CA1136131A - Pyrimidine compounds, processes for their preparation, pharmaceutical preparations containing these compounds, and their use in therapeutics - Google Patents

Abstract

Abstract of the disclosure The invention concerns the manufacture of compounds of the formula (I) in which Py represents an optionally substituted 4-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, and processes for their preparation. The compounds exhibit hypotensive and antihypertensive effects. They are prepared by reacting compounds of the formulae

Description

The present invention relates to 2-(pyrimidinyl-amino)-1,3-diaza-2-cycloalkene compounds of the formula I
~\
Py - N - C Alk (I) ' \ N

Rl in which formula Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and unsubstituted or 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;
1~ 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 Rl 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, radicals denoted by "lower" containing up to 4 carbon atoms, and their tautomeric compounds and acid addition salts. The new compounds are pharmaceutically ac~ive substances and can be used for the preparation of pharmaceutical preparations.

-1- .~

113~i131 In the context of the present description, radicals and compounds denoted by "lower" contain up to 4 carbon atoms.
Thus, lower alkyl represents especially methyl, and also ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert.-butyl.
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.
Lower alkyl sulphonyl is, for example, methylsulphonyl, ethylsul-phonyl, n-propylsulphonyl or isopropylsulphonyl.
Lower alkylthio is especially methylthio, furthermore also ethylthio, isopropylthio, n-propylthio, or also a straight or branched butylthio.
Halogen is especially halogen of an atomic number up to 35 aDd represents especially chlorine, furthermore fluorine or bromine.

113~;131 Lower alkylamino or di-lower alkylamino is, for example, methylamino, ethylamino, dimethylamino or diethylamino. Lower alkanoylamino may be, for example, acetylamino or propionylamino, lower alkoxycarbonylamino is, for example, methoxycarbonylamino or ethoxycarbonylamino, and lower alkyl ureido is, for example, 3-methylureido or 3,3-dimethylureido.
A lower alkylene group Alk is preferably unbranched lower alkylene and is especially ethylene, also l,3-propylene, or 1,4-butylene, but may also be branched lower alkylene, such as 1,2-propylene, 2-methyl-1,2-propylene or

2,3-butylene.
Salts of compounds of the abo~e formula I are acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acids, or with organic acids, such as corresponding carboxy-lic 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 ,, aci~ andelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or sulphonic acids, ~or example methanesulphonic a~id, ethanesulphonic acid, 2-hydroxyethanesulphonic 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 compo~nds in their free for~ and in the form of their salts, including also such acid addition salts, that may be used as intermediates, for example in the purifisation 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 effects.
Thus, they show hypotensive and antihypertensive effects hich can be demonstrated in anaesthetised cats in doses from approximately o.l mg/kg on intravenous administration (wherein also the pressorial effects of adrenalin and nor-adrenalin are antagonised) and on renally hypertonic rats in doses from approximately 10 mg/kg/day on oral administra-tion. Furthermore, the compounds according to the invention have an effect on the cardiac action, which can be demonstra-ted by means of the positively inotropic effects determine~ !
at concentrations from 100 ~g/ml, and by means of the negatively chronotropic effects determined at concentrations from 10 ~g/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 p~armacolo-gically active compounds, especially as antihypertensives for the treatment of raised blood pressure, for example 113~131 example in connection with essential hypertonia, and as cardiotonic agents.
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 substi-tuents from the group comprising lower alkyl, lower alkoxy, phenyl, amino, lower alkylamino, di-lower alkylamino or morpholino and/or halogen, and in which R
represents hydrogen or lower alkyl and R2 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.

3 13613~

The invention relates especially to compounds of the formula R ~ N ~ Alk' (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, especially ethylene, and each of the radicals R3, R4 and R5 represents hydrogen, lower alkyl having up to

4 carbon atoms, for example methyl, or lower alkoxy having up to 4 carbon atoms, for example methoxy, or halogen, for example chlorine or bromine, or di-lower alkylamino, for example dimethylamino or diethylamino, morpholino or phenyl, wherein preferably at least one of the radicals R3, R4 and R5, 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 ~ U ~. ~- CH2 (III), in which R'3 and R' independently of one another represent hydrogen, lower alkyl havin~ up to 4 carbon atoms, for exam~le methyl, or lower alkoxy having up to 4 carhon atoms, for exa~ple methoxy, halogen, for example chlorine, di-lower alkylamino, for example dimethylamino, wherein prefer~bly both of the radicals R' and R' are different 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 n is 2 and especially 1, and salts thereof, especially pharmaceuticallyacceptable,non-toxic acid addition salts.
The invention relates especially to the compounds of the formula I descri~ed in the Examples and salts thereof, especially pharmaceuticallyacceptable,non-toxic acid addition salts.
The compounds of the present inv2ntion can be prepared in accordance with methods known per se, for example by reacting a compound of the formula Py-X (IV), or a salt thereo~, with a compound of the formu~a Y - C Alk (V) N /
I
Rl _, ., . , . . . . _ . .. . , _ , . ... . . . . . . . . _ .. . . . . . . . .. .. . . . . ~
. . .. ..

or with a szlt th~reof, wllerein one of the radicals X and Y
re?resents an amino group of the formula ~ (VI~
and th~ other represents a group that can be split off together with hydrogen under the reaction conditions, and, if desired, converting a resultins compound of the formula I into a different compound of the formula T, 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, se~arating a resulting mixture of isomers into the individual isomers.
A group X or Y that can be split off together with hydrogen is, for exampl~, especially a free, or preferably an etheri~ied, ~,ercapto group, furthermore a reactive, functionally modified hydroxy group, or the nitroamino group. An etherified mercapto group is especially a mer-capto group etherified by an optionally substituted hydro-carbon radical, especially one of aliphatic character.It is especially lower alkylthio, for example methylthio, ethyl-thio or butylthio or phenyl-lower alkylthio, for example benzylthio. A reactive, functionally modified hydroxy group is a corresponding etherified or esterified hydroxy gcoup.
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 comoound of the form.ula IV the group X represents the amino group of the formula VI, ~hilst in a compound of the formula V the radical Y represents especially an etherified mercapto qroup, especially lower alkylthio, for example methylthio.
~ alts of startin~ substances o the formula rv and V are acid addition salts, for example salts with the abo~e-~entioned acids, especially with mineral acids, such as hydrohalic acids, for example hydrocnloric acid, hydriodic acid or sulphuric acid. In that case in particular the starting .~aterial that is different from an amino compound . _ . .. _ , _ . _~_ _._, . _ , _ _ ~ ._ . ~ ~ _ . ~.. ~ _ . _ _ . _, _ _ _ . ... ... , . . . , . . . _ . .
._ _ _ . . _ _ . _ .. _ _ _ 9 of the formula IV or V, and especially a starting material of the formula V in whicn Y represents ~n optionally etheri-fied mercapto group or a reactive, functionally modified hydroxy group, is used in the form of an acid addition salt.
~ he above reaction is carried out in a ~anner known se , for example in the absence or presence of a solvent or a mixture of solvents, if desired in the ~resence of an excess of the amine component used as starting material, whilst cooling or preferably whilst heating, for example at a temperature of from approximately 50 C to approximately 180 C, preferably at l~O 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 - N---C ~ 1 (VII), in which Y represents the imino group, a group that can be split off, the oxo group or thioxo group, and Y2 represents a group that can be split off, or Yl and Y 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 ~2~~A1k~NaRl (VIII3 and, if desired, carrying out addi~ional process steps.
.~ group that can be split off has aiready been defined 113~131 above unAer formula IV or V in connection with the substi-tuents X or Y. A co~pound of the formula VII is norm lly used in the ~orm of an acid ad~ition salt, especially a salt with a ,~ineral acid, such as a hydrohalic acid, for example hydrochloric, hydrobromic or hydriodic acid. The condensation ceaction to form the ring can be effected in one or two steps.
~ he 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, preferably, at elevated temperatures, ~or example at approximately 53 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 tem-peratures of from approximately 100 C to a~proximately 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 for-mula Py-l~-R (IVa) with a suitable isocyanate or iso-thiocyanate compound, such as an acyl isocyanate or acyl isothiocyanate, for example a lower al~oxycarbonyl isocyanate or lower alkoxycarbonyl isothiocy nate, such as ethoxycar~onyl isocyanate or isothiocyanate, or with an aroyl isocyanate or aroyl isothiocyanate, such as benzoyl isocyanate or ~enzoyl isothiocyanate(these being optionally prod~ced in situ , for~examp~e 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 ~-acylurea co~pound or ~-acylthiourea compound ~y hydrolysis, preferably in the presence of an alkaline agent, for example sodium hydroxide, ~nd converting the _orresponding urea or thiourea intermediate into the desired 0-or ~-substituted isourea 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 z HN
Z Z
Py - N -~C \ Alk (IX), in which Zl and Z together represent oxygen or sulphur and Z3 represents the radical R and Z represents hydrogen, or 2 is a grou~ that can be split off and Z2 and Z together form a bond, and Z represents the radical R , is subjected to a ring-closure reactlon, and, if desired, additional process steps are carried out.
The ring closure of the above starting material of the for~ula IX can be carried out by means of pyrolysis, operation being carried out at temperatures of from approxi-o omately lO0 C to approximately 200 C, if necessary or desired ln the presence of a suitable ~iqh-boilinq sol-vent, in a closed vessel, optionally under increas~d pres-sure, and/or under an inert gas atmosphere, for example a nitrogen atmosphere.

_ . , .. . .. ~ . _ . . _ . ~_,,.. __ , ...... _ .,, . .. , . . , . __ .. . _ . . . . _ . . .. . _ .. , _ ~
.. , _ __ _ _ ., _ _ .. . _ The starting material can be prepared in 2 manner known per se , for example by treating a compound of the formula Py-~=C=Z (X) or of the formula Py~ )-C(=Z)-~al (XI), wherein Hal represents halogen, especially chlorine and Z represents oxygen or sulphur, with an alkylenediamine compound OL the formula H2N-Alk-NH-R (VIII).
Ihe new compounds of the formula I can likewise be obtained by reacting a phosphinic aci~ halide of the formula ~ Alk ~ ~ lk\
R - N N - P - N N - R (XII), C/ I \C/
ll Hal O O

in which ~al represents halogen, with an amine compound of the formula Py-NH-R (IVa) and, if desired, carrying out additional process steps.
In a starting material of the formula XII, H~l is especially chlorine, and the reaction with the amine com-pound of the formula IVa is carried in the absence, but normally in the presence, of a solvent, such as a high-boiling solvent, for example xylene, preferably at elevated temperature, for example at approximately 100 C to approximately 200 C, if n~cessary in a closed vessel, optionally under increased pressure, or in an inert gas atmosphere, for examp~e a nitrogen atmcsphere.
~ he startin~ substances are known and can be prepared in a mann2r known ~er se . Thus, for example, compounds of ~he formula XII are obtained by reactin~ a compound of the formula Alk~
\ C / 1 (XII), with phosphorus oxychloride, for example in the presence of chloroform as the solvent, at a temperature of from o o approximately 20 C to approximately 40 C.
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 Rl and~or R2 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 example in a temperature ran~e from approxi-o omately 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 "Py" is substituted by halogen, for example by chlorine or bromine, may be dehalogenated. The dehalogena-tion can be effected with substances having a reducing action, especially with catalytically activated hydrogen or nascent ~ydrogen. The exchange of the halogen is effected, for example, ~y hydrogen in the presence of Raney nickel in, for example, alcoholic solution, in the presence ~13~31 of platinum in acetic acid or, preferably, in the presence of palla~ium on carbon in aaueou~ 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 mixtuces, 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 temperature of up to ~0 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 ~hich the radical "Py"
is substituted twice by halogen, for example by chlorine or bromine, in the 2- and 6-position can be converted by reaction with an optionally substituted amine into compounds of the formula I in which a halogen atom in 2-position 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, prefera~ly at the reflux temperature of the reaction mixture, and optionally under excess pressure.
Compounds o~ the ~ormula I in ~hich the radical "Py"
is substituted twice by halogen in the 2- and 5-position can be prepared from corresponding 2-halo-~-hydroxy or 2-halo-6-lower alkoxy compounds by reacting with a halogena-ting agent, ~or example a chlorinating a~ent such as phos-phorus oxychlor i~2 .

111 5~131 If lower alkoxy groups are present as substituents in the radical "Py", for example .~ethoxy or ethoxy groups or even phenoxy groups, then these can easily be converte~
by acidic or basic hydrolysis into compounds of the for~ula I in which the radical "Py" is substituted by hy~roxy.
The new starting substances and processes for their pre-paration 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 I with an acid, especially an organic or inorganic acid, which is suitable for the formation of pharmaceutically acceptable`
salts. Such acids are, for example : hydrohalic acids, sulphuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic car-boxylic or sulphonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, hydroxymaleic or pyruvic acid; phenyl-acetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxyben-zoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylenesulphonic acid; halobenzenesulphonic, toluenesul-phonic, 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 ~ith suitable ion exchangers or silver salts, lnto 2ifferent salts.

. . _ _ . . _ , ~, .. _ .. ., ~ . _ . . , . .... . _ . .. . , . . _ _ . , _ . , . .. .. . .. .. ... , _ _ .. ..
. _ . _ 113~31 The invention relates also to those forms of the process in which a compound obtainable at any stage of the process as an interme~iate is used 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 or a reac-tion component is ortionally used in the form of a derivative, for exam~le a salt.
Resultant mixtures of isomers can be separated into the individual isomers by methods which are ~nown per se,e.g. by fractional distillation, crystallisat~on and/or chromatography.
Advant~eously, for carrying out the ~rocesses accor-ding 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 pres~nt invention additionally relates to the compoun~s 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 o~ pharmaceutical pre-parations, especially preparations having an antihyper-tensive 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 l~ % to approximately 95 ~, preferably from approximately 20 ~ to approximately 95 ~ of the active substance. Pharmaceutical preparations according to the invention in dosage unit form are, for example, dragees, tablets, capsules, suppositories or ampoules. The 113f~131 ?har~aceutical preparations of the present invention are prepared in a ~anner ~nown per se , for example by means of conventional mixing, granulating, dragée-making, dissolving or lyophilising processes.
Thus, pharmaceutical preparations for oral use may be obtained by combining the active substance with solid carriers and, optionally, adjuncts, optionall~
granulating a resulting mixture and processing the mixture or granulate, if desired or necessary after tAe addition of suitable adjuncts, to form tablets or draqée cores.
~ uitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sor-bitol, cellulose preparations and/or calcium phosphates, for example tri-calcium phosp'nate or calcium hydrogen phos-phate; also binders, such as starch pastes prepared, for example, using maize, wheat, rice or potato starches, gela-tin, tr gacanth, methylcellulose, hydroxypropylmethylcellu-lose, sodium carboxymethylcetlulose and/or polyvinylpyrroli-done; and, if desired, disintegra~rs, such as the above-mentioned starches; furthermore, carboxymethyl starches, transversely cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow regulators a~
lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or poly-ethylene glycol. Dragée cores are provided with suitable coatings that may be resistant to ~astric juice, for which there are used, inter alia , concentrated sugar solutions that optionally contain gum arabic, talc, poly-vinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lac~uer solutio~s in suita~le organic solvents ~r solvent mixtures, or, for the preparation of coatings resistant to gastric juice, solutions of suita~le cellulose preparations, such as acetylcellulose phthalate or hydroxy~
propylmethylcellulose phthalate. Colourants or pigments may be added to the tablets or dragee coatings, for example to , . . . . . , _, ,, ., . . .. .. _ ~ . ~ _ _ . , . . . _ . , ,, . . _ . _ , , , _ . . , . _ _, .. .
. , . _ _ _ _ _ _ _ _ .

identify oe characterise different doses of active substance.
Other pharmaceutical oreparations that may be a~.ini-stered orally are dry-filled capsules made of gelatin, and also soft, sealed capsules consisting of gelatin and a plas-ticiser, such as glycerin or sorbitol. ~he dry-fiiled ca?sules 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 ma~nesium stearate, and optionally stabili-sers. 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 2 suppository base substance. Suitable base substances for suppositories are, for example, natural or synthetic triglycerides, paraf-fin 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 the 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 oils, for ex~mple sesame oil, or synthetic fatty acid esters, for example ethyl oleate or tri~lycerides, are used; or ~queous injection suspensions that contain substances increasing viscosity, for example sodium carboxymethylcellulose, sorbitol an~/or dextran and, optionally, stabilisers.

.. . . . . .... . . . . . .. . . . . . .

The invention likewise relaSes to the use of the compounds of the formula I or pharmaceutically acceptable, non-toxic salts of such compounds as pharmacologically active substances, especially as anti-hypertensive agents, preferably 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 400 mg, preferably from approximately 50 to approximately 200 mg of active substance.
The following Examples illustrate the above-described invention, with Examples 4, 16, 20, 21 and 23 being included for reference purposes.
Temperatures are given in degrees Centigrade.
Example 1 7.6 g of ethyienediamine are added to a suspension of 37.4 g of the hydroiodide of N-(2,6-dimethyl-4-pyrimidinyl)-S-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 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 isopropanol and in this manner the hydroiodide of 2-l(2,6-dimethyl-4-pyrimidinyl)amino~-2-imidazo-line is obtained, m.p. 269-271.

~; -19-113~131 - 2~ -~ he salt o~tainable in this ~anner is dissolved in 200 ml of water, the solution is rendered alkaline with 2N 3queous sodium hydroxi~e 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-4-pyrimidinyl)amino~-2-imidazoline in the form of white crystals is obtained as the residue, mp. 229-230 . A
further quantity of the product can be obtained ~y extrac-ting the aqueous mother liquor with chloroform.
The hydrochloride of 2-12,6-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.
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 50 ml of chloroform is treated dropwise with 13.1 q of ethoxycarbonyl icothiocyanate and the mixture is refluxed for one hour. On cooling, N-(2,6-dimethyl-4-pyrimidinyl)-N'-ethoxycarbonylthiourea crystallises out and is recry-stallised from 90 ~ aqueous ethanol; it melts at 163 -165 .
70 ml of a lN aqueous sodium hydroxide solution is added to 12.7 g of N-(2,6-dimethyl-4-pyrimidinyl)-N'-ethoxycarbonylthiourea which may be obtained in this manner and the mixture is boiled for one hour. On cooling, N-(2,5-dimethyl-4-pyrimidinyl)tAiourea is precipitated in the form of white crystals, mp. 236-238 .
~ mlxture of 20.4 9 of N-(2,6-dimethyl-4-pyrimidinyl)-thiourea and 13~ ml of methanol is treated with 16.7 g of methyl iodide and the mixture is refluxed for one hour, wh~reupon the starting material goes into solution. The solvent is evaporated under reduced pressure, and the hydro-iodide of N-(2,6-dimethyl-4-pyrimidinyl)-S-methylisothio-urea is obtained as the resid~e in the form of white 113S13~

crystals, mp. 200-205 ; the product is processe further without ?urification.

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-(2,6-dimethoxy-4-pyrimidinyl)-S-methylisothiourea in 750 ml of methanol, and the mixture is refluxed for 6 hours. After the evolution of methyl mercaptan and am~onia 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-[(2,5-dimethoxy~-pyrimidinyl)amino]-2-imidazoline is obtained, mp. 1~7-200 .
39.6 ml of a 2.26N solution of hydrogen chloride in ethanol is added to a suspension of 20 ~ of 2-[(2,6-dimethoxy-4-pyrimidinyl)amino~-2-imidazoline and 200 ml of ethanol.
The solution which may be obtained in this manner is con-centrated under reduced pressure after filtration, and ethyl acetate is added thereto in portions, whereupon crystallisa-tion commences. The crystalline material is filtered off and yields the hydrochloride of 2-[(2,6-dimethoxy-4-pyrimidinyl~amino~-2-imidazoline, mp. 193-195 .
The startinq 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 chloro-form 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. ~he mix-ture is cooled, the precipitate is filtered off ~nd washed with a mixture of ethanol and ethyl acetate. N-~2,6-dimethoxy-4-pyrimidi~yl~-N'-ethoxycarbonylthiourea is obtained in the form o~ yellow crys~als, mp. 177-180 .

A mixtur~ of 14.3 g of N-~2,6-dimethoxy-4-pyrimidinyl)-N'-ethoxycarbonylthiourea and 90 ml of lN
aqueous sodium hydroxide solution is refluxed for gO
minutes, whereupon the starting material first of all goes into solution and the crystalline product is then precipi-tated. This is filtered o~f, washed with water an~
suspended in lO0 ml of a hot l:l ~ixture of isopropanol and petroleum ether. N-(2,6-dimethoxy-4-pyrimidinyl)-thiourea is obtained in the form o~ yellow crystals, mp.
237-238 .
A suspension of 24.4 g of N-(2,4-dimethoxy-4-pyrimi-dinyl)thiourea in 2500 ml of acetone is treated dropwise ~ith o4.8 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 after-wards and deposits a crystalline ~aterial. This is filtered off, and yields the hydroiodide of N-(2,6-dimethoxy-4-pyrimidinyl)-S-methylisothiourea, mp. 1~5-187 , which is used without further purification.

Example 3 12.3 g of 4-amino-2-dimethylpyrimidine and 18.3 9 of tne hydroiodide of 2-methylthio-2-imidazoline are pulverised and thoroughly mixed, then heated to 2 bath temperature of 190 , at which temperature splitting off of methyl mercaptan commences. The bath temperature is lowered to 170 ; the mixture is left at this temperature one hour, is then 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 residue is taken up in a mixture of isopropanol and acetone an~
filtered; the residue is the hydroiodide of 2-~(2,5-dimethyl-4-pyrimidinyl)amino~-2-imidazoline and is partitioned between 2N aqueous sodium hydroxide solution and methylene chloride. The org~nic phase is separated, dried over ~13~131 magnesium sulphate and concentrated by evaporation. 2-[(2,6-Dimethyl-4-pyrimidinyl)amino]-2-imidazoline is obtained as semi-crystalline product which is taken up in wa.er and 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 2N aqueous sodium hydroxide solution is added to the solution which is then cooled. The crystalline preci~itate is filtered off; it melts at 227-229 .

Example 4 A solution of 11 g of the hydroiodide of N-(4,6-dimethoxy-2-methyl-5-pyrimidinyl)-S-methylisothiourea and 2.1 g of ethylenediamine in 100 ml of absolute ethanol is refluxed for 10 hours. The mixture is subsequently concentrated by evaporation under reduced pressure, the residue is stirred thoroughly with a saturated aqueous solution of sodium carbonate and the precipitate is filtered off.~ After recrystallisation from dimethylformamide, 2-~(~ ,4-dimethoxy-2-methyl-5-pyrimidinyl)amino~-2-imidazoline is obtained, mp. 229 .
The starting material is prepared as follo~s:
6 ml of benzoyl chloride is added to a solution of 4.2 g of ammonium thiocyanate in 25 ml of acetone; the mixture is boiled up for a short while, and then treated dropwise with a solution of 8.5 9 of 5 amino-4,6-dimethoxy-2-methyl-113~131 pyri~idine in 45 ml of acetone. Subsequently, the mixture is refluxe~ for lS ~inutes and then the reaction solution is poured into 500 ~1 of water. The precipitated product is filtered off and washed well with water, then dissolved in a hot solution of 8 9 of so~ium hydroxide in 80 ml of water. The mixture is refluxed foc 5 minutes, cooled, the pH is adjusted to 9 by the addition o~ 2N hydrochloric acid, w~ereupon N-(4,6-dimethoxy-2-methyl-5-pyrimi~inyl)thiourea crystallises out, which, after recrystallisation from a mixture of water and dioxan, melts at 214-215 .
A mixture of 8.9 9 of N-(4,6-dimethoxy-2-methyl-5-pyrimidinyl)thiourea and 8.5 g of methyl iodide in 800 ml of methanol is refluxed for 3 hours and then concentrat~d intensively under reduced pressure. The hy~roiodide of N-(4,6-dimethoxy-2-methyl-5-pyrimidinyl)-S-methylisothio-urea thereupon crystallises out, mp. 168-170 , and is processed further without purification.

Example 5 A mixture of 40.0 g of the hydroiodide of N-(2,6-dimethyl-4-~yrimidinyl)-S-methylisothiourea and 18.3 g of propylenediamine are refluxed for 6 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-dimethyl-4-pyrimidinyl)amino]-1,4,5,6-tetrahydropyrimidine is obtained, mp. 161-163 , whlch is converted into the hydrochloride as follows :
~ o 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 con-centrated under reduced pressure to approximately one third of its volume and diluted portion-wise with ethyl ~36,131 - 2~ -acetate. The crystalline precipitate is filtered off and yields the dihydroc~loride of 2-[(2,6-dimethyl-4-pyrimidinyl)amino]-1,~,5,5-tetrahydropyrimidin~, mp. 255 -258 .

Example ~
A solution of 2~.6 9 of N-(6-chloro-2-methyl-4-pyrimidinyl~-S-methylisothiourea hydroiodide in 300 ml of methanol is added dropwise to a solution of 7.2 g of ethylenediamine in ~0 ml of methanol. The internal tempera-ture of the mixture is ~5 and is maintained for ~ hours.
~hen 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 -209 .
The hydrochloride is obtained by suspending 16.6 9 of the crude base in 20~ ml of hot ethanol and adding thereto 34.1 ml of 2.3N ethanolic hydrochloric acid, filtering the resulting clear solution with active char-coal and concentrating it on the rotary evaporator to approximately 80 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.
299-301 (decomposition~.
The isothiourea serving as starting material is obtained as follows :
a) 65.2 9 of 4,6-dichloro-2-methylpyrimidine are stirred in 750 ml of ethanol with 100 g of liquid ammonia in an autoclave for 12 hours at 80 , 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. By evapora-tion to approximately 100 ml further quantities of 4-amino-6-chloro-2-methylpyrimidine are obtained from the aqueous mother liquor. The combir.ed crude products are redissolved fro~ ethyl acetate, mp. 185-187 .
b) 28.7 g of the purified product are dissolved in 20C
ml of cnloroform and 50 ml of dimethylformamide; 20.2 g of ethoxycarbonyl isothiocyanate are ~dded to the solution and the ,~ixture is heated for 2 hours at 80 . The mixture is cooled, evaporated, and the residue, N -(6-chloro-2-methyl-4-pyrimidinyl)-N -ethoxycarbonylthiourea is recry-stallised from ethanol, mp. 142-143 .
c) by hydrolysis with lN sodium hydroxide solution ll hour, 130 ), N-~6-chloro-2-methyl-4-pyrimidinyl)thiourea of melting point 230 (discolouration and sintering) is obtained.
d) 13.5 g of this thiourea are suspended in 1500 ml of acetone, 37.8 g of methyl iodide are ~dded and the mixture is re~luxed for 2 hours. After 15 minutes dissolution occurs. The solvent is evaporated on a rotary evaporator, the crystals remaining are suspended in ether and isolated, mp. 179 (decomposition). They are the isothiourea hydroiodide mentioned as starting material.

Example 7 10.6 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 S0 ml of lN hydro-chloric acid, 1 g of 10 ~ palladium-on-carbon is added and the mixture is shaken with hydrogen at 48 under slight excess pressure (0.2 barJ. After absorption of the cal-culated a~ount (1120 ml), the shaking is interrupted, the mixture is filtered, concentrated by evaporation on the rotary evaporator and the crystalline residue is recry-stallised hot in e~hanol/methanol 1:1. The resulting crystals of the dihydrochloride of 2-~(2-methyl-4-pyrimidinyl)amino3-2-imidazoline melt at 252-255 .

Example ~
24.0 y of N-(6-chloro-2-methoxy-4-pyrimidinyl)-S-methylisothiourea hydroiodide are dissolved in 300 ml of methanol and added dro3wise to ~.~ g of ethylen~diamine in 75 ml of methanol. The mixture is heated for 6 hours at reflux temperature whilst stirring, whereupon crystalli-sation 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-~(6-chloro-2-me~hoxy-4-pyrimi~inyl)amino~-2-imidazoline of melting point 216 -219 is obtained.
Hydrochloride : 11.5 g of base are suspended in 50 ml of methanol, and 1 equivalent of 2.4~ 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 lO~ ml of acetone, the hydrochloride of 2-[(6-chloro-2-methoxy-4-pyrimidinyl)amino]-2-imidazoline of mp. 220 precipitates as crystals.
The i~othiourea used as starting material is obtained analogously to Example 5 :

a) N -(6-chloro-2-methoxy-4-pyrimidinyl)-N -ethoxy-carbonylthiourea of mp. 160-164 is obtained from 63.8 g of 4-amino-6-chloro-2-methoxypyrimidine (prepared from 2,6-dichloro-4-aminopyrimidine and sodium methanolate in methanol at 80 external temperature) and 52.4 g of ethoxycarbonyl isothiocyanate in boiling acetone.
b) the hydrolysis of this ester with 150 ml of 1~ sodlum hydroxide solution at boiling heat yields a crystalline precipitate. So~ution and precipitate are rendered weakly acidic with 1~ ml of glacial acetic acid, whereupon decar~oxylation occurs with foaming. N-~6-chloro-2-methoxy-~ Trade ~ark - translator.

113tj131 - ~3 -~-pyrimidinyl)thiourea is isolated, mp. above 33Q , ~nd is washed with ~ater.
c) the resulting urea is converted, ~s in Example ~, with methyl iodide into the isothioure3 hydroiodide, mp.
167 (decomposition) mentioned as starting material.

Example 9 ll.S g of 2-~(6-chloro-2-methoxy-4-pyrimidinyl)amino]-2-imidazoline obtained in accordance with Example 8 are suspended in 200 ml of methanol and 100 ml of dimethylformamide (~urissimum) and 2 g of 10 ~ palladium-on-carbon catalyst are added and the mixture treated with hydrogen at 0.2 bar excess pressur~ and a temperature of 49 . The absorption of hydrogen progresses more slowly than in Example 7. After it has finished, the catalyst is filtered, the mother liquor is concentrated by evapora-tion on a rotary evaporator, 100 ml of lN sodium hydroxide solution is added to the residue and the residue is extracte 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, 1 eq~ivalent of ethanolic hydrochloric acid, then, by adding acetone and ethyl acetate, it is precipitated as crystals.
The resulting 2-[(2-methoxy-4-pyrimidinyl)amino]-2-imidazoline hydrochloride melts at 170-172 (decomposition).

Example lO
22.75 q of the 2-[(6-chloro-2-methoxy-4-pyrimidinyl)-amino]-imidazoline prepared in accordance with Example 3 are dissolved in lOO ml of lN aqueous hydrochloric acid and 300 ml of water, 2 g of lO ~ palladium on carbon catalyst are added thereto, and the mixture is hydrogenated at 0.2 ~ar excess pressure and 60~ internal temperature.After a~sorpti~n of 2320 ml ~calculated 2240 ml) the hydrogenation is broken off, the mixture is suctioned off the catalyst and concentrated fully oy evaporatio., on a rotary evaporator. The residu2 is eva-~orated twice with 100 ml of alcohol, the crystals are sus-?ended hot in 150 ml of isopropanol and again isolated. As a result of the methoxy group splittins off, 2-[2-(hy~roxy-4-2yrimidinyl)~mino]-2-imidazoline hydrochloride has formed, and has a melting point of 256-258 (decomposition).

Example 11 23.0 g of N-(6-chloro-2-dimethylamino-4-pyrimidinyl)-S-methylisothiou.ea hydroiodide are dissolved in 400 ml o methanol and ad~ed dropwise to a solution of 9.0 g of ethylenediamine in 7; ml of methanol. ~he 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 concen-trated on a rotary evaporator to approximately 75 ml, suc-tion-filtered, the crystalline portion is stirred with 150 ml of water, is isolated, and washed with water and isopro-panol. The resulting 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline melts at 268-271 After re-crystallisation from dimethylsulfoxide-methano~ the product melts at 278-279~.
The resulting base has the calculated amounts of 2N
aqueous hydrochloric acid added to it, whereupon the hydro-chloride partially crystallises. By addition of 4 times 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 hydrochloride melts at 279-280 .
At room temperature 3.42 g o methanesulphonic acid are added to a suspension of 7.8 g of base in 300 ml of water, whereu2on a clear solution is obtained. The solution is evaporated to dryness, and the residue is recrystallised from methanol/ether. The methanesulphonate obtained in this manner melts at 25~-259 .
The isothiourea used as starting ~material is obtained ~nalogously to Example 6 :

~3.3~131 - 3û -a) 4-Amino-6-chlor~2-dimethylamin~pyrimidine of melting point 151-152 is prepared from 4-amino-2,6-dichloro-pyrimidi-ne with dimethylamine in methanol in exothermic reaction.
34.5 g of this compound are reacted with 26.2 g of ethoxycarbo-nyl isothiocyanate in 150 ml of acetone under reflux to give Nl-(6-chloro-2-dimethylamino-4-pyrimidinyl)-N3-ethoxy-carbonyl-thiourea, mp. 206-208.
b~ The hydrolysls of this compound with 170 ml of lN
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-2-dimethylamino-4-pyrimidinyl)thiourea melts at 235 (decom-position).
c) 29.0 g of this thiourea are suspended in 2.9 litres of acetone and 71 g of methyl iodide are added. On reflux-ing, the suspension goes into solution and crystallises out again shortly afterwards. The mixture is cooled and the crystalline precipitate of N-(6-chloro-2-dimethylamino-4-pyrimidinyl)-S-methylisothiourea hydroiodide of melting point 220 (decomposition) is isolated.

Example 12 11.1 g of 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)-amino~-2-imidazoline base (prepared according to Example 11), are dissolved with 19.5 ml of lN hydrochloric acid and 80 ml of water, and hydrogenated with hydrogen wit'n 2 g of 10 ~ palladium-on-carbon at 0.2 bar excess pressure.
The temperature is 52-55 . After 15 hours, the calculated amount of hydrogen (438 ml~ has been taken up. The sblution is filtered off the catalyst, the aqueous mother liquor is concentrated on a rotary evaporator, the residue is dissolved in 75 ml of isopropanol and is allowed to crystal-lise. The resulting 2-E(2-dimethylamino-4-pyrimidinyl)-amino~-2-imidazoline dihydrochloride melts at 275-278 (decomposition).

113~131 Example 13 In the same manner as described in Exampl~ 11, from 11.5 9 of Ithylenediamine in lOC ml of methanol, to which 38.0 g of N-(6-chloro-2-diethylamino-4-pyrimidinyl)-S-met~ylisothiourea hydroiodide in 200 ml of methanol are added dropwise, there is obtained after ~ hours' stirring under reflux 2-[(6-chloro-2-diethylamino-4-pyrimidlnyl)-amino3-2-imidazoline base of melting point 231-232 .
By suspending 21.5 g of the base in 50 ml of methanol and adding two equivalents (67 ml) of 2.39N ethanolic hydrochloric acid, followed by 300 ml of ethyl acetat~, the dihydrochloride is obtained, which, on drying in high vacuum, is transformed into the monohydrochloride of ~elting point 2C3-2C5 .
The starting material for the above-described synthesis can be obtained in analogy to Example 11 :
a) from 4-amino-2,6-dichloropyrimidine with an excess of diethyla~ine in methanol at 80 external temperature, 4-amino-6-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 28.5 ~
of ethoxycarbonyl isothiocyanate in ~oiling acetone, N -(6-chloro-2-diethylamino-4-pyrimidinyl)-N -ethoxycarbonyl thiourea melting at 141-145 is obtained;
c) by hydrolysis of 48.0 g of the resulting ester with 250 ml of lN sodium hydroxide solution under reflux, ~
chlorc-2-diethylamino-4-pyrimidinyl)thiourea of melting point 175-180 is obtained; and d) from this crude thiourea (~5.8 g) with 40 9 of methyl iodide in 750 ml of acetone under reflux, ~ c~loro-2-diethylamino-4-pyrimidinyl)-S-methylisothiourea hydroiodide of meltin~ point 178-l~Q (decomposition3 used as starting material i~ obtained.

113~31 Example 14 In the sa.~e .~anner as described in ~xamples 11 ana 13, 2-[(o-chloro-2-di-n-butylamino-4-pyrimidinyl)amino]-2-imidazoline and its hydrochloride are obtained from N-(6-chloro-2-di-n-butylamino-4-pyrimidinyl)-S-methylisothio-urea hydroiodide and ethylenediamine in m~thanol. The free base melts at 167-168 , and the hydrochloride at 148-150 .
The starting material for this dibutylamino derivative is obtained in the same reaction sequence as described in Examples 11 and 13 from 4-amino-2-di-n-butylamino-6-chloro-pyrimidine.

Example 15 10.3 g of ethyler.ediamine are introduced into 40 ml of methanol and, whilst stirring, at 70 3C.3 g of N-(5-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 tem-perature. The solvent with the s~spended crystals is 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 s~dium hydroxide solution.The crystall~e base is isolated, washed twice with warm water, then treated with isopropanol and ether. In this manner, 2-[(Ç-dimethylamino-2-methyl-4-pyrimidinyl)amino~-2-imidazoline mp. 28~-288 is obtained which is shown to be analytically pure.
Its hydrochloride is obtained as monohydrochloride, mp~ 281-283 , by suspending the b~se in isopropanol, adding 1 equivalent of ethanolic 2.3N hydrochloric acid, and precipitating ~ith ethyl acetate.

113~31 The starting material for th~ above described synth~sis can be obtained analogously to Examples 11 and 13 :
a) from 4-amino-6-chloro-2-methyl pyri~idine melting at 185-1~7 used in Example 6 and 4 times the theoretical amount of di~ethylamine in methanol, at 120 in a pressurized vessel 4-amino-6-dimethylamino-2-methyl pyrimidine of mp. 176-179 is obtained;
b) by reacting 2g.0 ~ of this pyrimidine with 25.0 of ethoxycarbonyl isotniocyanate in boiling c`nloroform, N -(6-dimethylamino-2-methyl-4-pyrimidinyl)-N -ethoxy-carbonylthiourea is obtained, melting at 140-143 (after recrystallisation from alcohol);
c) by hydrolysing 31.0 q of the resulting ester with 2~0 ml of lN sodium hydroxide solution at boiling temperature, ~-(6-dimethylamino-2-methyl-4-pyrimidinyl)thio-urea melting at 245-247 is obtained; and d) from 19.3 g of this resulting thiourea, with 51.3 g of methyl iodide in 2000 ml of acetone and 200 ml of methanol N-(6-dimethylamino-2-methy1-4-pyrimi~inyl)-S-methyl-isothiourea hydroiodide melting at 225-227~ is obtained under reflux.

Example 16 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-dihyd-roxy-5-pyrimidinyl)-S-methylisothiourea hydroiodide in 500 ml of warm methanol, and the whole is refluxed fox 15 hours.
After a short time, a white precipitate ~egins to form. The mixture is cooled, filtered with suction and the precipitate, which, in addition to the imidazoline ~ase also contains hydroiodide that is not readily soluble and non-reacted iso-thiourea hydroiodide, is washed several times in the course of 12 hours with water of 50 which contains lO % methanol. The melting point thereby rises from 268~ ~decomposition) to 290 ~decomposition) and finally remains constant at 328-330.

113~i~31 The latter melting point corresponds to the pure 2-[(2,6-dihydroxy-5-pyrimidinyl)amino]-2-imidazoline which is present for the most part in its tautomeric for~, 2-[(2,6-dioxo-1,2,3,6-tetrahydro-5-pyrimidinyl)amino]-2-imidazoline.
The hydrochloride is obtained by dissolving 7.5 g of the base in 38.5 ml of lN hydrochloric acid under heat.
The solution is filtered, concentrated ~y 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 crystallisation occurs. Mp. 275 ~decomposition).
Hydrochlorides (mp. 133 , decomposition) containing water of crystallisation are dried in high vacuum until a melting point of 275 is reached.
The starting material for the above described synthesis is obtained in analogy to Examples 11, 13 and 15 in the following manner :
a) 12.5 g of 5-aminouracil are suspended in 150 ml of dimethyl sulphoxide and 13.1 g of ethoxycarbonyl isothio-cyanate are added. The mixture is stirred for 3 hours at 60 , a clear solution is obtained, this is poured into water, suction-filtered and N -(2,6-dihydroxy-5-pyrimidinyl)-N -ethoxycar~onylthiourea is o~tained which is suspended in boiling acetone to purify it. Mp. > 300 ;
b) by hydrolysing this compound (12.~ 9) for one hour with 150 ml of lN sodium hydroxide solution, at reflux temperature, by cooling, adding a total of 50 ml of glacial acetic acid, crystalline N-(2,6-dihydroxy-5-pyrimidinyl)-thiourea of mp. > 30G is obtained, which is suspended in hot isopropanol to purify it;
c) by reacting 27.9 g of tnis compound with 21.3 g of methyl iodide in lB00 ml of methanol and lOaO ml of dimethylformamide at 83 , N-(2,6-dihydroxy-5-pyrimidinyl)-S-methylisothiourea hydroiodide of melting point 245 (decomposition) is obtainQd.

~13~131 - 3~ -Example 17 To a solution of 8.5 g of ethylenediamine in 80 ml of methanol,the solution of 26.0 g of N-~2,6-diethyl-5-methyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide in 250 ml of metha-nol 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 ~ase melting at 128-131 are obtained, which are converted into the hydrochloride of 2-[t2,6-diethyl-5-methyl-4-pyrimidinyl)amino]-2-imidazoline by dissolving 13.8 g of the base in ethanol, adding 32.0 ml of 1.82N ethanolic hydrochloric acid and bringing the hydrochloride to cry-stallisation with a little ether. Mp. 190-192 .
The starting material for the above described synthesis can be obtained analogously to Examples 11, 13, 15 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 dimethyl-formamide, and 26.2 g of ethoxycarbonyl isothiocyanate, after 3 hours refluxing N -(2,6-diethyl-5-methyl-4-pyrimidinyl)-N -ethoxycarbonylthiourea of melting point 85-89 is obtained.
b) From 49.5 g of this compound, N-(2,6-diethyl-5-methyl-4-pyrimidinyl)thiourea melting at 151-154 is obtained by hydrolysing with 100 ml of 2N sodium hydroxide ~olution, under reflux, and neutralising with glacial acet~c acid to p~ 5.
c) From 17.1 ~ of this compound and 43.2 g of methyl iodide in 400 ml of hot acetone, N-(2,5-diethyl-5-methyl-4-pyrimidinylj-S-methylisothiourea hydroiodide melting at 180-182 is obtained.

113~i131 Example 13 27.0 g of N-(2-phenyl-4-pyrimidinyl)-S-methylisothio-urea hydroiodide in 300 ml of methanol, are added dropwise to 9.0 g of ethylenediamine in 100 ml of methanol. The mixture is heated at 8~ for 6 hours, whilst stirring, evaporated to dryness on a rotary evaporator, the crystal-line compound is suspended in ~ater, then in isopropanol-ether mixture and in this manner 2-[(2-phenyl-4-pyrimidinyl) -amino]-2-imidazoline melting at 230-232 is isolated.
From 1~ g of the imidazoline base, the dihydrochloride is obtained as crystals melting at 255-2S7 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 vla 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-pyrimidinyl)-N -ethoxycarbonyl-thiourea melting at 185-188 is obtained;
b) from 66.4 g of the ester, ~-(2-phenyl-4-pyrimidinyl)-thiourea melting at 237 (decomposition) is obtained by hydrolysis with 300 ml of lN sodium hydroxide solution at boiling heat;
c) from 38.3 g of this thiourea and 100 g of methyl iodide in 3.8 litres of boiling acetone, ~-(2-phenyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide melting at 20~ (decomposition) is obtained.

xample_l9 22.8 g of ~-~2-phenyl-4-pyrimidinyl)-S-methylisothio-urea hydroiodide (starting material from Example 18) and 9.~ g of propylenediamine (1,3-diaminopropane) are refluxed in 3~ ml o~ methanol for 5 hours whilst stirring. The mixture is evaporated to dryness on the rotary evaporator, the oily residue is partitioned between 300 ml of water and . .

i131 - 3~ -300 ml of chloroform, and the organic p~ase is dried and evaporated and brought to crystallis3tion with 50 ml of ethyl aceta'_ and 25 ~1 o~ ether. The resulting 2-~(2-phenyl-4-pyrimidinyl)amino]-1,4,5,6-tetrahydropyrimidine melts at 166-169 .
From this base, the monohydrochloride of melting point o o 255 (sintering from 246 ) is o~tained in acetone with one equivalent of ethanolic hydrochloric acid.

Example 20 A solution of 44.1 g of the hydroiodide of N-(2-methyl-

5-pyrimidinyl)-S-methylisothiourea and 17.6 g of ethylenedi-amine in 400 ml of absolute ethanol is refluxed for 12 hours. After filtration an~ concentration by evaporation to dryness, the oily residue is partitioned between 400 ml of chloroform and approximately 325 ml of a semi-saturated soda solution, the layers are separated and subsequently the agueous layer is extracted several times with chloro-form. The combined chloroform extracts, after drying and concentration, when petroleum ether is added to them give a cry~talline precipitate of 2-~(2-methyl-5-pyrimidinyl)-amino]-2-imidazoline melting at 187-189 .
Ether and a little ethyl acetate are slowly added to a solution produced by heating 21.3 g of the above base in 200 ml of isopropanol and 12.2 9 of methanesulphonic acid, whereupon crystallisation gradually occurs. The resulting methanesulphonate of 2-~2-methyl-5-pyrimidinyl)-amino3-2-imidazoline, after recrystallisation from a mixture of methanol and acetone, melts at 149-151 .
The hydroiodide of N-(2-methyl-5-pyrimidinyl)-S-methylisothiourea can be prepared as follows :
Approximately 42 9 of ethoxycar~onyl isothiocyanate are added dropwise to a solution of 25.5 9 of 2-methyl-5-aminopyrimidine in 750 ml of chloroform at room temperature and the ~lxture is then stirred for one hour at room tem-perature and for two and a half hours under reflux. After . _ _ _ . _ . _ , .. . ,, _ ., , , . ... . . _ . . ... . . .

113~13~
- 3~ -concentration by evaporation _o dryness, the solid residue is recrystallised from boiling absolute ethanol. In this manner, .~-(2-methyl-5-pyrimidinyl)-N'-ethoxycarbonylthio-urea melting at 183-185 is obtained.
390 ml of a lN aqueous sodium hydroxide solution are added to 53 g of the N-(2-methyl-5-pyrimidinyl)-N'-ethoxy-carbonyl thiourea thus obtained. The resulting solution is refluxed for 3 hours, cooled, and the pH is ad~usted to approximately 8 b~ the addition of 6N hydrochloric acid, whereupon N-(2-methyl-5-pyrimidinyl)thiourea crystallises out, and, after recrystallisation from boilin~ absolute ethanol, melts at 191-193 with decomposition.
A suspension of 28.75 g of the above N-(2-methyl-5-pyrimidinyl)thiourea and 113 g of methyl iodi~e in 1400 ml of acetone is heated to reflux, whereupon the starting material dissolves. Approximately 20 minutes later, crystals precipitate. The solution is boiled for a further one and three-quarter hours, is cooled to room temperature, the hydroiodide of N-(2-methyl-5-pyrimidinyl)-S-methyliso-thiourea is suction-filtered and washed with a little acetone and ether. Melting point approximately 152 with decomposition.
By concentration in vacuo , a further ~uantity of the crystalline hydroiodide can be obtained from the mother liquor.

Example 21 In an analogous manner the following are obtained :
a) 2-~(5-pyrimidinyi)amino]-2-imidazoline melting at 232-234 from N -(5-pyrimidinyl)-N -ethoxycarbonylthio-o ourea, mp. 191-193 ; the hydrochloride melts at 241-243 (decomposition);
b) 2-1(2-n-b~tyl-5-pyrimidinyl)amino3-2-imidazoline of meltin~ point 145-1~7 from N -~2-n-butyl-5-~yrimidinyl) -N -ethoxycarbonylthiourea, m~. 13~-135 ; the methane-sulphate ~elts at 10~ to 102 ;

... . _ . _ _ _ .. .. . _ .. , , .. .. .... , .. . ...... ... .. . .... .. ... .. _ . . . . .. _ , . . . . ..
.. .. .

_ ~9 _ c) 2-[(2-phenyl-5-pyrimidinyl)amino]-2-imidazoline of melting point 25~-252 from N -(2-phenyl-5-pyrimidinyl)-;1 -ethoxycarbonylthiourea, mp. 195-198 ; the hydro-chloride melts at 230-233 .
d) 2-[(6-chloro-2-(4-morpholino)-4-pyrimidinlyl)amino]-2-imidazoline of melting point 250-252 from N -(6-chloro-2-(4-morpholino)-4-pyrimidinyl)-N -ethoxy-carbonylthiourea, mp. 185-189 ; the hydrochloride melts at 274-275 .

Example 22

6.12 g of ethylenediamine are added to a suspension of 18 g of N-(2-dimethylamino-~-methyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide in 180 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 suction-filtered and washed with isopropanol and ether. The resul-ting 2-~(2-dimethylamino-6-methyl-4-pyrimidinyl)aminol-2-imidazoline melts at 280-283 .
4.5 g of methanesulphonic acid are added to a suspen-sion of 10.35 g of this base in 300 ml of a~solute 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 the methanesulphonate of melting ooint 226-228 is deposited.
The isothiourea used as starting material is obtained analogously to Example 6 :
4-amino-2-dimethylamino-6-methylpyrimidine is reacted with 11~15 g of ethoxycarbonyl isothiocyar.ate in 200 ~1 Oc absolute tetrahydrofuran under reflux to give ~ -(2-dimethylamino-6-methyl-4-pyrimidinyl)-N -ethoxycarbonyl-thiourea of melting point 199-2~1 .
This compound is refluxed with 180 ml of sodium hydroxide solution and 1~ ml of ethanol for 2 hours. The ... , . . , .. , . . . . . . .. . . , _ , 1136~31 -- ~C --mixture is conc~ntrated in vacuo znd adjusted to ~H 7.5 with 2~ hydrochloric acid; the crystalline mash is suction-filtered. After recrystallisation from boiling alcohol, the resulting N-(2-dimethylamino-6-methyl-4-pyrimidinyl)-thiourea melts at 241-243 .
10.9 9 of this thiourea are suspende~ in 1.2 litres of acetone and 29.5 g of methyl iodide are added thereto.
Cn refluxing, the suspension goes into solution and cry-stallises out again shortly afterwards. The mixture is refluxed for a further hour and the crystalline precipitate of N-(2-dimethylamino-6-methyl-4-pyrimidinyl)-S-methyliso-thiourea hydroiodide melting at 211-214 is suction-filtered.

Example 23 In one portion, 6.4 g of N-(2-diethylamino-5-pyrimidinyl)-S-methylisothiourea hydroiodide ar~ added to a solutlon of 2.1 g of ethylenediamine in 40 ml of methanol, and the mixture is refluxed for ~ hours. The yellow reaction solution is concentrated by evaporation under reduced pressure. 75 ml of 2~1 sodium hydroxide solution are added to the residue and the mixture ls extracted by shaking with petroleum ether to remove the 5-amino-2-dimethylaminopyrimidine. The aqueous-oily layer is extracted several times with ethyl acetate. After recry-stallisation from ethyl acetate, 2-[(2-diethylamino-5-pyrimidinyl)amino~-2-imidazoline of melting point 1~9-171 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 point 144-147 crystallises out.
The isothiourea used as starting material is ~re-pared as follows:

1136~31 29.~ g of N,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 ~60 ml of ethanol, and the ~ixture 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 pyrimidine of melting ~oint 235-240 (decomFosition) is precipitated.
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-diethyla~ino-4,5-dihydroxy ~yrimidine are then added in portions. ~hen 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-4,5-dihydroxy-5-nitropyrimidine melting at 280-282 (decomposition) is suction-filtered.
25.1 g of 2-diethylamino-4,6-dihydroxy-5-nitropyrimi-dine are refluxed for 90 minutes in 150 ml of phosphorus oxychloride and 38 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 o~tained from the ether phases is recry-stallised from cyclohexane. In this manner, 2-diethylamino-4,6-dichloro-5-nitropyrimidine of melting point 31-93 is obtained.
24.5 g of 2-diethylamino-4,6-dichloro-5-nitro-pyrimidine are hydroqenated in 250 ml of ethanol with 12 g of Raney nickel as the catalyst. After absorption of 3 mole equiYalents of ~ydrogen, the mixture is fi~tered off the catalyst and the filtrate acidified with 3~ alcoholic hydrochloric acid. Subsequently, the solution is inten-sively concentrated under reduced pressure until crystalli-sation commences. The crystals are suction-filtered and 113~131 in this ~anner 2-dietAylamino-4,6-dichloro-5-amino2yrimidine dihydrochloride is obtained.
20.5 g of 2-diethylamino-4,6-dichloro-5-aminopyrimi-dine dihydrochloride are hydrogenated at room temperature in 60~ ml of ethanol with 2 g of palladium-on-carbon (5 ~) as the catalyst, and 23 g of anhydrous sodium acetate.
~fter absorption of 2 mole e~uivalents of ~ydrogen, the mixture is filtered t~ remove the catalyst and the precipitated inorganic salts, and the filtrate is rendered strongly acidic with excess 8~ alcoholic hydrochloric acid and con-centrated by evaporation to dryness under reduced pressure.
The oily residue, which contains 2-diethylamino-5-~minopyrimidine 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 concentra-ted by evaporation to dryness ln vacuo. The residue is chroma-tographed on silica gel by eluting with toluene with an in-creas~ng addition of ethyl acetate. In this manner N1-(2-diethyl-amino-5-pyrimidinyl)-N3-ethoxycar~onylthiourea of melting point 130-132 is obtained.

7.35 g of N -(2-diethylamino-5-pyrimidinyl)-N -ethoxycarbonylthiourea are refluxed for 1 hour with 70 ml of lN sodium hydroxide solution. After coolin~, the reaction mixture is adjusted to pH 8, the precipitated crystals are suction-filtered, and recrystallised from ethyl acetate-petroleum ether. In this manner N-(2-diethylamino-5-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 ~ethyl iodide. The reaction solution is concentrated by evaporation and the residue crystallised from ethyl acetate with the addition of ether. In this manner ~-(2-diethyl-amino-5-pyrimidinyl)-S-methylisothiourea hy~roiodide of melting point 175-177 is obtained.

113S13~
- ~3 -Example 24 A mixture of 6.6 g of 2-[(5-chloro-2-dimethylamino-5-methyl-4-pyrimidinyl)amino~-2-imidazoline hydro-chloride, 2~0 ml of acetic acid and 30.25 ml of 1.5N hydro-chloric acid in glacial acetic acid is hydrogenated at 35 C and a press~re of 4 bars with the addition of 1.3 g of 2 13 % palladium-on-carbon catalyst until absorption of l 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-4-pyrimidinyl)amino~-2-imi~azoline hydrochloride which melts at 263 (decomposition) is obtained as a colourless crystallisate.
The starting material is prepared in accordance with Example 29.

Example 25 5.26 g of N-(6-chloro-2-dimethylamino-4-pyrimidinyl)-dithiocarbamic acid methyl ester are refluxed for 8 hours with 1.3 g of ethylenediamine in 50 ml of acetonitrile.
The solvent is then evaporated ln vacuo and l-(6-chloro-2-dimethylamino-4-pyrimidinyl)-3-(2-aminoethyl)thiourea obtained as residue is freed from moisture still adhering to it by evaporation with toluen~.
The dar~ oil remaining is heated in S0 ml of diphenyl ether for 2 hours at 200 . Thereupon the solvent is distilled off in a bulb tube under vacuum, the semi-crystalline residue is stirred with water, filtered, and the product is washed with water and isopropanol. The resulting 2-~(6-chloro-2-di~ethylamino-4-pyrimidinyl)amino~-2-imida~
line melts at 278-279.
~ -~6-chloro-2-dimethylamino-4-pyrimidinyl)dithio-carbamic acid methyl ester used as starting material can be prepared in the following manner :

113~i131 - ~4 -~ of 4-amino-5-chloro-2-dimethylaminopyrimi~ine are introduced into 100 ml of dimethylformamide. To this mixture are added in portions over S minutes 2.4 g of sodium hydroxide at 0 , and the mixture is stirred for 15 minutes. 1.5 ml of carbon disulphide are added dropwise at 0-5 , and the whole is stirred for 30 minutes 1.2 g of sodium hydride ~re added, again at 0-S , the mixture is stirred for 15 minutes, and then at the same temperature Q.75 ml of carbon disulphide is added and stirring is con-tinued for a further 30 minutes. After repeated addition of 1.2 9 of sodium hydride and 0.75 ml of carbon disulphide in the above-described manner, after 30 minutes at 0-5 2.8 ml of methyl iodide are added and the reaction solution 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 p~ 5-6 with 2N hydro-chloric acid. The precipitated product is extracted with methylene chloride, dried and concentrated by evaporation, whereupon N-(6-chloro-2-dimethylamino-5-pyrimidinyl)dithio-carbamic acid methyl ester crystallises out on the addition of ether and is filtered off. Mp. 150-151 .

Example 26 38 g of 6-chloro-2-dimethylamino-g-(dimethylthio-methyleneimino)pyrimidine and 9.2 ml of ethylenediamine in 400 ml of methanol are stirred for 14 hours at 60 .
The precipitated 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline is isolated by filtration and melts at 278-279.
The starting material is prepared as follows :
19.8 g of sodium hydride (~0 ~ in oilj are added in portions to ~ solution of 70 g of 4-amino-6-chlcro-2-dimethylamino-pyrimidine in 75C ml of ~imethylormamlde under a nitrogen atmosphere, whilst being cooled with ice and common salt, in such a manner that the temperature does not excess 10 . The mixture is cooled for a further hour in ~n ice ~13~131 batn until the vigorous evolution of hydrogen ceases. Then 12.' ml of carbon disulphide are added dropwise whilst coolin~ at C-10 ~nd this temperature is maint2ined for one hour. A further 9.9 g of sodium hydride are added in portions at 0-10 . The reaction mixture is stirred for 30 minutes in an ice bath, after which 6.1 ml of carbon 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 9 of sodium hydride and 6.1 ml of carbon disulphide. After addition of the carbon disulphide, the mixture is stirred foc 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 temperature does not rise above 15 . The cooling bath is then taken away and the mixture stirred for a further 2 hours. 20~ ml of water are then slowly added dropwise, whilst cooling with ice, and the reaction mixture is poured onto 2000 ml of water. The preci~itated 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 ar~ dried over sodium sulphate, filtered, and concentrated to a volume of approximately 150 ml. On cooling in an ice bath, colourless 6-chloro-2-dimethylamino-4-(dimethylthio methyleneimino)pyrimidine which melts at 85-S7 crystallises out.
In the same manner, 2-[(2,6-dichloro-4-pyrimidinyl)-amino~-2-imidazoline (mp. 215-217 ) is obtained from 4-amino-2,6-dichloropy{imidine. 2,5-Dichloro-4-(dimethylthio methyleneimino)pyrimldine occurring as intermediate thereby melts at g9-100 .

Example 27 4.7 ~ of 2-~(2,6-dichloro-4-pyrimi~inyl)amino-2-imidazoline and 7.8 ml of alcoholic dimethylamine solution 113~131 - ~6 -(33 ~) are refluxeZ for 90 ~inutes in 30 ml of ethanol.
Th~ 2-~(~-chloro-2-dimethyla~ino-~-pyrimiainyl)a.~ino]-2-imidazoline which has precipitated is suction-filtered whilst still hot and washed with water and ethanol. The product is identical with that of Example 11.
The starting material is prepared according to Example 26.
Example 28 One drop of carbon disulphide is added to a mixture of 1 9 of 6-chloro-2-dimethylamino-4-cyanoaminopyrimidine and 0.5 ml of ethylenediamine and tho mixture is heatod for 1 hour at 100 . The reaction mixture is then con-centrated on a rotary evaporator and the residue is sus-pended in 50 ml of hot ethanol. The insoluble 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)aminol-2-imidazoline is suction-filtere~ whilst hot and melts at 264-268 . After re-crystallisation from dimethylsulfoxide-methanol the melting point rises to 278-279.
The starting material is prepared as follows :
1.75 9 of sodium hydride ~50 % in oil) are added in portions to a solution o~ ~.3 g of 4-amino-6-chloro-2-dimethylaminopyrimidine 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 above 10 . The mixture is cooled for a further 30 minutes in the ice bath until the vigorous evolution of hydrogen ceases. A solution of 3 g of cyanogen bromide in 30 ml of dimethylformamide is then slowly added dropwiâe ~hilst coolin~ with ice, wherein the tem~erature should not exceed 20 . When the addition is complete, the mixture is stirred for a further 30 minutes at 0-10 , and ia 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.
~y recrystallisation of the residue frcm ethanol, crystalline ~-chloro-2-dimethy'amino-4-cyanoamino?yrimidine 113~131 - ~7 -melting at 223-232 is obtained.

~xample 29 2.9 g (0.01 mole) of 6-chloro-2-dimethylamino-4-(dimethylthiomethyleneimino)-5-methyl pyrimidine and 0.6 g (0.01 mole) of ethylenediamine are dissolved in 50 ml of absolute methyl alcohol and the mixture is stirred for 16 hours at 60 . The mixture is then cooled to room tempera-ture and the precipitated 2-[(5-chloro-2-dimethylamino-S-methyl-4-pyrimidinyl)amino3-2-imidazoline is isolated by filtration. The crystallisate is suspended in methyl alcohol, acidified with SN methanolic hydrochloric acid and the clear solution is concentrated 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-dimethyl2mino-S-methyl-4-pyrimidinyl)amino]-2-imidazoline hydrochloride which m~lts at 300 with decomposition is obtained as the colourless crystallisate.
The starting material is prepared as follows :
At 60 reaction temperature, 35.8 g (0.27 mole) of N,N-dimethyl g~anidine 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 mole3 of 2-cyanopropionic acid ethyl ester in 110 ml of absolute methyl alcohol is added dropwise within 30 minutes and the white suspension is boiled for a further one hour. After the mixture has cooled, it is filtered, and the filtrate is adiusted to pH 5-6 with 4.5N methanolic hydrochloric acid. The preci~itated crystallisate is filtered off and washed with cold methyl alcohol and diethyl ether. After drying in a high vacuum at 73 C, 4-aminc-2-dimethylamino-6-hydroxy-5-methyl~yrimidine hydrochloride monohydrate of melting point 285-290 is obtained as ~he colourless 113fjl31 crystallis2te.
A ~ixture of 5.G (0.024~ ~lole) of 4-a,~ino-2-dimethyl-amino-6-hydroxy-5-methylpyrimidine hydrochloride, 22.3 ~1 ~0.244 mole) of phosphorus oxychloride and 2.55 ml (0.0103 mole) of triet~ylamine is refluxed for 9 hours, whilst stirring. The excess phosphorus oxychloride is then distilled off under reduced pressure and the viscous oil cemaining is discharged onto ice water. The reaction temperature rises as ~ar as 50 . ~hen the reaction has subsided, the mixture is stirred for a further one hour at 60 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 55-60 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 chloro-form each time. The combined chloroform extracts are dried with sodium sulphate and concentrated by evaporation under reduced pressure. After recrystallisation of the residue from isopropyl alcohol, with the addition of active carbon, 4-amino 6-chloro-2-dimethylamino-5-methylpyrimidine melting ~t 170-172 is obtained as yellow crystallisate.
Q.33 g (0.0069 mole) of sodium hydride (50 ~ in oil) is added to a solution of 2 g (0.0107 mole) of 4-amino-6-chloro-2-dimethylamino-5-methylpyrimidine in 20 ~1 of absolute dimethylformamide under a nitrogen atmosphere and whilst cooling with ice and common salt, and the mixture is stirred for one hour at 0-5 . 0.2 ml (0.0033 mole) of carbon disulphide is then added whilst cooling at 0-10 C and this temperature is maintained for one hour.
further 0.33 g of sodium hydride is added at 0-5 and stirring is continued for 30 minutes at 0 , whereu~on a further 0.2 ml of carbon disulphide is added and the mix~ure is stirred for one hour whilst cooling ~ith ice.
Then, as described above, the mixture is again treated with 0.34 g of sodium hydride and 0.25 ~1 of carbon disulphide.

... . ... ,, ~

~13f~31 After t~e addition of the carbon disulphi~e, stirring is continue~ for a further one hour in the ice b~th. Whilst cooling with ice an~ common salt, 1.65 ml (0.02~7 mole) of methyl iodide ar~ then added dropwise over the course of approximately 15 minutes such that the temperature do^s 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 S0 ml of ice water and extracted three times with 30 ml of ethyl acetate each time. The com~ined ethyl acetate extracts are dried with sodium sulphate and concentrated by evapora-tion under reduced pressure. By extracting the residue by boiling with petroleum ether, mineral oil is remove2. To remove moisture and traces of dimethylformamide still adher-ing, the mixture is treated with toluene, and 6-chloro-2-dimethylamino-4-(dimethylthiomethyleneimino)-5-methyl-pyrimidine, which is used 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 115-117 oeing obtained~
The following compounds are also prepared in the same manner :
2-[(2-.~ethylamino-4-pyrimidinyl)amino3-2-imidazoline;its hydrochloride melts at 275-280;
2-L(6-Chloro-2-propylamino-4-pyrimidinyl)amino]-2-imidazoline hydrochloride, mp. 23~-234 ;
2-[(6-Chloro-2-(N-methyl-N-propylamino-4-pyrimidinyl)amino)-2-imidazoline hydrochloride, mp. 187-189 ;
2-[(2-Propylamino-4-pyrimidinyl~amino)-2-imidazoline, mp.
23C-233 .
The 4-amino-6-chloro-2-propylaminopyrimidine used as starting material can be prepared in the following manner :
A mixture of 12.3 g of 4-amino-2,6-dichloropyrimidine and 16.4 ml of n-propylamine in 7~ ml of methyl ~lcohol 113~131 - 5~ -is heated to reflux whilst stirring and then the solution, wnich soon becomes cleae, is boiled for a further 16 ~ours.
It is then concentrated by evaporation to dryness under reduced pressure. The residue is rendered alkaline with 2N sodiu.~ 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 ~rom petroleum ether, the solution is filtered off and 4-amino-6-chloro-2-propyl-amino~yrimi~ine melting at 85-90 is obtained.
The 4-amino-6-chloro-2-(~l-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-6-chloro-2-(N-methyl-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 % palladium-carbon catalyst, a mixture of 3.7 g of 4-amino-6-chloro-2-propylaminopyrimidine, 140 ml of glacial acetic acid and 30 ml of 2N hydrochlori_ acid is hydrogenated at room tem-perature and a pressure of 4 bar until 1 mole equivalent of hydrogen has been absorbed. ~he mixture is then filtered to remove the catalyst and the filtrate concentrated by eva-poration under reduced pressure. The residue is rendered alkaline with 2~ sodium carbonate solution, with the addi-tion of ice, and extracted several times with chloroform.
The combined chloroform extracts are drieA with sodium sul-phate, and concentrated ~y evaporation under reduced pressure. The 4-amino-2-propylaminopyrimidine remaining is used without further purification for the following sta~e.

1136,13~ ~

Example 30 The ~ollowing compounds may also be prepared analogously to the methods described in the preceding examples :
2-[(2,6-diethoxy-4-pyrimidinylamino]-2-imidazoline, mp.
193-195 ;
2-~(2-dimethyl2mino-5-methoxy-4-pyrimidinyl)amino~-2-imidazoline, mp. 90-92 ;
2-[(2-isopropoxy-5-methoxy-4-pyrimidinyl)amino]-2-imidazo-line mp. 209-215 ;
2-[(2-butoxy-6-methoxy-~-pyrimiainyl)amino]-2-imidazoline mp. 184-18~ ;
2-[(o-chloro-2-isopropoxy-4-pyrimidinyl)amino]-2-imidazo-line, mp. 210-211 ;
2-[(2,6-bis-dimethylamino-4-pyrimidinyl)amino]-2-imidazo-line, mp. 310-312 and 2-[(2-isopropoxy-4-pyrimi~inyl)amino3-2-imidazoline,mp.261-263.
The startinq materials are prepared as follows :
11.5 9 (0.5 mole) of sodium are dissolved in 400 ml of absolute alcohol, heated whilst stirring to boiling and, in approximately 20 minutes, ~2.8 q (0.2 mole) of 4-amino-2,6-dichloropyrimidine are added in portions. The mixture is then boiled for a further 8 hours, filtered, and the filtrate is evaporated under reduced pressure. The resi-due is triturated with water, filtered and recrystallised from alcohol. 4-amino-2,6-diethoxypyrimidine melting at 106-108 is obtained.
32.8 9 (0.2 mole) of 4-amino-2,6-dich~oropyrimidine, 400 ml of isopropanol and a solution of 4.6 q (0.2 mole) of sodium in 100 ml of isopropanol are refluxed for 15 hours. The mixture is concentrated under reduced pressure, the residue is triturated with water and by filterinq a crude product is obtained which melts at 108-112 . After recrystallisation from isopropanol, 4-amino-6-chloro-2-isopropoxypyrimidine melting at 125-127 is obtained.

113~13~
~2 -18.8 9 (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 and the fil-trate concentrated ~y evaporation under reduced pressure.
The residue is triturated with water, filtered, and recry-stallised from methanol. 4-amino-2-isopropoxy-6-methoxy-pyrimidine melting at 89-90 is obtained.
Instead of the cleaned compound, the above described crude product that melts at 108-112 may also be used.
4-amino-2-n-butoxy-6-methoxypyrimidine melting at 94-9~ is prepared in an an~logous manner.
The resulting 4-amino compounds can be converted into the corresponding S-methyl isothiourea compounds in accor-dancs- with Example 1. Their r~action with ethylenediamine yields the corresponding imidazoline products.

Example 31 In analogy to the preceding Examples, for example according to Examples 11 and 13, the following compounds may also be obtained :
2-[~2-methyl-6-phenylamino-4-pyrimidinyl)amino~-2-imidazoline. Mp. 263-265 . The hydrochloride melts at 311-313 .
2-[6-(4-methoxyphenyl)amino-2-methyl-4-pyrimidinyl)-amino~-2-imidazolin~. Mp. 266-269 . The hydrochloride melts at 281-283 .
2-[(6-(4-chlorophenyl)amino-2-rnethyl-4-pyrimi~inyl~aminol-2-imidazoline. ~p. 282-284 . Th~ hydrochloride melts at 320-322 .
2-~2-methyl-o-phenoxy-4-p~rimidinyl)amino]~2-imidazoline.
The hydrochloride melts at 302-30S .
The new compounds an~ their new pre-sta~es used as starting materials are prepared analogously to those of Examples 11 or 13 as follows :
Ad 1) : startin~ from 4-amino-6-chloro-2-methylpyrimi-dine and aniline, 4-amino-2-methyl-6-phenylaminopyrimidine, , 113~131 mp. 192-194 , is obtained. After reaction with ethoxy-carbonyl isothiocyanate this yields the corresponding ethoxycarbonylthiourea (mp. 199-200 ), which is hydro-lysed with lN sodium hydroxide solution to give the corres-ponding thiourea (mp. 2~7-230 ). ~he reaction of this thiourea with methyl iodide yields the N-(2-methyl-5-phenyl-amino-4-pyrimidinyl)-S-methylisothiourea hydroiodide used as starting material and which melts at about 150 .
Ad 2) : starting ~rom 4-amino-6-chloro-2-methylpyrimi-dine and p-anisidine, 4-amino-6-(4-methoxyphenyl)amino-2-methylpyrimidine, mp. 243-245 , is obtained. Ater reac-tion with ethoxycarbonyl isothiocyanate in acetone and di-methylformamide this yields the corresponding ethoxycar-bonylthiourea (mp. 198-200 ), which is hydrolysed with 1~ sodium hydroxide solution to give the corresponding thiourea, (mp. 221-224 ). ~he reaction of this thiourea with methyliodide in methanol-dimethylfor~amide yields the N-[6-(4-methoxyphenyl)amino-2-methyl-4-pyrimidinyl]-S-methyl-isothiourea hydroiodide used as starting material and which melts at 165-167 .
Ad 3) : starting from 4-amino-6-chloro-~-methylpyrimi-dine and p-chloroaniline, 4-amino-6-(4-chlorophenyl)amino-2-methylpyrimidine, mp. 180-182 is obtained. After reac-tion with ethoxycarbonyl isothiocyanate in acetone and dimethylformamide, this yields the corresponding ethoxycarbonylthiourea (mp. 200-202 ), which is hydrolysed with 2N sodium hydroxide solution to ~ive the corresponding thiourea. (Mp. 242-245 with decomposition.) The reaction of this thiourea with methyl iodide in acetone yields N-[6-(4-chloro- phenyl)amino-2-methyl-4-pyrimidinyll-~-methylisothiourea hydroiodide which is used as starting material and melts at 212-21~ .
Ad 4) : starting from 4-amino-6-chloro-2-methylpyrimi-dine and sodium phenoxide, 4-amino-2-~,ethyl-6-phenoxy~yrimidine (mp. 165-167 ) is o~tained. After reaction with ethoxycarbonyl isothiocyanate in acetone, 113~131 - 5~ -this yie!ds the corresponding ethoxycarbonylthiouroa (mp, 139-141 ), ~hich is hy~rolysed with lN sodium hydroxide solution to give the corresponding thiourea (mp. 221-224 ). The reaction of the last-named compound with metnyl iodide in ~ethanol-dimet~ylformamide yields N-(2-~ethyl-5-pnenoxy-4-pyrimidinyl)-~-methylisothiourea hydroiodide used as starting material.

Example 32 In analogy to the methods described in the preceding Examples the following compounds may also be prepared :
2-[(4-pyrimidinyl)al~ino]-2-imidazoline.
2-[(2-butylamino-4-pyrimidinyl)amino~-2-imldazoline.

Example 33 Tablets containing ~.1 g of the hydrochloride of 2-[(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 g lactose 50.0 g wheat starch 73.0 g colloidal silica 13.0 g magnesium stearate 2.0 g talc 12.0 g water q.s.

The 2-~'2,6-dimethyl-4-pyrimidinyl)amino]-2-imid~zo-line hydrochloride is mixed with a part of the ~,~heat starch, with the lactose and the colloidal silica and the mixture is forced through a sieve. Another part of the wheat starch is 113t:~131 made into a paste with 5 times tne amount o' water on a water bath, and the above powder mixture is ~neaded -~ith this paste until a slightly plastic mass forms. This is pressed through a sieve of 3 mm mesh width and dried, and the dried granulate is again forced through a sieve. The remaining wheat starch, the talc and the magnesium stearate are added and the resulting mixture ~s 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 manuf~ctured in an analogous manner.

Claims (22)

Claims:

1. Process for the production of new 2-(pyrimidinyl-amino)-1,3-diaza-2-cycloalkene compounds of the formula I

(I) in which formula Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and unsubstituted or substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogen, tri-fluoromethyl, 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, thio-morpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, and in which 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, radicals denoted by "lower"
containing up to 4 carbon atoms, and their tautomeric compounds and acid addition salts, which consists in a) reacting a compound of the formuly Py-X (IV), or a salt thereof, with a compound of the formula (VI) or with a salt thereof, wherein one of the radicals X and Y represents an amino group of the formula -N(R2)-H (VI) 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 Y1 represents the imino group, a group that can be split off, the oxo group or thioxo group, and Y2 re-presents a group that can be split off, or Y1 and Y2 to-gether represent a triple-bonded nitrogen atom, when R2 is hydrogen, or the corresponding tautomeric form, or a salt thereof with an alkylenediamine compound of the formula H2N-Alk-NHR1 (VIII), or c) reacting a phosphinic acid halide of the formula (XII), in which Hal represents halogen, with an amine compound of the formula Py-NH-R2 (IVa), and, if desired, dehalogenating a resulting compound of the formula I, in which the rest Py contains halogen, or replacing the halogen in 2-position by unsubstituted or substituted amino, in a resulting compound in which the rest Py is substituted in the 2- and 6-position by halogen, and/or, if desired, converting any resulting base into an acid 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.

2. Process according to claim 1, wherein in the reaction a) starting materials are used in which a group X or Y
that can be split off together with hydrogen is a free or etherified mercapto group, a reactive functionally modi-fied hydroxy group or the nitroamino group.

3. Process according to claim 1, wherein in the reaction b) starting materials are used, in which a splittable group Y1 or Y2 represents a free or etherified hydroxy group, a reactive, functionally modified hydroxy group or the nitroamino group.

4. Process according to claim 1, wherein in the reaction b) the condensation reaction to form the ring is carried out in one or two steps.

5. Process for the production of compounds of formula I
shown in claim 1, in which Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom unsubsti-tuted or substituted by one, two or three identical or different substituted from the group comprising lower alkyl, hydroxy, lower alkoxy, halogen, phenyl, phenoxy or phenylamino, each of which can be substituted by lower alkyl, lower alkoxy, or halogen;
amino, lower alkylamino, di-lower alkylamino, morpholino, and in which R1 and R2 independently of one another represent 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" con-taining up to 3 carbon atoms, their tautomeric compounds and acid addition salts thereof, which consists in a) reacting a compound of the formula Py-X (IV), or a salt thereof, with a compound of the formula (VI) or with a salt thereof, wherein one of the radicals X
and Y represents an amino group of the formula -N(R2)-H
(VI) 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 Y1 represents the imino group, a group that can be splitt off, the oxo group or thioxo group, and Y2 represents a group that can be split off, or Y1 and Y2 together represent a triple-bonded nitrogen atom, when R2 is hydrogen, or the corresponding tautomeric form, or a salt thereof with an alkylenediamine compound of the formula H2N-Alk-NHR1 (VIII), or c) reacting a phosphinic acid halide of the formula (XII), in which Hal represents halogen, with an amine compound of the formula Py-NH-R2 (IVa), and, if desired, dehalo-genating a resulting compound of the formula I, in which the rest Py contains halogen, or replacing the halogen in 2-position by unsubstituted or substituted amino, in a resulting compound in which the rest Py is substituted in the 2- and 6-position by halogen, and/or, if desired, converting any resulting base into an acid 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.

6. Process for the production of compounds of formula I
shown in claim 1, 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, amino, lower alkylamino, di-lower alkylamino or morpholino and/or halogen, and in which R1 represents hydrogen or lower alkyl and R2 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" con-taining up to 4 carbon atoms, and halogen having an atomic weight of up to 35, and acid addition salts thereof, which consists in a) reacting a compound of the formula Py-X (IV), or a salt thereof, with a compound of the formula (VI) or with a salt thereof, wherein one of the radicals X
and Y represents an amino group of the formula -N(R2)-H
(VI) 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 Y1 represents the imino group, a group that can be split off, the oxo group or thioxo group, and Y2 re-presents a group that can be split off, or Y1 and Y2 together represent a triple-bonded nitrogen atom, when R2 is hydrogen, or the corresponding tautomeric form, or a salt thereof with an alkylenediamine compound of the formula H2N-Alk-NHR1 (VIII), or c) reacting a phosphinic acid halide of the formula (XII), in which Hal represents halogen, with an amine compound of the formula Py-NH-R2 (IVa), and, if desired, dehalo-genating a resulting compound of the formula I, in which the rest Py contains halogen, or replacing the halogen in 2-position by unsubstituted or substituted amino, in a resulting compound in which the rest Py is substituted in the 2- and 6-Position by halogen, and/or, if desired, converting any resulting base into an acid 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.

7. Process according to claim 1, wherein there are prepared compounds of the formula (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 R3, R4 and R5 represents hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms, halogen, di-lower alkylamino, morpholino or phenyl, and acid addition salts thereof.

8. Process according to claim 1, wherein there are prepared compounds of the formula III

(III) in which R? and R? independently of one another represent hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms, halogen or di-lower alkylamino, and n is 1 or 2, and acid addition salts thereof.

9. Process according to claim 1, wherein 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline and an acid addition salt thereof is prepared.

10. Process according to claim 1 for the preparation of 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl) amino]-2-imidazoline, which comprises reacting N-(6-chloro-2-dimethylamino-4-pyrimidinyl)-S-methylisothiourea hydro-iodide with ethylenediamine.

11. Process according to claim 1, wherein 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino)-2-imidazoline and an acid addition salt thereof is prepared.

12. Process according to claim 1 for the preparation of 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-2-imidazoline, which comprises reacting N-(6-chloro-2-methyl-4-pyrimidinyl)-S-methylisothiourea hydroiodide with ethyleneamine.

13. Process according to claim 1, wherein 2-[(6-chloro-2-diethylamino-4-pyrimidinyl)amino]-2-imidazoline and an addition salt thereof is prepared.

14. Process according to claim 1 for the preparation of 2-[(6-chloro-2-diethylamino-4-pyrimidinyl)amino]-2-imidazoline which comprises reacting N-(6-chloro-2-diethylamino-4-pyrimidinyl)-S-methylisothiourea hydro-iodide with ethylenediamine.

15. New 2-(pyrimidinyl-amino)-1,3-diaza-2-cycloalkene compounds of the formula I

(I) in which formula Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom and unsubstituted or substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogen, tri-fluoromethyl, 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, thio-morpholino, lower alkanoylamino, lower alkoxycarbonylamino, ureido, 3-lower alkylureido and 3,3-di-lower alkylureido, and in which R1 and R2 independently of one another re-presents 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 acid addition salts, whenever prepared by a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

16. New 2-(pyrimidinyl-amino)-1,3-diaza-2-cycloalkene compounds of the formula I as defined in claim 1, in which Py represents 4-pyrimidinyl bonded via a carbon atom to the nitrogen atom unsubstituted or substituted by one, two or three identical or different substituents from the group comprising lower alkyl, hydroxy, lower alkoxy, halogen, phenyl, phenoxy or phenylamino, each of which can be substituted by lower alkyl, lower alkoxy, or halogen; amino, lower alkylamino, di-lower alkylamino, morpholino and in which R1 and R2 independently of one another represent 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 3 carbon atoms, their tautomeric compounds and acid addition salts thereof, whenever prepared by a process as claimed in claim 5 or by an obvious chemical equivalent thereof.

17. New 2-(pyrimidinyl-amino)-1,3-diaza-2-cycloalkene compounds of the formula I as defined in claim 1, 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, amino, lower alkylamino, di-lower alkylamino or morpholino and/or halogen, and in which R1 represents hydrogen or lower alkyl and R2 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 acid addition salts thereof, whenever prepared by a process as claimed in claim 6 or by an obvious chemical equivalent thereof.

18. Compound of the formula III

(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 R3, R4 and R5 represents hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms, halogen, di-lower alkylamino, morpholino or phenyl, and acid addition salts thereof, whenever prepared by a process as claimed in claim 7 or by an obvious chemical equivalent thereof.

19. Compound of the formula III

(III) in which R? and R? independently of one another repre-sents hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms, halogen or di-lower alkylamino, and n is 1 or 2, and acid addition salts thereof, whenever prepared by a process as claimed in claim 8 or by an obvious chemical equivalent thereof.

20. 2-[(6-chloro-2-dimethylamino-4-pyrimidinyl)amino]-2-imidazoline, whenever prepared by a process as claimed in claim 10 or by an obvious chemical equivalent thereof.

21. 2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-2-imidazoline, whenever prepared by a process as claimed in claim 12 or by an obvious chemical equivalent thereof.

22. 2-[(6-chloro-2-diethylamino-4-pyrimidinyl)amino]-2-imidazoline, whenever prepared by a process as claimed in claim 14 or by an obvious chemical equivalent thereof.