IE49803B1 - 4-or 5-pyrimidinyl-amino-1,3-diaza-2-cycloalkenes,processes for their preparation,pharmaceutical preparations containing these compounds,and their use in therapeutics - Google Patents

Abstract

Compounds of the formula I in which Py represents an optionally substituted 4-or 5-pyrimidinyl radical bonded via a carbon atom to the nitrogen atom, R1 and R2 independently of one another represent hydrogen, lower alkyl or lower alkenyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 4 carbon atoms, their tautomeric compounds and salts, exhibit hypotensive and antihypertensive effects.

Description

The present invention relates to 2-(pyrimidinylamino)-1,3-diaza-2-cycloalkene compounds, in particular of the formula Py-N-Cf .Alk R V R2 I (I) in which Py represents a 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, lower alkylsulphonyl, amino; phenyl, phenoxy or phenylamino, each of which can be substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkyl amino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido or Py represents a 5- pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising hydroxy, trifluoromethyl, lower alkylsulphonyl, amino; phenyl, phenoxy or phenylamino, each of which can be substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxy carbonylaraino , ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, and R^ and Rg independently of one another represent hydrogen, lower alkyl or lower alkenyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 4 carbon atoms, and their tautomeric compounds and salts, and processes for their preparation, the compounds of the formula I and their salts as pharmacologically active compounds, pharmaceutical preparations containing such compounds, and the use of the new compounds as pharmacologically active substances and for the preparation of pharmaceutical preparations.

In the context of the present description, radicals 5 and compounds denoted hy lower” contain preferably up to 7, and especially up to 4, carbon atoms.

Lower alkyl represents, for example, especially methyl, and also ethyl, n-propyl, isopropyl,.n-butyl, isobutyl, or tert.-butyl, and also n-pentyl, neopentyl, n-nexyl or n-heptyl.

Lower alkenyl represents, for example, especially allyl, or a 1-, 2- or 3-methylallyl group.

Lower alkoxy is, for example, especially methoxy, but may also be ethoxy, n-propoxy, isopropoxy, or n-butoxy, furthermore n-pentyloxy.

Lower alkyl sulphonyl is, for example, methylsulphonyl, ethylsulphonyl, n-propylsulphonyl or isopropylsulphonyl.

Lower alkylthio is especially methylthio, furthermore also ethylthio, isopropylthio, n-propylthio, or also a straight or branched butyl thio.

A eycloalkyl radical is especially a eycloalkyl group having 3 to S ring carbon atoms, and is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

Halogen is especially halogen of an atomic number up to 35 and represents especially chlorine, furthermore fluorine or bromine.

An optionally substituted phenyl or phenoxy radical 30 can be substituted-by one, two or three identical or different substituents. Such substituents are, for example, lower alkyl, optionally functionally modified hydroxy or mercapto, such as etherified hydroxy, for example lower alkoxy, lower alkenyloxy or lower alkylenedioxy, further35 more lower alkylthio, or halogen, trifluoromethyl, nitro, amino, including substituted amino, for example lower alkylamino or di-lower alkylamino, and optionally functionally modified carboxy, such as esterified carboxy, for example lower alkoxycarbonyl. 9803 Lower alkenyloxy is, roc example, especially vinyloxy oc allyloxy.

Optionally substituted amino can be substituted by lower alkyl oc optionally substituted phenyl, and is, for example, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, phenylamino, 4-methoxyphenylamino or 4-chlorophanylamino.

It may also be substituted by lower alkylene which may contain oxygen, sulfur or optionally lower alkyl-substituted nitrogen as ring member, and may be, for example, lower alkyleneamino, for example pyrrolidino or piperidino, oxalower alkyleneamino, for example morpholino, thia-lower alkyleneamino, for example thiomorpholino or aza-lower alkyleneamino, for example piperazino or 4-lower alxylpiperazino, such as 4-methylpiperazino. Substituted amino may also be acylamino, such as lower alkanoylamino, for example acetylamino or pcopionylamino, lower alkoxycarbonylamino, for example methoxycarbonylamir.o or ethoxycarbonylamino, or ureido optionally substituted by lower alkyl, for example ureido, 3-methylureido or 3,3dimethylureido.

A lower alkylene group Alk is preferably unbranched lower alkylene and is especially ethylene, also 1,3propylene, or 1,4-butylene, but may also be branched lower alkylene, such as 1,2-propylene, 2-methyl-l,2-propylsne or 2,3-butylene.

Salts of compounds of the above formula I are acid addition salts, especially pharmaceutically acceptable, nontoxic acid addition salts with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acids, or with organic acids, such as corresponding carboxylic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or sulphonic acids, for example methanasulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulohonic acid, ethane-1,2-disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid.

In view of the close relationship between the new compounds in their free form and in the form of their s^lts, including also such acid addition salts, that may be used as intermediates, for example in the purification of the new compounds or for their identification, in the preceding and following text the free compounds are to be understood optionally also as the corresponding salts in respect of general sense and intended use.

The compounds of the present invention possess valuable properties, especially pharmacological affects.

Thus, they show hypotensive and antihypertensive effects which can be demonstrated in anaesthetised cats in doses from approximately o.l mg/kg on intravenous administration (wherein also the pressocial effects of adrenalin and noradrenalin are antagonised) and on renally hypertonic rats t in doses from approximately 10 mg/kg/day on oral administration. Furthermore, the compounds according to the invention have an effect on the cardiac action, which can be demonstrated by means of the positively inotropic effects determined at concentrations from 100 pg/ml, and by means of the negatively chronotropic effects determined at concentrations from 10 /ig/ml on the isolated guinea pig atrium. The compounds of the formula I have a favourable therapeutic index, that is to say, a favourable relationship between the effective and the toxic dose. The compounds of the present invention are therefore used as pharmacologically active compounds, especially as antihypertensives for the treatment of raised blood pressure, for example 43803 examples in connection with essential hypertonia, and as cardiotonic agents.

The invention relates especially to compounds of the formula I in which Py represents a 4-Pyrimidinyl bonded via a car· bon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, halogen, amino; phenyl which can be substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, or Py represents a 5-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising hydroxy or amino; phenyl which can be substituted by lower alkyl, lower alkoxy, hydrogen, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, and in which Rg and Rg independently of one another represent hydrogen, lower alkyl or lower alkenyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 4 carbon atoms, radicals denoted by lower containing up to 4 carbon atoms, and their tautomeric compounds and salts thereof, especially pharmaceutically acceptable, nontoxic acid addition salts.

The invention relates especially to compounds of the formula I in which Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising lower alkyl, lower alkoxy, phenyl, lower alkylamino, di—lower alkylamino or morpholino and/or 48803 Ί halogen, or Py represents a 5-pyrimidinyl_bonded via a carbon atom to the nitrogen atom optionally substituted by one, two or three identical or different substituents from the group phenyl, lower alkylamino, di-lower alkylamino or mor5 pholino and/or halogen and in which R^ represents hydrogen or lower alkyl and S2 represents hydrogen or lower alkyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 3 carbon atoms, radicals denoted by lower containing up to 4 carbon atoms, and halogen having an atomic weight of up to 35 , and salts thereof, especially pharmaceutically acceptable, non-toxic acid addition salts. The invention relates especially to compounds of the formula Λ* *3”v.

, N &->lk' (ID V H V H in which Alk' R, , R and R 3 4 5 represents lower alkylene having up to 4 carbon atoms which separates the two nitrogen atoms by 2 to 3 carbon atoms, especially ethylene, and each of the radicals represents hydrogen, lower alkyl having up to 4 carbon atoms, for example methyl, halogen, for example chlorine or bromine, di-lower alkylamino, for example dimethylamino or diethylamino, morpholino or phenyl, if the group A 3\= Rg,R4 and Rg represents a 4-pyrimidinyl and each of the radicals represents di-lower alkylamino, for example dimethylamino or diethylamino, morpholino or phenyl if the group /*4 JX— )· v‘w’ represents a 5-pyrimidinyl, wherein preferably at least one of the radicals Rg, R^ and Rg, but preferably two thereof, is different from hydrogen, and salts thereof, especially pharmaceutically acceptable,non— · toxic acid addition salts.

The invention relates especially to compounds of the formula (III) in which R' and R' independently of one another represent hydrogen, lower alkyl having up to 4 carbon atoms, for example methyl, or lower alkoxy having up to 4 carbon atoms, for example methoxy, halogen, for example chlorine, di-lower alkylamino, for example dimethylamino, wherein preferably both of the radicals R' and R' are different 3 4 from hydrogen and are especially lower alkyl, for example methyl, lower alkoxy, for example methoxy, halogen, for example chlorine, or di-lower alkylamino, for example dimethylamino, and is 2 and especially 1, and salts thereof, especially pharmaceutically acceptable,nontoxic acid addition salts.

The invention relates especially to the compounds of the formula I described in the Examples and salts thereof, especially pharmaceutically acceptable, non-toxic acid addition salts.

The compounds of the present invention can be prepared in accordance with methods known per se, for examcle by reacting a compound of the formula Py-X (XV), or a salt thereof, with a compound of the formula (V) a. 803 or with a salt thereof, wherein one of the radicals X and Y represents an amino group of the formula -M(R^)-a (VI) and the other represents a group that can be split off together with hydrogen under the reaction conditions, and, if desired, converting a resulting compound of the formula I into a different compound of the formula I, and/or,if desired, converting a resulting salt into the free compound or into a different salt,'and/or, if desired, converting a resulting free compound into a salt, and/or, if desired, separating a resulting mixture of isomers into the individual isomers.

A group X or Y that can be split off together with hydrogen is, for example, especially a free, or preferably an etherified, mercapto group, furthermore a reactive, functionally modified hydroxy group, or the nitroamino group. An etherified mercapto group is especially a mercapto group etherified by an optionally substituted hydrocarbon radical, especially one of aliphatic character.It is especially lower alkylthio, for example methylthio, ethyl20 thio or butyl thio or phenyl-lower alkylthio, for example benzylthio. A reactive, functionally modified hydroxy group is a corresponding etherified or esterified hydroxy group. Such a group is, inter alia , lower alkoxy, for example methoxy, or halogen, for example chlorine or bromine, or lower alkylsulphonyloxy, for example methanesulphonyloxy.

Preferably, in a compound of the formula IV the group X represents the amino group of the formula VI, whilst in a compound of the formula V the radical Y represents especially an etherified mercapto group, especially lower alkylthio, for example methylthio.

Salts of starting substances of the formula IV and V are acid addition salts, for example salts with the abovementioned acids, especially with mineral acids, such as hydrohalic acids, for example hydrochloric acid, hydriodic acid or sulphuric acid. In that case in particular the starting material that is different from an amino compound η 43803 of the formula IV or V, and especially a starting material of the formula V in which Y represents an optionally etherified mercapto group or a reactive, functionally modified hydroxy group, is used in the form of an acid addition salt.

The above reaction is carried out in a manner known per se , for example in the absence or presence of a solvent or a mixture of solvents, if desired in the presence of an excess of the amine component used as starting material, whilst cooling or preferably whilst heating, for example 0 at a temperature of from approximately 50 C to o o approximately 180 C, preferably at ISO C, if necessary in a closed vessel, optionally under pressure, and/or under an inert gas atmosphere, for example a nitrogen atmosphere.

The starting substances are known, or can be prepared in a manner known per se .

The new compounds can likewise be prepared by reacting a compound of the formula Py 2 (VII) , in which Y Y and Y 1 2 represents the imino group, a group that can be split off, the oxo group or thioxo group, and represents a group that can be split off, or together represent a triple-bonded nitrogen atom, when R^ is hydrogen, or the corresponding tautomeric form, or a salt thereof with an alkylenediamine compound of the formula SgN-Alk-NHR^ (VIII) and, if desired, carrying out additional process steps.

A group that can be split off has already been defined 49303 above under formula IV or V in connection with the substituents X or Y. A compound of the formula VII is normally used in the form of an acid addition salt, especially a salt with a mineral acid, such as a hydrohalic acid, for example hydrochloric, hydrobromic or hydriodic acid. The condensation reaction to form the ring can be effected in one or two steps.

The above reaction can be carried out in the absence or presence of a solvent, such as a, preferably, polar solvent. In that case, the process is carried out at room temperature or, oreferably, at elevated temperatures, for o o example at approximately 50 C to approximately 200 C, wherein, in the absence of a solvent, the mixture of the two reactants (the compound of the formula VII, preferably in the form of an acid addition salt, and a compound of the formula VIII, preferably in excess) is heated to temo peratures of from aporoximately 100 C to approximately o 200 C. The reaction can be performed in a closed vessel, optionally under increased pressure, and/or under an inert gas atmosphere, such as a nitrogen atmosphere.

The starting substances are known or can be prepared in a .manner known per se , for example those of the formula VII, for example by treating an amine compound of the formula Py-NH-R^ (IVa) with a suitable isocyanate or iso25 thiocyanate compound, such as an acyl isocyanate or acyl isothiocyanate, for example a lower alkoxycarbonyl isocyanate or lower alkoxycarbonyl isothiocyanate, such as ethoxycarbonyl isocyanate or isothiocyanate, or with an aroyl isocyanate or aroyl isothiocyanate, such as benzoyl isocyanate or benzoyl isothiocyanate(these being optionally produced in situ , for* example by treating an alkali metal cyanate or thiocyanate or ammonium cyanate or ammonium thiocyanate with a suitable acid halide, for example an acid chloride or with a suitable acid ester), by removing the acyl group from a resulting M-acylurea compound or H-acylthiourea compound by hydrolysis, 43803 preferably in the presence of an alkaline agent, for example sodium hydroxide, and converting the corresponding urea or thiourea intermediate into the desired 0-or 3-substituted isoucea or isothiourea compound of the formula VII by treating with a reactive ester of an alcohol, such as a lower alkylhalide, for example methylchloride, bromide or iodide, or with di-lower alkylsulphate, for example dimethylsulphate.

In a special process variant of the preceding process, the new compounds of the formula I can likewise be obtained when a compound of the formula P.

A-lk (IX) in which Z and Z 1 2 Z and Z 2 3 together represent oxygen or sulphur and represents the radical R^ and represents hydrogen, or is a group that can be split off and together form a bond, and represents the radical S^, is subjected to a ring-closure reaction, and, if desired, additional process steps are carried out.

The ring closure of the above starting material of the formula IX can be carried out by means of pyrolysis, operation being carried out at tsmoeratures of from apocoxio o mately 100 C to approximately 200 C, if necessary or desired in the presence of. a suitable high-boiling solvent, in a closed vessel, optionally under increased pressure, and/or under an inert gas atmosphere, for example a nitrogen atmosphere.

Ths starting material can be prepared in a manner •t.nown per se , for example by treating a compound of the formula ?y-9=C=Z (X) or of the formula ?y-N(R )-C(=Z)-Hal (XI), wherein Hal reoresents 1 1 5 halogen, especially chlorine and Z represents oxygen or sulphur, with an alkylanediamine compound of the formula H^N-Alk-NH-R (VIII).

If desired, compounds of the formula I can be converted into different compounds of the formula I.

Thus, for example, in compounds of the formula I in which R and/or represents hydrogen, these can be replaced by lower alkyl, for example, methyl or ethyl, in a manner known per se , for example by treating the corresponding compound with a reactive ester of a lower alkanol, such as a lower alkyl halide, for example methyl or ethyl chloride, bromide or iodide, or with a di-lower alkyl sulphate, for example dimethyl sulphate. In that case, operation is carried out in the absence, or preferably in the presence, of a solvent, if necessary whilst cooling or heating, for examDle in a temperature range from aporoxio o mately 0 C to approximately 100 C, in a closed vessel, optionally under increased pressure, and/or in an inert gas atmosphere, for example a nitrogen atmosphere.

Furthermore, compounds of the formula I in which the radical Ry is substituted by halogen, for example by chlorine or bromine, may be dehalogenatsd. The dehalogenation can be effected with substances having a reducing action, especially with catalytically activated hydrogen or nascent hydrogen. The exchange of the halogen is effected, for example, by hydrogen in the presence of Raney nickel in, for example, alcoholic solution, in the presence . 48803 of platinum in acetic acid or, preferably, ir. the presence of palladium on carbon in aqueous solution when using a salt of the compound to be dehalogenated, or in a solvent that is inert for the reaction.

As solvents there may be used, for example, ethers, for example tetrahydrofuran or dioxan, lower alkanols, for example methanol or ethanol, or solvent mixtures, for example methanol/formamide. The reaction is carried out, for example, at room temperature, but may also be carried out at slightly elevated temperature, for example at a 0 temperature of up to SO C and under a slight excess pressure. The dehalogenation may, however, also be carried out with nascent hydrogen, for example with zinc, especially with zinc powder or, alternatively, with metallic copper. Furthermore, sodium amalgam and sodium methylate or ethylate in alcoholic solution may also be used.

Compounds of the formula I in which the radical Py is substituted twice by halogen, for example by chlorine or bromine, in the 2- and S-position can be converted by reaction with an optionally substituted amine into compounds of the formula I in which a halogen atom in 2position has been replaced by an optionally substituted amino.

The reactions with an optionally substituted amine are carried out, for example, in alcoholic solution at elevated temperature, preferably at the reflux temperature of the reaction mixture, and optionally under excess pressure.

Compounds of the formula I in which the radical Py is substituted twice by halogen in the 2- and S-position can be prepared from corresponding 2-halo-S-hydroxy or 2halo-S-lower alkoxy compounds by reacting with a halogenating agent, for example a chlorinating agent such as phosphorus oxychloride. 43803 If lower alkoxy groups ate present as substituents in the radical Py, for example methoxy or ethoxy groups or even phenoxy groups, then these can easily be converted by acidic or basic hydrolysis into compounds of the formula I in which the radical py is substituted by hydroxy.

The new starting substances and processes for their preparation likewise form the subject matter of the invention.

Depending on the process conditions and the starting substances, the compounds of the formula I are obtained in free form or in the form of their salts which can be converted in the customary manner into one another or into other salts. Acid addition salts can be obtained, for example, by reacting a free compound of the formula ΐ with an acid, especially an organic or inorganic acid, which is suitable for the formation of pharmaceutically acceptabl salts. Such acids are, for example : hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, hvdroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylenesulphonic acid; haloben2enasulphonic, toluenesulphonic, naphthalenesulphonic or sulphanilic acid; or ascorbic acid; methionine, tryptophan, lysine or arginine. Acid addition salts of compounds of the formula I can be converted, for example, by treating with alkaline agents, such as alkali metal hydroxides, or with basic ion exchangers, into the free bases, or for example by treating with suitable ion exchangers or silver salts, into differen salts .

The invention relates also to those forms of the process in which a compound obtainable at any stage of the process as an intermediate is U3ed as starting material and the missing process steps are carried out, or the process is broken off at any stage, or in which a’ starting material is formed under the reaction conditions of a reaction component is optionally used in the form of a derivative, for example a salt.

Resultant mixtures of isomers can be separated into the individual isomers by methods which are known per se,e.g. by fractional distillation, crystallisation and/or chromatography.

Advantageously, for carrying out the processes according to the invention, those starting substances that lead to the initially specially mentioned groups of final products and especially to the specially described or emphasised final products are used.

The present·invention additionally relates to the compounds of the formula I and their pharmaceutically acceptable, non-toxic acid additon salts for use as medicaments, especially as antihypertensives, for example for the treatment of raised blood pressure and especially to their use for the preparation of pharmaceutical preparations, especially preparations having an antihypertensive action.

The present invention also relates to pharmaceutical preparations that contain compounds of the formula I or pharmaceutically acceptable acid additon salts of such compounds. The pharmaceutical preparations according to the invention are for enteral administration, such as oral or rectal administration, and for parenteral administration, and the preparations contain the pharmacological active substance alone or together with a pharmaceutically acceptable carrier.

The new pharmaceutical preparations contain from approximately 10 i to approximately 95 %, preferably from approximately 20 i to approximately 90 % of the active substance. Pharmaceutical preparations according to the invention in dosage unit form are, for example, drage'es, tablets, capsules, suppositories or ampoules. The onarmaceutical preparations of the present invention are for example by means dragee-making, prepared in a manner Known per se , of conventional mixing, granulating, dissolving or lyophilising processes.

Thus, pharmaceutical preparations for oral use may be obtained by combining the active substance with solid carriers and, optionally, adjuncts, optionally granulating a resulting mixture and processing the mixture oc granulate, if desired oc necessary after the addition 10 of suitable adjuncts, to form tablets or dragee .cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-calcium phosphate or calcium hydrogen phos15 phate; also binders, such as starch pastes prepared, for example, using maize, wheat, rice or potato starches, gelatin, tragacanth, methylce-llulose, hydroxypcopylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if desired, disintegrators, such as the 20 above-mentioned starches; furthermore, carboxvmethyl starches, transversely cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow regulators and lubricants, for example silica, talc, stearic acid or salts 25 thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that may be resistant to gastric juice, for which there are used, inter alia , concentrated sugar solutions that optionally contain gum arabic, talc, polv30 vinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of coatings resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxy35 propylmethylcellulose phthalate. Colourants or pigments may be added to tne tablets or dragee coatings, for example to identify or characterise different doses of active substance.

Other pharmaceutical preparations that may be administered orally are dry-filled capsules made of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerin or sorbitol. The dry-filled capsules may contain the active substance in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilisers may likewise be added.

Pharmaceutical preparations for rectal administration are, for example, in the form of suppositories consisting of a combination of the active substance and a suppository base substance. Suitable base substances for suppositories are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. It is also possible to use gelatin rectal capsules that contain a combination of the active substance and a base substance. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form, for example in tha form of a water-soluble salt, are especially suitable; also suitable are suspensions of the active substance, such as corresponding oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oiis, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, ara used; or aqueous injection suspensions that contain substances increasing viscosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, stabilisers. 43893 The invention likewise relates to the use of the compounds of the formula I or pharmaceutically acceptable, nontoxic salts of such compounds as pharmacologically active substances, especially as anti-hypertensive agents, prefer5 ably in the form of pharmaceutical preparations. The dosage of active substance administered is dependent on the species of warm-blooded animal, the body weight, age and individual condition, and on the form of administration. The daily dose administered to a warm-blooded animal of about 70 kg body weight is, on average, from approximately 25 to approximately 4C0 mg, preferably from approximately 50 to approximately 200 mg of active substance.

The following Examples illustrate the above-described invention; however, they are not intended to restrict its . scope in any way whatsoever. Temperatures are given in degrees Centigrade.

Example 1 7.6 g of ethylenediamine are added to a suspension of 37.4 g of the hydroiodide of N-(2,S-dimethyl-420 pyrimidinyl)-3-methylisothiourea in 200 ml of methanol and the mixture is heated on a water bath. After 5 minutes, a clear solution is obtained, which is refluxed for one hour. The solvent is removed under reduced pressure with' the aid of a rotary evaporator and the residue is heated o for 2 hours at 150 . When splitting off of methyl mercaptan has ended, the mixture is cooled, suspended in diethyl ether and then filtered. The filter residue is suspended in 50 ml of hot tert.-butanol and allowed to stand for a while. The mixture is filtered, washed with iso30 propanol and in this manner the hydroiodice of 2-((2,5dimethyl-4-pyrimidinyl) amino]-2-imidazoli.ne is obtained, mp. 269-271°.

The salt obtainable in this manner is dissolved in 200 ml of water, the solution is rendered alkaline with 2N aqueous sodium hydroxide solution, and the crystalline material is filtered off. The free base is dissolved in chloroform, the- solution is dried over magnesium sulphate and concentrated by evaporation. 2-[(2,6-dimethyl-4pyrimidinyl)amino]-2-imidazoline in the form of white o crystals is obtained as the residue, mp. 229-230 . A further quantity of the product can be obtained by extracting the aqueous mother liquor with chloroform.

The hydrochloride of 2-[2,S-dimethyl-4-pyrimidinyl)amino]-2-imidazoline can be obtained by treating a solution of the free compound in isopropanol with the calculated amount of a 1.9N solution of hydrogen chloride in ethanol. o The crystalline product melts at 298-300 .

The starting material can be prepared as follows: a suspension of 12.3 g of 4-amino-2,6-dimethylpyrimidine in 30-ml of chloroform is treated dropwise with 13.1 g of ethoxycarbonyl isothiocyanate and the mixture is refluxed for one hour. Cn cooling, N-(2,6-dimethyl-4-pyrimidinylJN'-ethoxycarbonylthiourea crystallises out and is recrystallised from 90 % aqueous ethanol; it melts at 1S3 o 135 . ml of a IN aqueous sodium hydroxide solution is added to 12.7 g of N-(2,S-dimethyl-4-pyrimidinyl)-N'ethoxycarbonylthiourea which may be obtained in this manner and the mixture is boiled for one hour. On cooling, N-(2,3dimethyl-4-pyrimidinyl)thiourea is precipitated in tne form o of white crystals, mp. 238-233 .

A mixture of 20.4 g of N-(2,6-dimethyl-4-pyrimidinyl)thiourea and 130 ml of methanol is treated with 16.7 g of methyl iodide and the mixture is refluxed for one hour, whereupon the starting material goes into solution. The solvent is evaporated under reduced pressure, and the hydroiodide of N-(2,S-dimethyl-4-pyrimidinyl)-S-methylisothiourea is obtained as the residue in the form of white 43803 ο crystals, mp. 200-205 ; ths product is processed further without purification.

Example 2 12.0 g of ethylenediamine in 100 ml of methanol are added dropwise to a suspension of 35.7 g of the hydroiodide· of N-(2,5-dimethoxy-4-pyrimidinyl)-S-methylisothiourea in 750 ml of methanol, and the mixture is refluxed for 5 hours. After the evolution of methyl mercaptan and ammonia is complete, the reaction mixture is concentrated under reduced pressure to a volume of about 100 ml, and cooled for 15 hours. The crystalline precipitate is filtered off and washed firstly with water, and then with ethyl acetate; in this manner 2-[(2,6-dimethoxy4-pyrimidinyl)amino]Ίο imidazoline is obtained, mp. 197-200 . 39.5 ml of a 2.25N solution of hydrogen chloride in ethanol is added to a suspension of 20 g of 2-[(2,S-dimefchoxy-4pyrimidinyl)amino]-2-imidazoline and 200 ml of ethanol.

The solution which may be obtained in this manner is concentrated under reduced pressure after filtration, and ethyl acetate is added thereto in portions, whereupon crystallisation commences. The crystalline material is filtered off and yields the hydrochloride of 2-((2,6-dimethoxy-4o pyrimidinyl)amino]-2-imidazoline, mp. 193-195 .

The starting material can be obtained as follows: a mixture of 29.0 g of 4-amino-2,6-dimethoxypyrimidine and 24.5 g of ethoxycarbonyl isothiocyanate in 100 ml of chloroform is refluxed for 2 hours, then cooled, and concentrated by evaporation under reduced pressure, and the residue is suspended in 200 ml of hot 95 % aqueous ethanol. The mixture is cooled, the precipitate is filtered off and washed with a mixture of ethanol and ethyl acetate. M-(2,5dimethoxy-4-oyrimidinyl)-N'-ethoxvcarbony1thiourea is o obtained in the form of yellow crvstals, mo. 177-180 .

A mixture of 14.3 g of N-(2,S-dimethoxy-4pyrimidinyl)-N'-ethoxycarbonylthiourea and 90 ml of IH aqueous sodium hydroxide solution is rafluxed for 90 minutes, whereupon the starting material first of all goes into solution and the crystalline product is then precipitated, This is filtered off, washed with water and' suspended in 100 ml of a hot 1:1 mixture of isopropanol and petroleum ether. 11-(2,6-dimethoxy-4-pytimidinyl)thiourea is obtained in the form of yellow crystals, mp. 237-233°.

A suspension of 24.4 g of U-(2,4-dimethoxy-4-pyrimidinyl)thiourea in 2500 ml of acetone is treated dropwise with 34.3 g of methyl iodide and the mixture is refluxed for one hour while stirring. After a short time a clear solution is obtained, which becomes turbid shortly afterwards and deposits a crystalline material. This is filtered off, and yields the hydroiodide of N-(2,6-dimethoxy-40 pyrimidinyl!-3-methylisothiouraa, mp. 135-137 , which is used without further purification.

Example 3 12.3 g of 4-amino-2,6-dimethylpyrimidine and 18.3 g of the hydroiodide of 2-methylthio-2-imidazoline are pulverised and thoroughly mixed, then heated to a bath o temperature of 190 , at which temperature splitting off of methyl mercaptan commences. The bath temperature is o lowered to 170 ; the mixture is left at this tamperatura o one hour, is tnen cooled to 50 and the warm melt is dissolved in a 1:1 mixture of acetone and methanol. The solution is filtered and the filtrate is concentrated by evaporation to dryness under reduced pressure. The residua is taken up in a mixture of isopropanol and acetone and filtered; the residue is the hydroiodida of 2-((2,3dimethyl-4-pyrimidinyl)amino]-2-imidazoline and is partitioned between 211 aqueous sodium hydroxide solution and methylene chloride. The organic phase is separated, dried over magnesium sulphate and concentrated by evaporation. 2-((2,6Dimethyl-4-pyrimidinyl)amino]-2-imidazoline is obtained as semi-crystalline product which is taken uo in water and o filtered off in crystalline form, mp. 225-229 . The product displays no mixed-melting point depression with a sample of the material which may be obtained in accordance with the process of Example 1, and is identical with this according to thin-layer chromatography (system : methanol).

A further quantity of the free compound can be obtained from the isopropanol/acetone mother liquor by concentrating this by evaporation under reduced pressure, dissolving the residue in water, rendering the aqueous solution alkaline with 2N aqueous sodium hydroxide solution and extracting with methylene chloride. The organic extract is concentrated by evaporation, the residue dissolved in water, and a small amount of 211 aqueous sodium hydroxide solution is added to the solution which is then cooled. The crystalline precipitate is filtered off; it melts at 227-229 .

Example .4 A mixture of 40.0 g of the hydroiodida of N-(2,6dimethyl-4-oyrimidinyl)-S-methylisothiourea and 18.3 g of propylenediamina ara refluxed for 3 hours. The mixture is cooled, filtered and the clear solution is evaporated to dryness under reduced pressure. The residue is taken up in 100 ml of water, and extracted three times with 150 ml of chloroform each time. The organic extract is dried over magnesium sulphate and concentrated by evaporation.

In this manner, 2-[(2,6-cimethyl-4-pyrimidinyl)amino]0 1,4,5,5-tetrahydropyrimidine is obtained, mp. 151-133 , which is converted into the hydrochloride as follows : To a solution of 12 g of 2-[(2,6-dimethyl-4-pyrimidinyl)amino]-1,4,5,6-tetrahydropyrimidine in 80 ml of isopropanol prepared at elevated temperature are added 42.7 ml of a 2.7N solution of hydrogen chloride in ethanol. The solution is concentrated under reduced pressure to approximately one third of its volume and diluted portion-wise with ethyl acetate. The crystalline precipitate is filtered off and yields the dihydrochloride of 2-[(2,6-dimethyl-4oyrimidinyl)amino]-l,4,5,5-tetrahydropyrimidine, mp. 255 o 253 .

Example 5 A solution of 20.6 g of N-(6-chloro-2-methyl-4pyrimidinyl)-S-methylisothiourea hydroiodide in 300 ml of methanol is added dropwise to a solution of 7.2 g of ethylenediamine in 30 ml of methanol. The internal temperao ture of the mixture is 65 and is maintained for 6 hours.

When evolution of methyl mercaptan and ammonia is complete, the mixture is evaporated on a rotary evaporator and the residue is suspended in 150 ml of water, suction-filtered and washed with water. The crude base melts at 207 o 203 .

The hydrochloride is obtained by suspending 16.S g of the crude base in 200 ml of hot ethanol and adding thereto 34.1 ml of 2.3N ethanolic hydrochloric acid, filtering the resulting clear solution with active charcoal and concentrating it on the rotary evaporator to approximately 30 ml and bringing the hydrochloride of 2[(6-chloro-2-methyl-4-pyrimidinyl)amino]-2-imidazoline to crystallisation with ethyl acetate and a little ether, mp. o 299-301 (decomposition).

The isothiourea serving as starting material is obtained as follows ; a) 65.2 g of 4,6-dichloro-2-methylpyrimidina are stirred in 750 ml of ethanol with 100 g of liquid ammonia in an o autoclave for 12 hours at 30 , the precipitated ammonium chloride is filtered off, the mixture is concentrated by evaporation on a rotary evaporator, the residue suspended hot in 1 litre of water and suction-filtered. 3v evaporation to approximately 100 ml further quantities of 4-amino6-chloro-2-methylpyrimidina are obtained from the aqueous mother liquor. The combined crude products are redissolvsd ο from ethyl acetate, mp. 133-137 . b) 23.7 g of the purified product are dissolved in 200 ml of cnloroform and 30 ml of dimethylformamide; 25.2 g of ethoxycarbonyl isothiocyanate are added to the solution o ς and the mixture is heated for 2 hours at 80 . The mixture ’ 1 is cooled, evaporated, and the residue, N -(o-chloro-2mechyl-4-cyrimidinyl)-N -ethoxycarbonylthiourea is recryo stallised from ethanol, mp. 142-143 . c) by hydrolysis with IN sodium hydroxide solution (1 o hour, 130 ), N-(6-chlcro-2-methyl-4-pyrimidinyl)thiourea o of melting point 230 (discolouration and sintering) is obtained. d) 13.5 g of this thiourea are suspended in 1500 ml of acetone, 37.3 g of methyl iodide are added and the mixture is refluxed for 2 hours. After 15 minutes dissolution occurs. The solvent is evaporated on a rotary evaporator, the crystals reniaining are suspended in ether and isolated, o mp. 179 (decomposition). They are the isothiourea hydroiodide mentioned as starting material. 2o Example β .6 g of the 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-2-imidazoline base obtained according to Example 6 are dissolved in 200 ml of water and 50 ml of IN hydrochloric acid, 1 g of 10 % oalladium-on-carbon is added and o the mixture is shaken with hydrogen at 48 under slight excess pressure (0.2 bar). After absorption of the calculated amount (1120 ml) , the shaking is interrupted, the mixture is filtered, concentrated by evaporation on the rotary evaporator and the crystalline residue is recry30 stallised hot in eth3nol/methanol 1:1. The resulting crystals of the dihydrochloride of 2-((2-methyl-4o pynmid inyl) amino]-2-imidazoline melt at 252-255 . 4S803 Example 7 24.0 g of N- (6-chloro-2-methoxy-4-pyrimidinyl) -3methylisothiourea hydroiodide are dissolved in 300 ml of methanol and added dropwise to 3.0 g of ethylenediamine in 75 ml of methanol. The mixture is heated for δ hours at reflux temperature whilst stirring, whereupon crystallisation occurs; the mixture is concentrated on the rotary evaporator and the residue is suspended in 200 ml of water. Subsequently, the residue is isolated and washed with water. In this manner, 2-((S-chloro-2-methoxy-4oyrimidinyl)amino]-2-imidazoline of melting point 215 o 219 is obtained.

Hydrochloride : 11.5 g of base are suspended in 50 ml of methanol, and 1 equivalent of 2.4N ethanolic hydrochloric acid is added. The mixture is diluted with 50 ml of ethanol, filtered with Celite*, and the clear mother liquor is evaporated on the rotary evaporator to half its volume.

After the addition of 100 ml of acetone, the hydrochloride of 2-((5-chloro-2-methoxy-4-oyrimidinyl)amino]-2-imidazoline o of mp. 220 precipitates as crystals.

The isothiourea used as starting material is obtained analogously to Example 5 ; 3 a) M -(6-chloro-2-mathoxv-4-pyrimidinyl)-N -ethoxvo carbonylthiourea of mp. 150-154 is obtained from 53.3 g of 4-amino-5-chloro-2-msthoxypvrimidine (prepared from 2,5dichloro-4-arainopyrimidine and sodium methanolate in methanol o at 30 external temperature) and 52.4 g of ethoxyearbonyl isothiocyanate in boiling acetone. o) the hydrolysis of this ester with 150 ml of IM sodium hydroxide solution at boiling heat yields a crystalline precipitata. Solution and precipitate ara rendered weekly acidic with 10 ml of glacial acetic acid, whereupon decarboxylation occurs with foaming. N-(6-chioro-2-meehcxy* Trade Mark 43803 ο 4-pyrimidinyl)thiourea is isolated, mp. above 33C , and is washed with water. c) the resulting urea is converted, as in Example 5, witn methyl iodide into the isothiourea hydroiodide, mp. o 167 (decomposition) mentioned as starting material.

Example 8 11.5 g of 2-[(6-chloro-2-methoxy-4-pyrimidinyl)amino]2-imidazoline obtained in accbrdance with Example 8 are suspended in 200 ml of methanol and 100 ml of dimethylformamide (purissimum) and 2 g of 10 % palladium-oncarbon catalyst are added and the mixture treated with hydrogen at 0.2 bar excess pressure and a temcerature of o . The absorption of hydrogen progresses mors slowly than in Example 6 After it has finished, the catalyst is filtered, the mother liquor is concentrated by evaporation on a rotary evaporator, 100 ml of IN sodium hydroxide solution is added to the residue and ths residue is extracted with chloroform. The chloroform residue consists of a slowly crystallising base, which is converted directly into its hydrochloride by adding to it, in 50 ml of acetone, equivalent of ethanolic hydrochloric acid, then, by adding acetone and ethyl acetate, it is precipitated as crystals.

The resulting 2-[(2-methoxy-4-pyrimidinyl)amino]-2o imidazoline hydrochloride melts at 170-172 (decomposition).

Example 9 22.75 g of the 2-((6-chloro-2-methoxv-4-pyrimidinyl)amino]-imidazoline prepared in accordance with Example 7 are dissolved in 100 ml of IN aqueous hydrochloric acid and 300 ml of water, 2 g of 10 % palladium on carbon catalyst are added thereto, and the mixture is hydrogenated at 0.2 bar excess pressure and SO0 internal temperature.After absorption of 2320 ml (calculated 2240 ml) the hydrogenation is broken off, the mixture is suctioned off the catalyst and concentrated fully by evaporation on a rotary evaporator. The residue is evaporated twice with ICO ml cf alcohol, the crystals are suspended hot in 150 ml of isopropanol and again isolated. As a result of the methoxy group splitting off, 2-(2-(hydroxy4- pyrimidinyl)aminoI-2-imidazoline hydrochloride has formed, o and has a melting point of 256-253 (decomposition).

Example 10 23.0 g of N-(6-chloro-2-dimethylamino--4-pyrimidinyl)5- methylisothiourea hydroiodide are dissolved in 400 ml of methanol and added dropwise to a solution of 9.0 g of ethylenediamine in 75 ml of methanol. The mixture is stirred for 6 hours at reflux temperature, whereupon the ammonia and methyl mercaptan evolution comes to a halt and crystals are precipitated. The suspension is concentrated on a rotary evaporator to approximately 75 ml, suction-filtered, the crystalline portion is stirred with 150 ml of water, is isolated, and washed with water and isopropanol. The resulting 2-((5-chloro-2-dimethylamino-4o pyrimidinyl)amino]-2-imidazoline melts at 263-271 .After recrystallisation from dimethylsulfoxide-methanol the product melts at.278-279°.

The resulting base has the calculated amounts of 2N aqueous hydrochloric acid added to it, whereupon the hydrochloride partially crystallises. Sy addition of 4 times o the amount of water, at 75 a clear solution is obtained which, after filtration, is evaporated on a rotary evaporator, the residue is suspended in isopropanol, suction-filtered and washed with ethyl acetate. The o hydrochloride melts at 279-230 .

At room temperature 3.42 g of methanesulphonic acid are added to a suspension of 7.3 g of base in 300 ml of water, whereupon a clear solution is obtained. The solution is evaporated to dryness, and the residue is recrystallised from methanol/ether. The methanesulphonata obtained in o this manner melts at 256-259 .

The isothiourea used as starting material is obtained analogously to Example 5 : 43803 a) 4-Amino-6-chloro-2-dimethylaminopyrimidine of melting point 151-152’ is prepared from 4-amino-2,6-dichloro-pyrimidine with dimethylamine in methanol in exothermic reaction. 34.5 g of this compound are reacted with 26.2 g of ethoxycarho nyl isothiocyanate in 150 ml of acetone under reflux to give N^-(6-chloro-2-dimethylamino-4-pyrimidinyl)-N -ethoxy-carbonyl thiourea, mp. 206-208°. b) The hydrolysis of this compound with 170 ml of IN sodium hydroxide solution at reflux temperature yields a thick crystalline mash which is suction-filtered and washed thoroughly with water. The resulting N-(6-chloro-2o dimethylamino-4-pyrimidinyl)thiourea melts at 233 (decomposition) . c) 29.0 g of this thiourea are suspended in 2.9 litres of acetone and 71 g of methyl iodide are added. Cn refluxing, the suspension goes into solution and crystallises out again shortly afterwards. The mixture is cooled and the crystalline precipitate of N-(6-chloro-2-dimethylamino4-pyrimidinyl)-S-methylisothiourea hydroiodide of melting o point 220 (decomposition) is isolated.

Example 11 11.1 g of 2-((5-chloro-2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline base (prepared according to Example 10), are dissolved with 19.5 ml of IN hydrochloric acid and 30 ml of water, and hydrogenated with hydrogen with 2 g of 10 % oalladium-on-carbon at 0.2 bar excess oressure. o The temperature is 52-55 . After 15 hours, the calculated amount of hydrogen (433 ml) has been taken up. The solution is filtered off the catalyst, the aqueous mother liquor is concentrated on a rotary evaporator, the residue is dissolved in 75 ml of isoprocanol and is allowed to crystallise. The resulting 2-[(2-dimethylamino-4-ovrimidinvl)' o amino;-2-imidazoline dihydrochloride melts at 275-27S (decomuosition). 48803 Example 12 In the same manner as described in Example 10, from 11.5 g of ethylenediamine in 100 ml of methanol, to which 33.0 g of N-(6-chloro-2-diethylamino-4-pyrimidinyl)-Smethylisothiourea hydroiodide in 200 ml of methanol ace added dropwise, there is obtained after 6 hours' stirring under reflux 2-( (6-chloro-2-diethylamino-4-pyrimidinyl)o amino]-2-imidazoline base of melting point 231-232 . 3y suspending 21.5 g of the base in 50 ml of methanol and adding two equivalents (57 ml) of 2.39N ethanolic hydrochloric acid, followed by 300 ml of ethyl acetate, the dihydrochloride is obtained, which, on drying in high vacuum, is transformed into the monohydrochloride of melting o point 203-205 .

The starting material for the above-described synthesis can be obtained in analogy to Example 10 : a) from 4-amino-2,6-dichloropyrimidine with an excess o of diethylamine in methanol at 30 external temoerature, o 4-amino-0-chloro-2-diethylaminopyrimidine melting at 110 is obtained which is used further as crude product; b) by reacting 43.6 g of this pyrimidine with 23.5 | of ethoxycarbonyl isothiocyanate in boiling acetone, M (6-chloro-2-diethylamino-4-pyrimidinyl)-N -ethoxycarbonyl o thiourea melting at 141-145 is obtained; c) by hydrolysis of 48.0 g of the resulting ester with 250 ml of IN sodium hydroxide solution under reflux, N—(6— chloro-2-diethylamino-4-pyrimidinyl)thiourea of melting o point 175-130 is obtained; and d) from this crude thiourea (35.3 g) with 40 g of methyl iodide in 750 ml of acetone under reflux, N-(S-chloro-2diethylamino-4-oyrimidinyl)-S-methylisothiourea hydroiodide o of melting point 173-180 (decomposition) used as starting material is obtained.

Example 13 In the same manner as described in Examples 10 and 13, 2-((5-chloro-2-di-n-butylamino-4-pyrimidinyl)amino]2-imidazoline and its hydrochloride ara obtained from M5 (S-chloco-2-di-n-butylamino-4-pyr imidinyl)-3-methylisothiourea hydcoiodide and ethylenediamine in methanol. The free o base melts at 167-168 ,'and the hydrochloride at 148-150°.

The starting material for this dibutylamino derivative 10 is obtained in the same reaction sequence as described in Examples 10 and 12 from 4-amino-2-di-n-butylamino-5-chloropyrimidine.

Example 14 .3 g of ethylenediamine are introduced into 40 ml 0 of methanol and, whilst stirring, at 70 30.3 g of M(S-dimethylamino-2-methyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide in 350 ml of methanol are added dropwise and the reaction mixture is maintained for 6 hours at this temperature. The solvent with the suspended crystals is 2o brought to dryness on a rotary evaporator and the residue is suspended in 300 ml of water. A sample shows that the crystals still contain small amounts of hydroiodide. They are therefore dissolved in 200 ml of 2N hydrochloric acid and precipitated with 5N sodium hydroxide solution.The crystalline base is isolated, washed twice with warm water, then treated with isopropanol and ether. In this manner, 2-((5dlmethylamino-2-methy1-4-pyrimidinyl)amino]-2-imidazoline 0 mp. 286-288 is obtained which is shown to be analytically pure .

Its hydrochloride is obtained as monohydrochlorida, mp. 231-233 , by suspending the base in isopropanol, adding 1 equivalent of ethanolic 2.3N hydrochloric acid, and precipitating with ethyl acetate. 48803 The starting material for the above described synthesis can be obtained analogously to Examples 10 and 12 . a) from 4-amino-6-chloro-2-methyl pyrimidine melting at 135-187° used in Example 5 and 4 times the theoretical o amount of dimethylamine in methanol, at 120 in a oressurized vessel 4-amino-6-diraethylamino-2_raethyl “ o pyrimidine of rap. 176-179 is obtained; b) by reacting 29.0 g of this pyrimidine with 25.0 g of ethoxycarbonyl isothiocyanate in boiling chloroform, N1-(6-diraethylamino-2-methyl-4-pyrimidinyl)-N -ethoxyo carbonylthiourea is obtained, melting at 140-143 (after recrystallisation from alcohol); c) by hydrolysing 31.0 g of the resulting ester with 200 ml of IN sodium hydroxide solution at boiling temperature, N-(6-diraethylamino-2-methyl-4-pyrimidinyl)thiourea melting at 245-247 is obtained; and d) from 19.3 g of this resulting thiourea, with 51.9 g of methyl iodide in 2000 ml of acetone and 200 ml of methanol N-(6-dimethylamino-2-methyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide melting at 225-227° is obtained under reflux.

Example 15 To a boiling solution of 9.5 g of ethylenediamine in 50 ml of methanol are added dropwise 26.0 g of N-(2,6-dihydroxy-5-pyrimidinyl)-S-methylisothiourea hydroiodide in 500 ml of warm methanol, and the whole is refluxed for 15 hours.

After a short time, a white precipitate begins to form. The mixture is cooled, filtered with suction and the precipitate, which, in addition to the imidazoline base also contains hydroiodide that is not readily soluble and non-reacted isothiourea hydroiodide, is washed several times in the course of 12 hours with water of 50“ which oontains 10 % methanol. The melting point thereby rises from 268° (decomposition) to 290° (decomposition) and finally remains constant at 328-330°.

The latter melting point corresponds to ths pure 2-((2,3dihydroxy-3-pyrimidinyl)amino]-2-imidazoline which is present for the most part in its tautomeric form, 2-((2,5dioxo-1,2,3,6-tetrahydro-5-pyrimidinyl)amino]-25 imidazoline.

The hydrochloride is obtained by dissolving 7.5 g of the base in 33.5 ml of IN hydrochloric acid under heat. The solution is filtered, concentrated by evaporation on a rotary evaporator, the residue is evaporated with 100 ml of ethanol, 50 ml of ethyl acetate and 50 ml of isopropanol are added to the residue and the whole is stirred until o crystallisation occurs. Mp. 275 (decomposition), o Hydrochlorides (mp. 130 , decomposition) containing water of crystallisation are dried in high vacuum until a melting o point of 275 is reached.

The starting material for the above described synthesis is obtained in analogy to Examples 1Q, 12and 14 in the following manner : a) 12.5 g of 5-aminouracil are suspended in 150 ml of 20 dimethyl sulphoxid.e and 13.1 g of ethoxycarbonyl isothiocyanate are added. The mixture is stirred for 3 hours at o , a clear solution is obtained, this is poured into water, suction-filtered and N -(2,S-dihydroxy-5pyrimidinyl)-N -ethoxycarbonylthiourea is obtained which o is suspended in boiling acetone to purify it. Mp. > 300 ; b) by hydrolysing this compound (12.9 g) for one hour with 150 ml of IN sodium hydroxide solution, at reflux temperature, by cooling, adding a total of 50 ml of glacial acetic acid, crystalline N-(2,6-dihydroxy-5-oyrimidinyl)o thiourea of mp. > 300 is obtained, which is suspended in hot isopropanol to purify it; c) by reacting 27.9 g of this compound with 21.3 g of methyl iodide in 1300 ml of methanol and 1000 ml of o cimetnvlformamide at SO , N-(2,6-dihydroxy-5-oyrimidinyl)o S-methylisothiourea hydroiodide of melting point 245 (decomposition) is obtained. 48803 Example 16 To a solution of 8.5 g of ethylenediamine in 80 ml of methanol,the solution of 26.0gof N-(2,6-diethyl-5-methyl-4pyrimidinyl) -S-methylisothiourea hydroiodide in 250 ml of methanol is added dropwise. The mixture is stirred and refluxed for 12 hours, evaporated in a rotary evaporator to dryness, dissolved in methylene chloride, washed twice with water, the solvent is again evaporated, the crystalline residue is suspended in ethanol and white crystals of the base o malting at 128-131 are obtained, which are convertaa into the hydrochloride of 2-((2,6-diethyl-5-methyl-4pyrimidinyl)amino]-2-imidazoline by dissolving 13.3 g of the base in ethanol, adding 32.0 ml of 1.32N ethanolic hydrochloric acid and bringing the hydrochloride to cryo stallisation with a little ether. Mp. 190-192 .

The starting material for ths above described synthesis can be obtained analogously to Examples 10, 12, and 15 as follows : a) From 33.0 g of 4-amino-2,6-diethyl-5-methylpyrimidine (kyanethin) in 200 ml of acetone and 50 ml of dimethylformamide, and 26.2 g of ethoxycarbonyl isothiocyanate, after 3 hours refluxing N -(2,5-diethyl-5-msthyl-4pyrimidinyl)-N -ethoxycarbonylthiourea of melting point o 83-39 is obtained. b) From 49.5 g of this compound, N-(2,o-diethyl-5-methylo 4-pyrimidinyl)thiourea melting at 151-154 is obtained by hydrolysing with 100 al of 2N sodium hydroxide solution, under reflux, and neutralising with glacial acetic acid to pH 5. c) From 17.1 g of this compound and 43.2 g of methyl iodide in 400 ml of hot acetone, N-(2,S-diethyl-5-methyl-4pvrimidinyl)-S-methylisothiourea hydroiodids melting ac o 180-182 is obtained.

Example 17 27.0 g of N-(2-phenyl-4-pyrimidinyl)-S-raethylisothiourea hydroiodide in 300 ml of methanol, are added dropwise to 9.0 g of ethylenediamine in 100 ml of methanol. The o mixture is heated at 30 for 6 hours, whilst stirring, evaporated to dryness on a rotary evaporator, the crystalline compound is suspended in water, then in 'isopropanolether mixture and in this manner 2-((2-ohenyl-4-pyrimidinyl) o -amino]-2-imidazoline melting at 230-232 is isolated.

From 15 g of the imidazoline base, the dihydrochloride o is obtained as crystals melting at 255-257 by suspending in methanol (50 ml), adding 2 equivalents of 2.3N ethanolic hydrochloric acid (54.4 ml), filtering the resulting solution and adding ethyl acetate.

The above used starting material is obtained via the following stages : a) from 51.3 g of 4-amino-2-phenyl pyrimidine and 40 g of ethoxycarbonyl isothiocyanate in 400 ml of boiling acetone, N -(2-phenyl-4-oyrimidinyl)-N -ethoxycarbonylo thiourea melting at 135-133 is obtained; b) from 65.4 g of the ester, N-(2-phenyl-4-pyrimidinyl)o thiourea melting at 237 (decomposition) is obtained by hydrolysis with 300 ml of IN sodium hydroxide solution at boiling heat; c) from 38.3 g of this thiourea and 100 g of methyl iodide in 3.3 litres of boiling acetone, N-(2-pheny1-4pyrimidinvl)-5-methylisothiourea hydroiodida melting at o 200 (decomposition) is obtained.

Example 18 22.8 g of N-(2-phanyl-4-pyrimidinyl)-3-methylisothiourea hydroiodide (starting material from Example 17) and 9.4 g of propylenediamine (1,3-diaminopropane) are refluxed in 300 ml of methanol for S hours whilst stirring. The mixture is evaporated to dryness on the rotary evaporator, the oily residue is partitioned between 300 ml of water and 48303 300 ml of chloroform, and the organic phase is dried and evaporated and brought to crystallisation with 50 ml of ethyl acetat· and 25 ml of ether. The resulting 2-((2phanyl-4-pyrinid inyl)amino]-1,4,5,6-tatrahydropytimidine melts at 166-169 .

From this base, the monohydrochlori'ds of meltinq ooint O 0 ’ * 255 (sintering from 246 ) is obtained in acetone with one equivalent of ethanolic hydrochloric acid.

Example 19 6.12 g of ethylenediamine are added to a suspension of 13 g of N-(2-diaethylamino-6-methyl-4-pyrimidinyl)-Smethylisothiourea hydroiodide in ISO ml of ethanol, whereupon a clear solution is formed. Subsequently, the mixture is refluxed for 6 hours. The reaction product that has already precipitated during the reaction is suctionfiltered and washed with isopropanol and ether. The resulting 2-((2-dimethylamino-6-methyl-4-pyrimidinyl)amino]-2imidazoline melts at 230-283 . 4.S g of methanesulphonic acid are added to a suspension of 10.35 g of this base in 300 ml of absolute ethanol and the mixture is heated on a water bath, whereupon a clear solution forms. The mixture is evaporated to half its volume, and 175 ml of ether are added gradually, whereupon o the methanesulphonate of melting point 226-223 is deposited.

The isothiourea used as starting material is obtained analogously to Example 5 : 4-amino-2-dimethylamino-6-methylpyrimidine is reacted with 11.15 g of ethoxycarbonyl isothiocyanate in 200 ml of absolute tetrahydrofuran under reflux to give N -(2dimethylamino-6-methyl-4-cyrimidinyl)-N -ethoxycarbonylo thiourea of melting point 199-201 .

This compound is refluxed with 180 ml of sodium hydroxide solution and 100 ml of ethanol for 2 hours. The 49SG3 mixture is concentrated in vacuo and adjusted to pH 7.3 witn 2M hydrochloric acid; the crystalline mash is suctionfiltered. After recrystailisation from boiling alcohol, the resulting N-(2-dimethylamino-5-methyl-4-oyrimidinyl)o thiourea melts at 241-243 . .9 g of this thiourea are suspended in 1.2 litres of acetone and 29.5 g of methyl iodide ara added thereto.

Cn refluxing, the suspension goes into solution and crystallises out again shortly afterwards. The mixture is refluxed for a further hour and the crystalline precipitata of M-(2-dimethylamino-6-methyl-4-oyrimidinyl)-S-methylisoo thiourea hydroiodide melting at 211-214 is suctionfiltered.

Example 2d In one portion, 5.4 g of M-(2-diethylamino-5pyrimidinyl)-S-methylisothiourea hydroiodide are added to a solution of 2.1 g of ethylenediamine in 40 ml of methanol, and the mixture is refluxed for 5 hours. The yellow reaction solution is concentrated by evaporation under reduced pressure. 75 ml of 2?I sodium hydroxide solution ara added to the residue and the mixture is extracted by shaking with petroleum ether to remove the 5-amino-2dimethylaminopyrimidine. The aqueous-oily layer is extracted several times with ethyl acetate. After recry25 stallisation from ethyl acetate, 2-[(2-diethylamino-5pyrimidinvl)amino)-2-imidazoline of melting point 159o 171 is obtained from the evaporated ethyl acetate extracts . 0.94 g of methanesulphonic acid is added to 1.1 g of the resulting base dissolved in 35 ml of isopropanol.

Cn addition of ether, the dimethanesulphonate of melting o point 144-147 crystallises out.

The isothiouraa used as starting material is prepared as follows: 48803 29.2 g of tl,N-diethyl guanidine hemisulphate and 23.5 g of malonic acid diethyl ester are added to a solution of 12.4 g of sodium in 360 ml of ethanol, and the mixture is refluxed for 3 hours. Subsequently, the reaction mixture is concentrated by evaporation. The residue is dissolved in 400 ml of water and adjusted to pH 3.5 with concentrated hydrochloric acid, whereupon 2-diethylamino-4,6-dihydroxy o pyrimidine of melting point 235-240 (decomposition) is precipitated. o At an internal temperature of 15-18 , within 25 minutes 65 ml of glacial acetic acid are added dropwise to 25 ml of fuming nitric acid (d * 1.52). Whilst stirring well, within 15 minutes 21 g of 2-diethylamino-4,5-dihydroxy pyrimidine are then added in portions. When the addition has ended, the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is poured onto ice and the precipitated 2-diethylamino-4,S-dihydroxy-5o nitropyrimidine melting at 230-232 (decomposition) is suction-filtered. .1 g of 2-diethylamino-4,6-dihydroxy-5-nitrooyriraidine are refluxed for 90 minutes in 150 ml of phosphorus oxychloride and 33 ml of diethylaniline. The black reaction solution is intensively concentrated under reduced pressure.

The oily residue is poured onto ice and extracted with ether. The residue obtained from the ether phases is recrystallised from cyclohexane. In this manner, 2-diethylaminoo 4,6-diohloro-5-nitropyrimidine of melting point 92-93 is obtained. 24.5 g of 2-diethylamino-4,5-dichloro-5-nitropyrimidine are hydrogenated in 250 ml of ethanol with 12 g of Raney nickel as the catalyst. After absorption of 3 mole equivalents of hydrogen, the mixture is filtered off the catalyst and the filtrate acidified with SN alcoholic hydrochloric acid. Subsequently, the solution is intensively concentrated under reduced pressure until crystallisation commences. The crystals are suction-filtered and 49303 in this manner 2-dietnylamino-4,S-dichloro-5-aminopyrimidina dinydrochloride is obtained. .5 g of 2-diathylamino-4,6-dichloro-5-aminopyrimidine dihydrochloride are hydrogenated at room temperature in 600 ml of ethanol with 2 g of oalladium-on-carbon (5 %) as the catalyst, and 23 g of anhydrous sodium acetate.

After absorption of 2 mole equivalents of hydrogen, the mixture is filtered to remove the catalyst and the precipitated inorganic salts, and the filtrate is rendered strongly acidic with excess SN alcoholic hydrochloric acid and concentrated by evaporation to dryness under reduced pressure.

The oily residue, which contains 2-diethylamino-5aminopyrimidine dihydrochloride, is refluxed in 250 ml of chloroform with 55 g of ethoxycarbonyl isothiocyanate and 25 ml triethylamine for 3 hours. The reaction solution is concentrated by evaporation to dryness in vacuo. The residue is'chromatographed on silica gel by eluting with toluene with an increasing addition of ethyl acetate. In this manner N^-fl-diethylamino-5-pyrimidinyl)-N2-ethoxycarbonylthiourea of melting point 130-132° is obtained. 3 7.35 g of N -(2-diethylamino-5-pyrimidinyl)-N ethoxycarbonylthiourea are refluxed for 1 hour with 70 ml of IN sodium hydroxide solution. After cooling, the reaction mixture is adjusted to pH S, the precipitated crystals are suction-filtered, and recrystaliised from ethyl ' acetate-petroleum ether. In this manner N-(2-diethylamino-5o pyrimidinyl)thiourea melting at 162-166 is obtained. 4.05 g of the above thiourea are stirred for 2 hours under reflux in 25 ml of acetone with 8.1 ml of methyl iodide. The reaction solution is concentrated by evaporation and the residua crystallised from ethyl acetate with the addition of ether. In this manner N-(2-diethylamino-5-cyrimidinyl)-S-methylisothiourea hvdroiodida of o melting ooint 175-177 is obtained. 48303 Example 21 A mixture of 5.5 g of 2-((6-chloro-2-dimethylamino5-methyl-4-pyrimidinyl) amino]-2-imidazolina hydrochloride, 200 ml of acetic acid and 30.25 ml of 1.5N hydrochloric acid in glacial acetic acid is hydrogenated at o C and a pressure of 4 bars with the addition of 1.3 g of a 10 % palladium-on-carbon catalyst until absorption of 1 mole equivalent of hydrogen. Thereafter the mixture is filtered to remove the catalyst, and the filtrate concentrated by evaporation under reduced pressure. After recrystallisation of the residue from ethyl alcohol, with the addition of active carbon 2-(2-dimethylamino-5-methyl-4pyrimidinyl)amino]-2-imidasoline hydrochloride which melts o at 263 (decomposition) is obtained as a colourless crystallisate.

The starting material is prepared in accordance with Example 26.

Example 22 .26 g of N-(6-chloro-2-dimethylamino-4-pyrimidinyl)dithiocarbamic acid methyl ester are refluxed for 3 hours with 1.3 g of ethylenediamine in 30 ml of acetonitrile.

The solvent is then evaporated in vacuo and 1-(S-chloro-2dijsethylamino-4-pyrimidinyl) -3- (2-aminoethyl) thiourea obtained as residue is freed from moisture still adhering to it by evaporation with toluene.

The dark oil remaining is heated in 50 ml of diphenyl o ether for 2 hours at 200 . Thereupon the solvent is distilled off in a bulb tube under vacuum, the semicrystalline residue is stirred with water, filtered, and the product is washed with water and isopropanol. The resulting 2-[(S-chloro-2-dimeehylamino-4-?yrimidinyl)amino]-2-imidazoline melts at 278-279®.

N-(6-chloro-2-cimethylamino—4-pyrimidinyl)dithiocarbamic acid methyl aster used as starting material can ba prepared in the following manner : g of 4-amino-5-chlaro-2-dimethylaminopytimidine ace introduced into 100 ml of dimethylformamide. To this mixture are added in portions over 5 minutes 2.4 g of sodium o hydroxide at 0 , and the mixture is stirred for 15 minutes. 1.5 ml of carbon disulphide are added dropwise o at 0-5 , and the whole is stirred for 30 minutes. 1.2 g o of sodium hydride are added, again at 0-5 , the mixture is stirred for 15 minutes, and then at the same temperature 0.75 ml of carbon disulphide is added and stirring is con10 tinued for a further 30 minutes. After repeated addition of 1.2 g of sodium hydride and 0.75 ml of carbon disulohide ό in the above-described manner, after 30 minutes at 0-5 2.3 ml of methyl iodide are added and the reaction solution o is allowed to heat up to 20 in 2 hours. Decomposition with water is then effected, insoluble material is filtered off, and the filtrate is adjusted to pH 5-6 with 2N hydrochloric acid. The precipitated product is extracted with methylene chloride, dried and concentrated by evaporation, whereupon N-(6-chloco-2-dimethylamino-5-pyrimidinyljdithio20 carbamic acid methyl ester crystallises out on the addition o of ether and is filtered off. i-lp. 150-151 .

Example -23 g of 6-chloro-2-dimethylamino-4-(dimethylthiomethyleneimino)pyrimidine and 9.2 ml of ethylenediamine o in 400 ml of methanol are stirred for 14 hours at SO .

The precipitated 2-[(S-chloro-2-dimethylamino-4pyrimidinyl)amino]-2-imidazoline is isolated by filtration and melts at 278-279°.

The starting material is prepared as follows : IS.3 g of sodium hydride (50 % in oil) are added in portions to a solution of 70 g of 4-amino-S-chloro-2-dimethylaminopyr imidine in 750 ml of dimethylformamide under a nitrogen atmosphere, whilst being cooled with ice and common salt, in such a manner that the temperature does not excess o . The mixture is cooled for a further hour in an ice 48803 bath until the vigorous evolution of hydrogen ceases. Than 12.3 ml of carbon disulphide ara addad droowisa whilst o cooling at 3-10 and this temperature is maintained rcr one hour. A further 9.9 g of sodium hydride are added in o portions at 0-10 . The reaction mixture is stirred for minutes in an ice bath, after which S.l ml of carbon o disulphide are added dropwise at 0-10 . The mixture is stirred for a further one hour whilst cooling with ice, then, as described above, is again treated with 9.9 g of sodium hydride and 6.1 ml of carbon disulphide. After addition of the carbon disulphide, the mixture is stirred for a further one hour in the ice bath. Whilst cooling with ice and common salt, 63.4 ml of methyl iodide are then added dropwise within about 30 minutes such that the o temperature does not rise above 15 . The cooling bath is then taken away and the mixture stirred for a further hours. 200 ml of water are then slowly added dropwise, whilst cooling with ice, and the reaction mixture is poured onto 2000 ml of water. The precipitated crude product is suction-filtered, thoroughly washed with water and then extracted three times by boiling with 1000 ml of cyclohexane each time. The combined cyclohexane extracts ara dried over sodium sulphate, filtered, and concentrated to a volume of approximately 150 ral. On cooling in an ice bath, colourless 3-chloro-2-dimethylaraino-4-(dimethylthio o methylenaimino)pyrimidine which melts at 35-37 crystallises out.

In the same manner, 2-((2,6-dichlcro-4-oyrimidinyl) o amino]-2-imidazoline (mp. 215-217 ) is obtained from 4amino-2,S-dichloropyrimidine. 2,5-Dichloro-4-(dimethylthio methyleneimino)pyrimidine occurring as intermediate thereby o melts at 95-100 .

Example 24 4.7 g of 2-[(2,5-dichloro-4-pyrimidinyl)amino-2imidazoline and 7.3 ml of alcoholic dimethyiamins solution (33 %) are refluxed Cor 90 minutes in 30 ml of ethanol.

Tha 2-( (5-chloro-2-d imethylamino-4-oyr imid inyl) am ino 1 -2imidazoline which has precipitated is suction-filtered whilst still hot ar.d washed with water and ethanol. The product is identical with that of Example 10.

The starting material is prepared according to Example 23.

Example One drop of carhon disulphide is added to a mixture of 1 g of S-chloro-2-dimethylamino-4-cyanoaminopyrimidine and 0.5 ml of ethylenediamine and the mixture is heated o for 1 hour at 100 . The reaction mixture is tnen concentrated on a rotary evaporator and the residue is suspended in 50 ml of hot ethanol. The insoluble 2-[ (6-chloro15 2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline is o suction-filtered whilst hot and melts at 264-253 . After recrystallisation from dimethylsulfoxide-methanol the melting point rises to 278-279°.

The starting material is prepared as follows : 1.75 g of sodium hydride (50 % in oil) are added in portions to a solution of 5.3 g of 4-amino-S-chloro-2diasthylaminopyrimidine in 60 ml of dimethylformamide under a nitrogen atmosphere, whilst cooling with ice and common salt, in such a manner that the temperature does not rise o above 10 . The mixture is cooled for a further 30 minutes in the ice bath until the vigorous evolution of hydrogan ceases. A solution of 3 g of cyanogen bromide in 30 ml of dimethylformamide is then slowly added dropwise whilst cooling with ice, wherein the temperature should not exceed o . tfhen the addition is complete, the mixture is o stirred for a further 30 minutes at 0-10 , and is then neutralised with 2N hydrochloric acid. The reaction mixture is poured onto 100 ml of ice water and extracted several times with ethyl acetate. The combined ethyl acetate extracts are dried with sodium sulphate and concentrated. 3y recrystallisation of ths residue from ethanol, crystalline S-chloro-2-dimethylamino-4-cyanoaminopyrimidine ο melting at 223-232 is obtained.

Example 26 2.9 g (0.01 mole) of 6-chloro-2-dimethylamino-4(dimethylthiomethyleneimino)-5-methyl pyrimidine and 0.5 g (0.01 mols) of ethylenediamine are dissolved in 50 ml of absolute methyl alcohol and the mixture is stirred for 16 o hours at 60 . The mixture is than cooled to room temperature and the precipitated 2-[(6-chloro-2-dimethylamino-5methyl-4-pyrimidinyl)amino]-2-imidazoline is isolated by filtration. The crystallisate is suspended in methyl alcohol, acidified with 5N methanolic hydrochloric acid and the clear solution is concantratad by evaporation under reduced pressure. After recrystallisation of the residue from methyl alcohol-diethyl ether, with the addition of active carbon, 2-[(6-chloro-2-dimethylamino-5-methyl-4pvrimidinyl)arainol-2-imidazoline hydrochloride which melts o at 300 with decomposition is obtained as the colourless crystallisate.

The starting material is prepared as follows : o At 60 reaction temperature, 35.8 g (0.27 mole) of Ν,Ν-dimethyl guanidine hydrogen sulphate is added to a fresh sodium methylate solution prepared from 12.4 g (0.54 mole) of sodium and 60 ml of absolute methyl alcohol, and the mixture is refluxed for 20 minutes. Thereafter, at reflux temperature a solution of 34.4 g (0.27 mole) of 2-cyanopropionic acid ethyl aster in 110 ml of absolute methyl alcohol is added dropwise within 30 minutes and tha white suspension is boiled for a further one hour. After the mixture has cooled, it is filtered, and the filtrate is adjusted to pH 5-5 with 4.5N methanolic hydrochloric acid. The precipitated crystallisate is filtered off and washed with cold methyl alcohol and diethyl ether. After o drying in a high vacuum at 70 C, 4-amino-2-dimechylaminoS-hydroxy-5-methylayrimidine hydrochloride monohydrata of o melting point 235-290 is obtained as the colourless crystallisate.

A mixture o£ S.C (0.0244 mole) of 4-amino-2-dimethylamino-S-hydroxy-5-methylpyrimidina hydrochloride, 22.3 ml (0.244 mole) of phosphorus oxychloride and 2,55 ml (0.0133 mole) of triethylamine is refluxed for 9 hours, whilst stirring. The excess phosphorus oxychloride is then distilled off under reduced pressure and the viscous oil remaining is discharged onto ice water. The reaction o temperature rises as far as 50 . When the reaction has subsided, the mixture is stirred for a further one hour o at SQ and is then cooled to room temperature. The pH is adjusted to 7 with concentrated sodium hydroxide solution and stirring is continued for a further one hour at 55o SO C. The pH has to be adjusted by adding concentrated sodium hydroxide solution several times. The mixture is then cooled and extracted four times with 40 ml of chloroform each time. The combined chloroform extracts acs dried with sodium sulphate and concentrated by evaporation under reduced pressure. After cecrystallisation of the residue 20 from isopropyl alcohol, with the addition of active carbon, 4-amino-S-chloro-2-dimethylamino-5-methyloyrimidine melting o at 170-172 is obtained as yellow crystallisate. 0.33 g (0.0069 mole) of sodium hydride (50 5 in oil) is added to a solution of 2 g (0.0107 mole) of 4-amino-625 chloro-2-d imethylai4ino-5-methyipyr imidine in 20 ml of absolute dimethylformamide under a nitrogen atmosphere and whilst cooling with ice and common salt, and the mixture o is stirred for one hour at 0-5 . 0.2 ml (0.0033 mole) of carbon disulphide is then added whilst cooling at o 0-10 C and this tenroerature is maintained for one hour. o A further 0.33 g of sodium hydride is added at 0-5 and o stirring is continued for 30 minutes at 0 , whereupon a further 0.2 ml of carbon disulphide is added and the mixture is stirred for one hour whilst cooling with ice.

Then, as described above, the mixture is again treated with 0.34 g of sodium hydride and 0.25 ml of carbon disulphide. 48803 After the addition of the carbon disulphide, stirring is continued for a further one hour in the ice bath. Whilst cooling with ice and common salt, 1.55 ml (0.0267 mole) of methyl iodide are then added dropwise over the course of approximately 15 minutes such that the temperature does o not rise above 10 . The cooling bath is then taken away and the stirring continued for a further 2 hours.

The reaction mixture is then poured onto 50 ml of ice water and extracted three times with 30 ml of ethyl acetate each time. The combined ethyl acetate extracts are dried with sodium sulphate and concentrated by evaporation under reduced pressure. By extracting the residue by boiling with petroleum ether, mineral oil is removed. To remove moisture and traces of dimethylformamide still adhering, the mixture is treated with toluene, and 6-chloro-2dimethylamino-4-(dimethylthiomethyleneimino)-5-methylpyrimidine, which is us^d directly in the form of crude product as starting material, is obtained as the oily residue.

Recrystallisation may optionally be carried out from cyclohexane, a colourless crystallisate which melts at o 115-117 being obtained.

The following compounds are also prepared in the same manner : 2- ((2-Methylamino-4-pyrimidinyl)amino] -2-imidazoline,· its hydrochloride'melts at· 275-280°; 2-[(6-Chloro-2-propylamino-4-oyrimidinyl)amino]-2o imidazoline hydrochloride, mp. 230-234 ; 2-[(S-Chloro-2-(N-methyl-N-propylamino-4-pyrimidinyl)amino]o 2-imidazoline hydrochloride, mp. 137-189 ; 2-((2-Propylamino-4-pyrimidinyl)amino]-2-imidazoline, mp. 230-233°.

The 4-amino-0-chloro-2-propylaminopyrimidine used as starting material can be prepared in the following manner : A mixture of 12.3 g of 4-amino-2,S-dichloropyrimidine and 16.4 ml of n-propylamine in 700 ml of methyl alcohol is heated to reflux whilst stirring and then the solution, wnich soon becomes clear, is boiled for a further IS hours. It is then concentrated ay evaporation to dryness under reduced pressure. The residue is rendered alkaline with 2M sodium carbonate solution and extracted several times with chloroform. The combined chloroform extracts are dried with sodium sulphate and concentrated by evaporation. After crystallisation of the residue from petroleum ether, the solution is filtered off and 4-amino-6-chloro-2-oropylo aminopyrimidine melting at 85-90 is obtained.

The 4-amino-6-chloco-2-(N-methyl-N-propylamino)pyrimidine used as starting material can be prepared in the same manner as 4-amino-6-chloro-2-propylaminopyrimidine described above, by using N-methyl-N-propylamine instead of n-propylamine for the reaction. 4-amino-S-chloro-2-(Mmethyl-N-propylamino)pyrimidine obtained in this manner is used in the form of crude product for the following stage .

The 4-amino-2-propylaminopyrimidine used as starting material can be prepared according to the following process: With the addition of 0.7 g of a 10 ί palladiumcarbon catalyst, a mixture of 3.7 g of 4-amino-5-chloro2-prooylaminopytiraidine, 140 ml of glacial acetic acid and 30 ml of 2N hydrochloric acid is hydrogenated at room tem25 perature and a pressure of 4 bar until 1 mole equivalent of hydrogen has been absorbed. The mixture is then filtered to .remove the catalyst and the filtrate concentrated by evaporation 'under reduced pressure. The residue is rendered alkaline with 2N sodium carbonate solution, with the addi30 tion of ice, and extracted several times with chloroform.

The combined chloroform extracts are dried with sodium sulphate, and concentrated by evaporation under reduced pressure. The 4-amino-2-propylaminopyrimidine remaining is used without further purification for the following stage.

Example 27 The following compounds may also be prepared analogously co the methods described in the preceding examples : 2-[(2,6-diethoxy-4-pyrimidinylamino]-2-imidazoline, mp, 193-195°; 2- [ (2-dimethylamino-6-ir,ethoxy-4-oyrimidinyl) amino] -2o imidazoline, me. 90-92 ; 2-[(2-isopcopoxy-6-methoxy-4-pyrimidinyl)amino]-2-imidazo10 line mp. 209-210 ; 2-[(2-butoxy-6-methoxy-4-pycimidinyl)amino]-2-imidazoline mp. 184-135°; 2-[(S-chloro-2-isooropoxy-4-pyrimidinyl)amino]-2-imidazoo line, mp. 210-211 ; 2-[(2,6-bis-dimethylamino-4-pyrimidinyl)amino]-2-imidazoo line, mp. 310-312 and 2-((2-isopropoxy-4-pyrimidinyl)amino]-2-imidazoline,mp.261-2S3e.

The starting materials are prepared as follows ; 11.5 g (0.5 mole) of sodium are dissolved in 400 ml 2o of absolute alcohol, heated whilst stirring to boiling and, in approximately 20 minutes, 32.8 g (0.2 mole)· of 4-amino2,6-dichloropyrimidine are added in portions. The mixture is then boiled for a further 3 hours, filtered, and the filtrate is evaporated under reduced pressure. The resi25' due is triturated with water, filtered and recrystallised from alcohol. 4-amino-2,6-diethoxypyrimidine melting at o 106-103 is obtained. 32.8 g (0.2 mole) of 4-amino-2,6-dichloropyrimidine, 400 ml of isopropanol and a solution of 4.5 g (0.2 mole) of sodium in 100 ml of isoprooanol are refluxed for 15 hours. The mixture is concentrated under reduced pressure, the residue is triturated with water and by filtering a o crude product is obtained which melts at 108-112 . After recrystailisation from isoprooanol, 4-amino-6-chloro-2o isooropoxypyrimidine melting at 125-127 is obtained. 43893 13.3 g (0.1 mole) of the last-named compound are boiled with a solution of 2.3 g (0.1 mole) of sodium in 100 ml of methanol. The mixture is filtered end the filtrate concentrated by evaporation under reduced pressure.

The residue is triturated with water, filtered, and recrystallised from methanol. 4-amino-2-isooropoxy-6-methoxyo pyrimidine melting at 39-90 is obtained.

Instead of the cleaned comoound, the above described o crude product that melts at 103-112 may also be used. 4-amino-2-n-butoxv-6-methoxyoyrimidine melting at o 94-95 is prepared in an analogous manner.

The resulting 4-amino compounds can bs converted into the corresponding 3-methyl isothiourea compounds in accordance with Example 1. Their reaction with ethylenediamine yields the corresponding imidazoline products.

Example 28 In analogy to the preceding Examples, for example according to Examples 10 and 12, the following compounds may also be obtained : 2-((2-methyl-6-ohenylamino-4-pyrimidinyl)amino]-2o imidazoline. Mp. 263-265 . The hydrochloride melts at 311-313°. 2-[6-(4-methoxyohenyl)amino-2-methyl-4-pyrimidinyl)o amino]-2-imidazoline. Mp. 266-269 . The hydrochloride o melts at 231-283 . 2-[(6-(4-chlorophenyl)amino-2-methy1-4-pyr imid inyl)amino]o 2-imidazoline. Mp. 232-234 . The hydrochloride melts at 320-322°. 2-((2-methyl-6-pnenoxy-4-pyrimidinyl)amino]-2-isidazoline. o The hydrochloride melts at 302-305 .

The new compounds and their new pre-stages used as starting materials acs prepared analogously to those of Examples 10 or 12 as follows : Ad 1) : starting from 4-amino-S-chloro-2-methylpyrimi35 dine and aniline, 4-amino-2-methyl-6-phenylaminopyrimidine, 48803 ο □ρ. 192—194 , is obtained. After reaction with etiicxvcarbonyl isothiocyanate this yields the corresponding 0 ethoxycarbonylthiourea (mp. 199—200 ), which is hydrolysed with lil sodium hydroxide solution to give the correso ponding thiourea (mp. 227-230 ) . The reaction of this thiourea with methyl iodide yields the ii-(2-methyl-S-phanylamino-4-pyriraidinyl)-S-methylisothiourea hydroiodide used as o starting material and which melts at about 150 .

Ad 2) : starting from 4-amino-S-chloro-2-methylpyrimidine and c-anisidine, 4-amino-6-(4-methoxyphenyl)amino-2* o methylpyrimidine, mp. 243-245 , is obtained. After reaction with ethoxycarbonyl isothiocyanate in acetone and dimethylformamide this yields the corresponding ethoxycaro bonylthiourea (mp. 198-200 ), which is hydrolysed with IN sodium hydroxide solution to give the corresponding o thiourea, (mp. 221-224 ). The reaction of this thiourea with methyliodide in mathanol-dimethylformamide yields the N-(6-(4-methoxyphenyl)amino-2-methyl-4-pyrimidinyl]-5-methyli3othiourea hydroiodide used as starting material and which o melts at 165-157 .

Ad 3) : starting from 4-amino-5-chloro-2-methylpyrimidine and o-chloroaniline, 4-amino-6-(4-chlocophenyl)amino-2- o methylpyrimidine, mp. 180-182 is obtained. After reaction with ethoxycarbonyl isothiocyanate in acetone and dimethylformamide, this yields the corresponding o ethoxycarbonylthiourea (mp. 200-202 ), which is hydrolysed with 2N sodium hydroxide solution to give the o corresponding thiourea. (Mp. 242-245 with decomposition.) The reaction of this thiourea with methyl iodide in acetone yields N-[5-(4-chloro- phenyl)amino-2methyl-4-pyrimidinyl]-3-methyli3othiourea hydroiodida which o is used as starting material and melts at 212-215 .

Ad 4) j starting from 4-amino-6-chloro-2-methyl?yrimidina and sodium phenoxide, 4-amino-2-methyl-6~ o pnenoxypyrimidine (mp. 165-1S7 ) is obtained. After reaction with ethoxycarbonyl isothiocyanate in acetone, this yields the corresoonding ethoxycarbonyl thiourea (mp. o 135-141 ), which is hydrolysed with IH sodium hydroxide solution to give the corresponding thiourea (mp. 221o 224 ), The reaction of the last-named compound with 5 methyl iodide in methanol-dimethylformamide yields N-(2methy1-6-phenoxy-4-pyr imidinyl)-3-methylisothiourea hydroiodide used as starting material.

Example ,29 In analogy to the methods described in the preceding 10 Examples the following compounds may also be prepared : 2-((4-pyrimidinyl)amino)-2-imidazoline. 2-[(2-butylamino-4-pyrimidinyl)amino]-2-imidazoline.

Example 30 Tablets containing 0.1 g of the hydrochloride of 215 ( (2,6-dimethyl-4-pyrimidinyl)amino]-2-imidazoline can be manufactured as follows : Composition (for 1000 tablets) 2-((2,6-dimethyl-4-pyrimidinyl)amino]- 2-imidazoline hydrochloride 100.0 9 20 lactose 50.0 g wheat starch . 73.0 g colloidal silica 13.0 g magnesium stearate 2.0 g talc 12.0 g 25 water q.s, The 2-((2,6-dimethy1-4-pyr imid inyl)amino]-2-imidazoline hydrochloride is mixed with a part of the wheat starch, with the lactose and the colloidal silica and the mixture is forced through a sieve. Another part of the wheat starch is 48803 made into a paste with 5 times the amount of water on a water bath, and the above powdar mixture is kneaded with this caste until a slightly plastic mass forms. This is pressed through a sieve of 3 mm mesh width and dried, and ths dried granulate is again forced through a siave. Tha remaining wheat starch, the talc and the magnesium stearate are added and the resulting mixture is compressed to form 0.25 g tablets.

Tablets or other pharmaceutical preparations which contain a different compound of the invention, for example, one from the preceding Examples, may be manufactured in an analogous manner.

Claims (53)

CLAIMS:

1. A compound of the general formula I A Py-N-cf .Alk R V R 2 I R. (I) in which Py represents a 4-pyrimidinyl bonded via a carbon 5 atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogen, trifluoromethyl, lower alkylsulphonyl, amino·, phenyl, phenoxy or phenylamino, each of which can be 10 substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen? lower alkyl amino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower 15 alkylureido or Py represents a 5- pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising hydroxy, trifluoromethyl, lower alkylsulphonyl, amino; phenyl, phenoxy or phenylamino, each 2. O of which can be substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxy carbonylamino , ureido, 3-lower alkylureido and 25 3,3-di-lower alkylureido, and Rg and Rg independently of one another represent hydrogen, lower alkyl or lower alkenyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 4 carbon atoms, and their tautomeric compounds .

2. A compound of the general formula I.shown in claim 1, in which Py represents a 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three Identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, halogen, amino; phenyl which can be substituted by lower alkyl, lower alkoxy, hydroxy, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, or Py represents a 5-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising hydroxy or amino; phenyl which can be substituted by lower alkyl, lower alkoxy, hydrogen, amino, lower alkylamino, di-lower alkylamino or halogen; lower alkylamino, di-lower alkylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, and in which R^ and Rg independently of one another represent hydrogen, lower alkyl or lower alkenyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 4 carbon atoms, radicals denoted by lower containing up to 4 carbon atoms, and their tautomeric compounds.

3. A compound of the general formula I shown in claim 1, in which formula Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and optionally substituted by one, two or three identical or different substituents from the group comprising lower alkyl, lower alkoxy, phenyl, lower alkylamino, di-lower alkylamino or morpholino and/or 48803 halogen, or Py represents a 5-pyrimidinyl bonded via a carbon atom to the nitrogen atom optionally substituted by one, two or three identical or different substituents from the group phenyl, lower alkylamino, di-lower alkylamino or morpholino and/or halogen and in which R^ represents hydrogen or lower alkyl and R^ represents hydrogen or lower alkyl, and Alk represents lower alkylene which separates the two nitrogen atoms by 2 to 3 carbon atoms, radicals denoted by lower containing up to 4 carbon atoms, and halogen having an atomic weight of up to 35.

4. A compound of the general formula IX n R 3-< > -N-cf \lk' \ η V 5 H (II) in which Alk' represents lower alkylene having up to 4 carbon atoms which separates the two nitrogen atoms by 2 to 3 carbon atoms, and each of the radicals Rg, R^ and Rg represents hydrogen, lower alkyl having up to 4 carbon atoms, halogen, di-lower alkylamino, morpholino or phenyl, if the group N/*4 R 3-V<- R 5 represents a 4-pyrimidinyl, and each of the radicals Rg, R^ and Rg represents di-lower alkylamino, morpholino or phenyl, if the group / R 4 R,\=· represents a 5-pyrimidinyl.

5. A compound of the general formula III in which and RJ independently of one another represent 5 hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having 4 carbon atoms, halogen or di-lower alkylamino, and n is 1 or 2.

6. 2-((2,6-Dimethyl-4-pyrimidinyl)amino]-2-imida2oline.

7. 2-((2,6-Dimethoxy-4-pyrimidinyl)amino]-2-imidazoline. 10

8. 2-( (2,6-Dimethyl-4-pyrimidinyl)amino]-1,4,5,6-tetrahydro-pyrimidine.

9. 2-((6-Chloro-2-methyl-4-pyrimidinyl)amino]-2-imidazoline.

10. 2- [ (2-Methyl-4-pyrimidinyl) amino] -2-imidazoline. 15

11. 2-((6-Chlow-2-methoxy-4-pyrimidinyl)amino]-2-imidazoline.

12. 2-((2-Methoxy-4-pyrimidinyl)amino]-2-imidazoline. 48803

13. 2-[(2-Hydroxy-4-pyrimidinyl)amino]-2-imidazoline.

14. 2-[(6-Chloro-2-dimethylamino-4-pyrimidinyl,amino]2-imidazoline.

15. 2- [ (2-Dimethylamino-4-pyrimidinyl)amino]-2-imidazo5 line.

16. 2- [ (6-Chloro-2-diethylamino-4-pyrimidinyl)amino]-2imidazoline.

17. 2-[(6-Chloro-2-di-n-butylamino-4-pyrimidinyl)amino]2-imidazoline. 10

18. 2-[ (6-Dimethylamino-2-methy1-4-pyrimidinyl)amino]2-imidazoline.

19. , 2-[(2,6-Dihydroxy-5-pyrimidinyl)amino]-2-imidazoline

20. 2-[(2,6-0iethyl-5-methy1-4-pyrimidinyl)amino]-2imidazoline. 15

21. 2-[(2-Pheny1-4-pyrimidinyl)amino]-2-imidazoline.

22. 2-[(2-Phenyl-4-pyrimidinyl)amino]-1,4,5,6-tetrahydropyrimidine.

23. 2-[ (2-Phenyl-5-pyrimidinyl) amino]-2-imidazoline.

24. 2- [ (6-Chloro-2-(4-morpholino)-4-pyrimidinyl)amino]2o 2-imidazoline.

25. 2.( (2-Dimethylamino-6-methyl-4-pyrimidinyl)amino]-2imidazoline.

26. 2-( (2-Diethylamino-5-pyrimidinyl)amino]-2-imidazoline.

27. 2-( (2-Dimethylamino-5-methyl-4-pyrimidinyl)amino]-25 imidazoline.

28. 2-((2,6-Dichloro-4-pyrimidinyl)amino]-2-imidazoline.

29. 2-( (6-Chloro-2-dimethylamino-5-methyl-4-pyrimidlnyl) amino]-2-imidazoline.

30. 2-( (2-Methylamino-4-pyrimidir.yl)amino]-2-imidazoline. 10

31. 2- ((6-Chloro-2-propylamino-4-pyrimidinyl)amino]-2imidazoline.

32. 2-((6-Chloro-2-(N-methyl-N-propylamino)- 4-pyr imidiny 1)amino-2-imidazoline.

33. 2-((2-Propylamino-4-ayriraidinyl)amino]-2-imidazoline. 15

34. 2-((2,6-Diethoxy-4-pyrimidinyl)amino]-2-imidazoline.

35. 2-( (2-DImethylamino-6-methoxy-4-pyrimidinyI)amino]2-imidazoline.

36. 2-((2-Isopropoxy-6-methoxy-4-pyrimidinyl)amino]2-imidazoline.

37. . 2- [ (2-Butoxy-6-methoxy-4-pyrimidinyl) amino] -2-imidazoline.

38. 2-[ (6-Chloro-2-iscpropoxy-4-pvrimidinyl)amino]-2imidazoline. 5

39. 2-[ (2,6-Bis-dimethylamino-4-pyrimidinyl)amino]-2imidazoline.

40. 2- [ (2-Isopropoxy-4-pyrimidinyl)amino]-2-imidazoline.

41. 2-[(2-Methyl-S-phenylamino-4-pyrimidinyl)amino]-2imidazoline. 10

42. 2-[(6-(4-Methoxyphenyl)-amino-2-raethyl-4-pyrimidInyl)amino]-2-imidazoline.

43. 2-[(6-(4-Chlorophenyl)-amino-2-methyl-4-pyrimidinyl) amino]-2-imidazoline.

44. 2- [ (2-Methyl-6-phenoxy-4-pyrimidinyl)amino]-2-imi15 dazoline.

45. 2-[(4-Pyrimidinyl)amino]-2-imidazoline.

46. 2-[ (2-Butylamino-4-pyrimidinyl) amino]-2-imidazoline.

47. An acid addition salt of a compound as claimed in any one of claims 1 to 46.

48. A therapeutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to 46.

49. A pharmaceutical preparation comprising a compound claimed in any one of claims 1 to 46 and 48 in admixture or conjunction with a pharmaceutically suitable carrier.

50. Process for the manufacture of new 2-(pyrinidinyl5 amino)-l,3-diaza-2-eycloalkene compounds of the formula I in which Py, R^, Rj and Alk have the meanings as defined under claim 1, their tautomeric compounds and acid addition salts, which consists in 10 a) reacting a compound of the formula Py-X (XV), or a salt thereof, with a compound of the formula (V) or with a salt thereof, wherein one of. the radicals X and Y represents an amino group of the formula -N(R 2 )-H (VI) 15 and the other represents a group that can be split off together with hydrogen under the reaction conditions, or b) by reacting a compound of the formula (VII) in which Y^ represents the imino group,.a group that can be split off, the oxo group or thioxo group, and Yg represents a group that can be split off, or Y^ and Yg together represent a triple-bonded nitrogen atom, when Rg is hydro5 gen, or the corresponding tautomeric form, or a salt thereof with an ' alkylenediamine compound of the formula HgN-Alk-NHR^ (VIII), and if desired, dshalogenating a resulting compound of the formula X, in which the residue Py contains halogen, or replacing the halogen in 2-position lo by unsubstituted or substituted amino, in a resulting compound In which the residue Py is substituted in the 2- and 6-positions by halogen, and/or, converting any resulting compound into another compound of the invention, and/or, if desired, converting any resulting base into an acid 15 addition salt thereof,· or any resulting salt into the corresponding free base or into another acid addition salt, and/or, if desired, resolving a mixture of isomers obtained into the single isomers.

51. The process for the preparation of compounds described 2o in any one of examples 1 to 18.

52. The process for the preparation of compounds described in any one of examples 19 to 29.

53. The compounds prepared according to any one of claims 50 to 52.