimed in claim 36 or claim 37 in the form of a powder, aqueous or oily emulsion, or drop solution. 43 o A composition as claimed in claim 36 substantially as herein describedo 44. A composition as claimed in claim 36 substantially as herein described with reference to any of Examples 6 to

10. -5 Each and every novel compound »—oompooitionj—prooeoo ^ fv and mothod horoin dio.oloaodc Da ed this 30th September, 1966 For the Applicants