DD297406A5 - PYRIMIDINE DERIVATIVES - Google Patents

Abstract

Novel aminopyrimidinium salts of formula I, wherein R1-6, Q, A and Y have different values, and certain closely related anhydrobase derivatives, pharmaceutical compositions containing them and methods of preparing new compounds. The compounds (salts and related anhydrobases) have a beneficial effect on the cardiovascular system and are useful in the treatment of cardiovascular disorders associated with increased cardiac velocity, such as hypertension. B. myocardial ischemia. Compounds of formula I of particular interest are those wherein R 1 is alkyl, alkenyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl; R 2 is alkyl, phenyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino; R6 is N (Re) Rf, wherein Re and Rf are independently selected from hydrogen and alkyl or together form alkylene; R4 is hydrogen, cycloalkylalkyl, alkyl, alkenyl, alkynyl, phenylalkyl, or R4 is alkylene or alkenylene linked to the nitrogen atom of the group QAN-; R5 is hydrogen; Q is phenyl or pyridyl; A is a direct bond or the group NR4; Y stands for a physiologically permissible anion; Formula I {pyrimidine derivatives; Aminopyrimidiniumsalze; aminopyrimidine; Anhydrobase derivatives of aminopyrimidinium salts; pharmaceutical compositions; increased heart rate; Kardiovaskularerkrankungen; myocardial ischemia}

Description

(a) R ¹ is alkyl, R ² is amino or alkylamino, R ⁴ is hydrogen or alkyl, R ⁶ is hydrogen or alkyl, Ft "is hydrogen or phenyl, optionally with an alkyl or alkoxy substituent, A is a direct bond and Q is phenyl optionally with an alkyl or alkoxy substituent;

(b) R ¹ is methyl or ethyl, R ² is amino, R ⁴ and R ⁵ are hydrogen, R ^s is methyl and QA- is unsubstituted phenyl; or

(c) R ¹ , R ⁶ and R ⁶ are methyl, R ² is methylamino, R ⁴ is hydrogen and QA- is 3,5-dimethylphenyl; R ² is methylthio, R ¹ , R ⁴ and R ⁶ are methyl, and in each of them Y has the above-mentioned meaning.

When R ^{4 is} hydrogen or when R ² and R ^{8 are} amino or alkylamino, then the amino derivatives of the invention may exist in a different tautomeric form than in formula I or in a mixture of one or more of the possible forms of the Tatomer.

It is also clear that if any of the substituents in the compounds of formula I contain a vitality center, then the compounds of the invention may exist in and be isolated in a selectable active or racemic form. The invention includes any tautomeric, optically active or racemic form of a compound of formula I having the above-mentioned positive pharmacological activity.

The compounds of formula I are quaternary salts and in some cases, e.g. When R ² or R ^{6 are} alkylamino and the other R ² and R ^{9 have} any of the meanings defined above, for example by treatment with a quaternary ammonium hydroxide (and especially in a macroreticular resin form) into the corresponding nonionic anhydrobase forms of the formula I a or I b are transformed (or in a tautomeric form thereof, when R ^{4 is} hydrogen or when the other of the groups R ² and R ^{6 are} amino or alkylamino). These nonionic forms of formula Ia or Ib, in which Alk is (C, e) alkyl, are a further inventive purpose and can be fully converted to quaternary salt forms, e.g. B. by treatment with a corresponding acid of the formula HY

A particular value is found in R 'when it is alkyl, e.g. B. (Ci_ ₇ ) alkyl such as methyl, ethyl, propyl, butyl, pentyl or heptyl, of which in value methyl and ethyl are generally preferred.

Of particular value are R ² or R ⁸ when they are acyl, e.g. For example, methyl, ethyl, propyl, butyl or isobutyl.

A particular value applies to R ¹ , R ² , R ⁴ , R ^s or R ^e when they are alkenyl, z. Allyl, but-2-enyl, but-3-enyl, 2-methyl-2-propenyl or pentenyl.

A particular value applies to R ¹ , if it is cycloalkyl, z. As cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and R ² or R ⁸ , for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

A particular value is given for R ¹ , R ² , R ⁴ or R ⁸ when they are phenyll-C 1 -5 -alkyl or for a phenyl (C 1-4 -alkyl) substituent which is part of R ⁴ , e.g. Benzyl, 1-phenylethyl or 2-phenylethyl.

A particular value applies to R ¹ , R ² , R ⁴ or R ⁸ when they are cycloalkyl-alkyl, for. For example, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl or 2- (cyclohexyl) ethyl.

A particular value applies to R ² or R ⁹ when they are alkoxyalkyl, e.g. Methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl.

A particular value applies to R ⁶ and R ⁹ when together they form (C 3 _e ) alkylene, eg. B. trimethylene, tetramethylene, Pentamethy len or a group of the formula -CH ₂ · C (CH ₃ I ₂ CH ₂ - or -CH ₂ · C (CH ₃ I ₂ · CH ₂ CH ₂ -.

A particular value applies to R ⁴ when it is alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or pentyl, of which methyl and especially ethyl are particularly preferred in terms of value.

A particular value applies to R ⁴ as alkynyl, z. For example, prop-2-ynyl or but-2-ynyl.

A particular value applies to R ² or R ⁶ as alkylamino, z. Methylamine, ethylamine, propylamine or butylamine, and when they are dialkylamino, e.g. For example, dimethylamine, diethylamine, methylpropylamine or dipropylamine.

A particular value applies to R ⁴ as alkylene or alenylene bonded to the nitrogen atom of the group QAN-, for example methylene, ethylidene, ethylene, isopropylidene, trimethylene, tetramethylene, vinylene or 1,3-propenylene; and a particular value for a substituent which may be present in a linking group, such as e.g. Methyl, ethyl, propyl, butyl, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl (the benzene moiety of the last four groups is optionally substituted as mentioned above).

A particular value applies to A as alkylene, z. Methylene, ethylene, trimethylene or tetramethylene, each of which may optionally have one or two methyl substituents; and as oxyalkylene, e.g. Oxyethylene, oxytrimethylene, methyleneoxyethylene or ethyleneoxyethylene, each of which may optionally have one or two methyl substituents.

A preferred value applies to A, if they are z. B. is a direct bond, methylene or ethylene.

Particular values for optional substituents which may be present in a phenyl or benzene moiety as defined above include, for example:

Halogen, fluorine, chlorine and bromine; Alkyl, methyl, ethyl and propyl; Alkenyl, allyl, 2-methyl-2-propenyl; Alkoxy, methoxy, ethoxy and propoxy; Alkylamino, methylamino, ethylamino; Dialkylamino, dimethylamino and diethylamino, alkylthio, methylthio and ethylthio; Alkylsulfinyl, methylsulfinyl and ethylsulfinyl ·; Alkylsulfonyl, methylsulfonyl, and ethylsulfonyl and alkylenedioxy, methylenedioxy, and isopropylideneoxy,

In general, it is preferred that Q is unsubstituted as a phenyl or benzene moiety or has up to three substituents.

Specific values for Q include, for example, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-nitrophenyl, 2-methylphanyl, 2-carboxyphenyl, 2-methoxyphenyl, 4-methylthiophenyl, 2,5-dinitrophenyl, 2,5-dimethylphenyl, 3 , 5-Dimethylphenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 3,5-dimethoxyphenyl, furyl, thienyl and pyridyl.

Specific values for the group QAN (R ⁴ K when R ^{4 is} alkylene or alkenylene include, for example, 1-indolyl, 3-methyl-indolyl, 3-ethyl-1-indolyl, 3-propyl-1-indolyl, 5 Bromo-1-indolyl, 5-chloro-indolyl, 5-fluoro-1-indolyl, 5-methyl-1-indolyl, 5-methoxy-1-indolyl, 1-indolinyl, 3-methyl-1-indolinyl, 3 Ethyl-1-indolinyl, 3-isopropyl-1-indolinyl, 1-indolinyl, 1,2,3,4-tetrahydro-1-quinolyl, 1,2,3,4-tetrahydro-2-isoquinolyl and 3,4-dihydroxy 1,4-Benzoaxin-4-yl.

For example, a preferred value for R ⁸ is alkylamine such as methylamine or ethylamine, R ⁸ is hydrogen, Q is phenyl (optionally substituted as above) and A is a direct bond.

. A ⁿ · uppe of compounds of the invention which are of particular interest comprises compounds of the formula II wherein: Ra is (Ci-to) alkyl, (C _M) alkenyl, phenyl, PhenyKC ^ -alkyl, ^ cycloalkyl or (! C _M ) cycloalkyl- (C, _M ) alkyl; Rb is (Ci ^) alkyl, phenyl, phenyl (C | _ ") alkyl, (C ₃ _e) cycloalkyl or (C _M) cycloalkyl (C, _4) alkyl, amino, (C, _ ₄₎ alkylamino or dialkylamino with up to six carbon atoms; R c is hydrogen, (C 1 -CycloalkylMC-C 1 -alkyl, (C 1 -C 4) alkyl, (C ₃ _j) alkenyl, (C _M ) alkynyl or phenyl C, _j) alkyl; or Rc is (Ci ^) alkylene or (C ₂ _4) A k6nylen, attached to the nitrogen atom of the group Qa.Aa.N-, each connection group optionally (a (C ^ lAlkyl-, phenyl or phenyl C |! _4 ), And each of the linking groups can thereby complete a ring, including c'er two adjacent carbon atoms of Q, the atoms of A and the nitrogen of the group -Aa.N-; Rd is hydrogen; Re and Rf are independently selected Hydrogen or (C 1) alkyl or together form (C _M ) alkylene; Qa is phenyl or pyridyl; Aa is a direct bond to the group -NRc; Y is a physiologically acceptable anion; and wherein any one or more of said phenyl components is optionally may be unsubstituted or have one or more substituents independently selected from halogen, trifluoromethyl, cyano, nitro, (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy.

The specific values for Ra, Rb, Rc, Rd, Re, Rf, Aa and Qa include, for example, the abovementioned relevant values for R ¹ , R ² , R ⁴ , R ⁶ , R ^e , Q and A.

A preferred value for R ¹ or Ra is z. As methyl, ethyl, butyl, phenyl or cyclohexyl, with methyl being particularly preferred. A preferred value for R ⁴ or Rc is z. Methyl or ethyl, with ethyl being particularly preferred.

Another group of compounds of particular interest according to the invention contains compounds of formula II wherein Qa is phenyl; Aa is a direct bond to the group -N (Rc) -; Ra is (C, _ ₇₎ alkyl or (C3-e) alkenyl; Rb is (C 1 -C 3) alkyl (such as methyl or ethyl); Rc is hydrogen, (C ^ lAlkyl (such as methyl, ethyl, propyl or pentyl), _(C3 ^) cycloalkylmethyl (such as cyclopropylmethyl), or (C ₃ ^) AIkGHyI (such as allyl or but-2-enyl), or Rc is (C ₂ -4) alkylene (such as ethylene or trimethylene) or (C ₂ -4> alkenylene (such as vinylene or 1,3-propenylene) and forms a ring, including the two vicinal carbon atoms of the benzene ring Qa and the nitrogen atom of the group -N (RcH Rd is hydrogen or (C 1 -C 3) alkyl (such as methyl or ethyl); Re and R f are independently selected from hydrogen and (C 1 -C 4) alkyl (such as methyl or ethyl); Y is a physiologically acceptable anion; wherein the benzene ring Qa is optionally unsubstituted or has one or two substituents independently selected from halo (such as fluoro, chloro or bromo), (C, _4) alkyl (such as methyl) and (C, _4) alkoxy (such as methoxy ).

Another group of compounds of particular interest according to the invention contains compounds of formula II wherein Qa is phenyl; Aa is a direct bond to the group -N (RcH Ra is methyl or ethyl, Rb is methyl, ethyl or propyl; Rc is ethyl; or Rc is ethylene or vinylene upon completion of an indoline or indole ring, respectively including two adjacent carbon atoms of the Benzene ring Qa and the nitrogen atom of the group -N (RcH Rd is hydrogen or methyl; Re is hydrogen and Rf is methyl or ethyl; Y is an ohysiologisr.h acceptable Anton; and wherein the benzene ring Qa may optionally be unsubstituted or one or two substituents independently selected from halogen (such as fluoro, chloro or bromo), (C 1-4) alkyl (such as methyl) and (C 1-4) alkoxy (such as methoxy).

Particularly physiologically acceptable counter anions Y include e.g. Halides (such as chloride, bromide or iodide), sulfate, fluoroborate, phosphate, nitrate, acetate, benzoate, butyrate, citrate, tartrate, dibenzoyl tartrate, fumarate, trifluoroacetate, methosulfate and p-toluenesulfonate.

A preferred group nichtionogner Anhydrobasenformen of the invention as explained above, comprising a compound of formula II wherein Ra, Rb, Rc, Rd, Af ₁ and Qa and have any of the meanings defined above, Alk is (C, ^) alkyl (especially methyl or ethyl).

The compounds of particular interest according to the invention include the compounds described in the accompanying examples, of which the ones of particular interest in Examples 20, 51, 56, 145, 148-149, 151, 156 and 158 are. The latter compounds described herein (or with the exception that the nonionic anhydrobase form is described in the first part of Example 56 as an alternative physiologically acceptable counteranion) constitute a further object of the invention.

The compounds of the invention can be prepared by standard methods of organic chemistry, which are already known from the preparation of structurally analogous compounds, for. 8. Processes described in standard pyrimidine chemistry. Such processes for the preparation of novel compounds of the formula I are a further object of the invention and represented by the following preferred processes, in which the various radicals of a general nature have the meanings explained below:

a. An amino compound of the formula III is reacted with an alkylating agent of the formula R'.Z, where Z is a suitable leaving group.

A preferred value of Z is z. As halide (especially iodide, bromide or chloride), sulfate and p-toluene sulfate. The reaction is generally carried out by heating the alkylating agent with the compound of formula III at a temperature of e.g. B. 40-12O ⁰ C and is suitably carried out in a suitable solvent or in a dilution, for example in an ether such as dioxane, tetrahydrofuran or tert-butyl methyl ether.

The starting materials of the formula III may, for. B. by reaction of the corresponding halo-pyrimidine of the formula IV, wherein X is chlorine or bromine, with the appropriate amine of the formula QAN (R ⁴ IH at a temperature of, for example, 40-15O ⁰ C are prepared Specific reactions may be carried out in the presence of a suitable solvent or co-solvent such as (C 1-4) alkanol or N, N-dimethylformamide, or the starting materials are prepared as a single concentrate of the reagents alone The amines of the formula QQN (R ⁴ ) H and the compounds of formula IV are generally known or can be prepared by methods well known and conventional in organic and pyrimidine chemistry Although it appears appropriate in principle to allow alkylation on each of the endocyclic nitrogen atoms, alkylation is generally preferred on the nitrogen of R ¹ in formula I, and any small amount of the alternative isomer can be removed by known ancestors for the purification of organic compounds , for example by chromatographic means or by fractional crystallisation. The general exception is when these compounds of formula III, in which R ^{e is} a tertiary amino group and R ^{2 is} other than alkylamino, whose compounds alkylate to conditions of process (a) predominantly on the nitrogen atom N (3), for their values of R ² and R ^e the corresponding compounds of formula I with

the following method (b) or (c) should be prepared. The alkylation position can be prepared by standard methods, for. B. by examining the nuclear Overhauser effect on the basis of the proton resonance of the sample material in question.

b. A pyrimidine salt of the formula V, wherein X is reacted as a suitable leaving group with an amine of the formula QAN (R ⁴ JH.

The process is considered analogous to the above-mentioned production of the starting material of formula IV and the general conditions. Therefore, the process generally proceeds at a temperature of, for example, 20-150 ° C. and in the presence of a suitable solvent or diluent such as (C 1) 3 (alkenol or Ν, Ν-dimethylformamide) A particularly suitable leaving group X is, for example a halo group (especially chloro or bromo), dichlorophosphinoyl / -O.PO- CI ₂ / or dibromophosphinylol / -O.PO- Br ₂ / The latter two groups should suitably be prepared in situ by reaction of the corresponding pyrimidinone with phosphorus (V ) oxide chloride or phosphorus (V) oxide bromide, as described, for example, in the accompanying examples.

(Note: those skilled in the art know that an exact identity of the group X is not generally critical to operation [b]). The pyrimidine salts of the formula V can optionally z. B. analogous to the above process (a), ie by reaction of a halopyrimidines of the formula IV with a suitable alkylating agent of the formula R ¹ .Z and in particular an iodide or bromide of the formula R'.I or R ¹ .Br be obtained. The Pyrimidinone itself can be prepared by standard methods, for. When R * is phenyl or the like as described in connection with Example 1-8 below.

c. For compounds in which R ^{s is} amino, alkylamino or dialkylamino as defined above, a pyrimidine salt of formula VI, wherein X is a suitable leaving group, is reacted with a suitable amine selected from ammonia (C | _e ) Alkylamine, dialkylamine having up to 6 carbon atoms, pyrrolidine, piperidine and morpholine or a salt thereof with a (Ci ^) alkanoic acid (ethanoic acid).

The process can be considered analogous to the process (b) described above, for the purposes of consideration and for the general reaction conditions. In general, an excess of starting amine or an alkanoic acid salt thereof is used.

The starting compounds of the formula VI can generally be obtained in a manner similar to the compounds of the formula V.

It is of value that the counteranion Y "in the formula I compounds can be completely converted, for example by reaction of the formula I compound with a suitable salt, for example a silver salt, or by ion exchange chromatography in one A basic macroreticular resin column in the form of its salts with the desired counteranion or by any other method If the nonionic anhydrobase form of a compound is required (e.g., a compound of formula I a, I b or II a), it may be e.g. Example, by reaction of the appropriate compound of formula I in which a group of R ² and R ^{s is} alkylamino be obtained with a macroreticular resin containing quaternary ammonium hydroxide groups The operation is conveniently carried out by exposing a solution of formula-I Compound in an aqueous solution such as an aqueous (C, _4) alkanol (eg, methanol, ethanol or propan-2-ol) with respect to the action of the resin at or near ambient emperature, eg by dropping the solution through a resin exchanger layer or column. The anhydrobase form may then conveniently be recycled to an ionic form of formula I by reaction with the corresponding acid of formula HY.

It is also of value that certain of the various optional substituents in the compounds of the present invention can be initiated by normal aromatic substitution reactions or by conventional functional group modifications before or immediately after process (a), (b) or (c) and, as such, in the process aspect of the invention. Such reactions and modifications include e.g. the introduction of nitro or halogen, the reductive alkylation of nitro, the oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl, and the reduction of alkynyl or alkenyl. The reactants and the reaction conditions for such processes are known in the chemical arts. As noted above, the compounds of the present invention have useful pharmacological properties and are useful in the performance of the Keith Flack sinus node in warm-blooded animals in a conducive, selective and medically useful manner, so that the substances are of use in the treatment of cardiovascular disorders in conjunction with an unduly high Heart rate and with minor effects on other hemodynamic parameters such as blood pressure and cardiac output. The beneficial and selective effect on the cardiovascular system can be demonstrated by using one or more of the following standard laboratory procedures.

a. Bradycardic effect (reduction of the beat rate of the self-propelled isolated right atrial heart atria)

This procedure involves dissection of the right atrium of a guinea pig heart, taking care not to damage the sinus node area. The atrium was dissolved in oxygen-saturated (95% O ₂ , 5% CO ₂ ) Tyrode solution (containing 8.0 g NaCl, 0.19 g KCl, 0.025 g MgCl ₂ , 0.05 g NaH ₂ PO ₄ , 1.0 g NaHCO ₃ , 0.2g CaCl ₂ and 2.7g glucose per liter of deionate) placed between two platinum tips connected via an amplifier to a conventional heart rate monitor which triggered the action potentials through the atrium. The preparation was bathed in oxygenated Tyrode's solution at 37 ⁰ C and left for 30 min to equalize., Before a solution of the test compound diluted in a mixture of Dimcthylsulfoxid and Crernophor EL, as required with Tyrode's solution was added. The further solutions of the test compound were added cumulatively at 15 minute intervals or when a stable heartbeat rate was reached. This allowed an IC ₂₀ (ie the micromolar concentration to reduce the heart rate by 20%) to be calculated. Typically, a compound of formula I has an IC _M of 10 micromoles or less.

b. Effect on the contraction force of the electrically stimulated left atrium of a guinea pig

This procedure involves dissection of the left atrium of a guinea pig in oxygen-saturated Tyrode's solution. The atrium was then clamped in a polyacrylate holder containing two stimulation electrodes of stainless steel. The free end of the auricle (usually the auricle) was attached to an isometric force transducer using silk thread. The atrium was then placed under quiescent tension of 1 g and allowed to equilibrate in oxygen-saturated Tyrode solution for 20 min before being stimulated by application of 2.5 Hz / 3 ms pulses at 1.5 times the threshold voltage (usually 3-7 V) , Then, the test compound (prepared essentially as in (a) above but using a physiological saline solution instead of the Tyrode's solution) was added with a solution (10 ^-5 M or less) of the test compound and measured for contractive force For example, at a concentration of 1-30 micromoles, the compound of formula I exhibits a contraction force reduction of less than 15%.

c. Bradicardial effect in an anesthetized rat

This procedure involves the use of Wistar rats (Alderley Park strain) anesthetized by intravenous injection of Alphaxalone / Alphadalone (1.5 ml per kg). A PE cannula was then inserted into the jugular vein and anesthesia maintained by infusing alphaxalone / alphadalone at 0.025-0.12 ml per kg per minute. Similarly, a PE cannula was inserted into the carotid artery and connected to a pressure transducer filled with physiological saline. With the signal of arterial blood pressure then an internally calibrated Herzfrequenzanzeigar was triggered and the transducer calibrated with a mercury manometer. The heart rate monitor and pressure transducer displays were then simultaneously recorded on a standard chart recorder. After cannulation, the rat preparation was left for 10 minutes for stabilization. Then, a solution of the test compound (prepared as in (a) in an amount of 1 ml per kg) was added via the venous cannula in four cumulative doses at intervals of 5 min each. For each test compound, a group of five rats was used. It was then possible to determine the effect on heart rate and blood pressure in comparison with the values of the control injection. Typically, in a compound of Formula I, when actively using this method to achieve a 30% reduction in heart rate (ie, an ED ₃₀ -DoSiS), an intravenous dose of 5 mg / kg or less is required.

Beneficial effects of a trial connection on the cardiovascular system such as bradikarde Wi. Effects that have no negative effect on cardiac output, blood pressure and / or cardiac output can also be determined in anesthetized dogs and in other dogs in which heart rate acceleration has been induced. In general, the compounds of the present invention show significant and predominantly selective bradycardic effects as evidenced by activity in at least two of the above-mentioned experimental procedures. With the compounds of the formula given in the above-mentioned in vivo experimental procedure, no open toxicity could be observed at doses many times those with significant adverse effects.

For example, the compound described in Example 51 below had a ICjo value of about 10 ^"6 M in procedure (a) and an ED ₃₀ -WeIiVOn 0.3 mg / kg intravenously to reduce heart rate in method (c). Other, The compounds of the formula given in the examples which follow are generally equally indicative of activity In the treatment of diseases of the cardiovascular system, such as in the treatment of myocardial ischemia, warm-blooded animals (and especially humans) must be considered in that a compound of formula I is to be administered orally, intravenously or otherwise medically acceptable (such as by inhalation, insufflation, sublingual or transdermal) such that a dose in the general size of, for example, 0.01 mg to However, it should be noted that the exact dose to be administered will be forced to vary according to the nature and severity of the disease, as well as the according to the age and sex of the patient to be treated. In general, pyrimidine salts of formula I (or the related nonionic anhydrobases) are presented in the form of a pharmaceutical composition, ie, together with a pharmaceutically acceptable diluent or carrier, and such a composition is a further object of the invention.

It should be recognized that it is advisable to prepare a specific pyrimidine salt of Formula I in situ using the appropriate anhydrobase and incorporating an acid of Formula HX during the preparation of a particular preparation.

A composition of the invention may be expressed in a variety of dosage forms. Dosage forms are z. As tablets, capsules, solutions or suspensions for oral use, are suppositories for rectal administration, sterile solutions or suspensions for intravenous or intramuscular injections are inhalations, powders, together with pharmaceutically acceptable inert dry-diluents such as lactose, insufflation or patch transdermal application. The compositions may conveniently be used in unit dosages, e.g. B. with 5-200 mg of the formula I compound, brought out.

A composition can be prepared by conventional methods using known pharmaceutically acceptable diluents and carriers. Tablets and capsules for oral use may conveniently be coated with a sheath, e.g. As a protective sheath (eg., On the basis of cellulose acetate phthalate), be provided so that the dissolution of the active ingredient of the formula I in the stomach minimized or unpleasant taste is covered.

The compositions of the invention may also contain one or more substances of value in the treatment or conditions of the cardiovascular to be treated. Therefore, in addition to the compound of formula I z. Contain one or more known substances selected from platelet aggregation inhibitors, prostanoid constrictor antagonists or synthase inhibitors (such as thromboxane A ₂ , antagonist or synthase inhibitors), cyclooxygenase inhibitors, blood antidiabetic agents, antihypertensives (such as angiotensin-containing enzyme inhibitors), inotropic agents, β-adrenergic antagonists, thrombolytic agents, vasodilators and calcium antagonists.

In addition to their use in therapeutic medicine, the compounds of formula I are useful as pharmacological tools in the development and standardization of test systems for the assessment of novel cardiovascular agents in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice.

The invention will now be illustrated by the following non-limiting examples, unless otherwise specified

has been:

(i) The evaporations were carried out as vacuum rotary evaporation;

(ii) operations were carried out at room temperature, ie at 18-26 ⁰ C;. (iii) or the Flammensäulenchromatografie Mitteldruckflüssigchromatografie (MPLC) were performed (on silica gel either Fluka Kieselgel 60 / Catalog No. 60738 / Fluka AG, Buchs, Switzerland, or on Merck Kieselgel Art.9385 the

Merck, Darmstadt);

(iv) the yields are given by way of illustration and not necessarily by conscientious

Process angulation achievable maximum;

(v) Proton NMR spectra were normally determined at 200 MHz in deuterium-labeled dimethylsulfoxide using tetramethylsilane (TMS) as the internal standard and are reported as chemical shifts (delta values) in parts each

Million parts of TMS using the conventional abbreviations used to denote the peaks, ie

s - singlet, m - multiple, t triplet, br - wide, d - doublet;

(vi) all final products were characterized by microanalysis, NMR and / or mass spectroscopy; and (vii) using conventional abbreviations for single radicals and recrystallization solvents, e.g. B.

Me = methyl, Et = ethyl, Pr = propyl, Pr ¹ = isopropyl, Bu = butyl, Bu ¹ = isobutyl, Ph = phenyl; EtOAc = ethyl acetate, Et ₂ O = ether, Pr ¹ OH = propan-2-ol, H ₂ O = water. example 1

A mixture of 1,4-dihydro-1-heptyl-6-methyl-3-methylamino-4-pyrimidinone monohydrate (0.75 g, 2.9 mM) and phosphorus (V) oxide chloride (3.5 mL, excess) heated at a bath temperature of 13O ⁰ C for 2.5 hours. The excess of phosphorus (V) oxide chloride was removed by evaporation. The residue was mixed with toluene (20 mL), then the volatiles were evaporated. The process was repeated with a new quantum of toluene (20 ml) to give 4-chloro-1-heptyl-6-methyl-2-methylaminopyrimidinium chloride as the crude dry substance. This material was mixed with ethanol (5ml) and N-methylaniline (0.8g, 7.5mM). The resulting solution was heated at reflux for 2.5 hours. Ethanol was evaporated and to the residue was added water (10 ml). The aqueous mixture was extracted with ether (4x10 ml), the extracts were separated. The aqueous phase was extracted with methylene chloride (4x10ml). The water from these extracts was removed via phase separation filter paper and the solution evaporated. The brown oily residue on trituration with ether crystallized to a white dry matter (0.742 g). This was prepared from TS Acetonether to 1-heptyl-6-methyl-2-methylamino-4-N-Methylanilinpyrimidinchforid recrystallized as a crystalline solids (0.49 g, 46% yield), mp 154-155 ⁰ C, microanalysis results.: C 65.7%, H 8.6%, N 14.9%, C ₂₀ H ₃ IN ₄ Cl · 0.25H ₂ O required 65.3% C, 8.6% H, 15.2% N; NMR: 0.9 (3H, t, CH ₃ ), 1.3 [1OH, complex, (CH ₂ J ₆ ], 2.36 (3H, s, CH ₃ ), 2.9 (3H, br, NCH _3), 3.5 (3H, s, NCH _3), 4.0 (2H, t, NCH _2), 5.8 (1H, br, aromatic), 7.4-7.6 (5H, complex, aromatic), 8.65 (1H, br, NH).

Example 2

The procedure described in Example 1 was repeated using N-ethylaniline. Was obtained 4-N-ethyl-1-heptyl-6-methyl-2-Methylaminopyrimidinchlorid (0.527 g, yield 48%), mp 126-128 ⁰ C, microanalysis results. C 66.7%, H 9.0 %, N 14.5%; C ₂₁ H ₃₃ N ₄ Cl requires 66.9% C .. 8.8% H and 14.9% N; NMR: 0.87 (3H, t, CH _3), 1.2 (3H, t, CH _3), 1.26 [1OH, complex, (CH _{2) 6),} 2.3 (3 H, s, CH _3), 3.0 (3 H, br, NCH _3), 4.0 (4H, complex, _NCH2), 5.6 (1H, br, aromatic), 7.3-7.6 (5H , complex, aromatic).

The pyrimidinone starting material for Examples 1 and 2 was prepared as follows:

(i) A solution of heptylamine (9.66g, 84mM) in methylene chloride (30ml) was added dropwise to a stirring suspension of 2H-3,4-dihydro-6-methyl-2-thioxo-1,3-oxazin-4-one (6g, 42mM) in methylene chloride (120ml). The resulting solution was left at ambient temperature for 16 hours and the solvent was evaporated. A mixture of the residue in ethanoic acid (20 ml) was heated at reflux for 30 minutes. The solvent was evaporated and the residue was purified by flame column chromatography on Fluka Kieselgel 60 using ether as eluent to give 2,3-dihydro-1-heptyl-6-methyl-2-thioxo-4 (1 H) -pyrimidinone as a dry substance (ii) The thioxo compound (2.42g, 1.01mM) from (i) in acetonitrile (30ml) and methyl iodide (4ml, excess) was refluxed for 8 hours. The solvent was evaporated and the residue was shaken with a mixture of methylene chloride (20 ml) and a saturated aqueous sodium carbonate solution (30 ml). The organic layer was removed with water (20 ml) and the water was separated via phase separation filter paper. Removal of the solvent by evaporation gave an oily residue which gradually hardened it to give 1,4-dihydro-l-heptyl-6-methyl-2-methyl-thio-4-pyrimidinone (2.2g) ice dry solid, which without further cleaning was used.

(iii) Methyl ammonium acetate (14 g, excess) was added to a methylthio compound (2.2 g) from (ii). The mixture was heated at a bath temperature of 175-18O ⁰ C for 0.5 h and then allowed to cool. Water (10 ml) was added and the oily mixture extracted with methylene chloride (4 × 10 ml). The water was removed from the separations over phase separation filter paper. After evaporation of the solvent, a residue was left, which was treated with water (10 ml). The crystalline dry substance was precipitated, collected by filtration, washed with water and recrystallized from ethyl acetate to give 1,4-dihydro-1-heptyl-6-methyl-2-methylamino-4-pyrimidinone monohydrate (1.68 g, 65% yield). ., m.p. 100-103 ⁰ C, microanalysis results: C 61.5%, H 9.8%, N 16.7%; C ₁₃ H ₂₂ N ₃ O.H ₂ O requires 61.4% C, 9.4% H and 16.5% N.

Examples 3-8

The procedure described in Example 1 was repeated using the appropriate 4-chloro-substituted pyrimidine derivative of the formula V (X = Cl) (obtained in situ from the corresponding 4-pyrimidinone) and the appropriate aniline. Therefore, the following compounds of the formula I were formed (R ^B = H, R ^e = CH ₃ , A = direct bond, Q = phenyl, Ϋ = CD:

hydrogenation Ex. R ¹ R ² R ⁴ Mp ₁ ⁰ C Yield% Rekrist.-Del. _ 3 cyclohexyl NH ₂ et 219-220 34 {Me ₂ C0 / Et ₂ 0) 0.25H ₂ O 4 phenyl NHMe me 227-228 37 (Me ₂ CO) 1.0H ₂ O 5 phenyl NHMe et 128-129 15 (EtOAc) 1.33H ₂ O 6 phenyl NH ₂ Ma 125-127 8 (Me ₂ C0 / Et ₂ 0) 0.25H ₂ O 7 4-MeO-phenyl NH ₂ et 215-216 46 (Me ₂ C0 / Et ₂ 0) 0.75H ₂ O 8th phenyl NH ₂ et 249-250 11 (EtOACVEt ₂ O

The starting material for Example 3 was prepared as follows:

(i) Cyclohexylthiourea (27.8g, 176mM) and 2,6,6-trimethyl-1,3-dioxin-4-one (90%, 36ml, 229mM) were heated at a bath temperature of 120 ° C for two hours. After cooling, the mixture was triturated with ether. The resulting dry matter was purified by filtration chromatography on silica gel (Fluka Kieselgel 60) using methylene chloride / pentane (1: 1) as eluent. The resulting material was purified by further chromatography on silica gel (Kieselgel 60) using ethyl acetate / pentane (1: 4). The result was 1-cyclohexyl-3- (3-oxobutanoyDthioharnstoff (17.7 g, 42%) as a dry substance, mp 100-102 ⁰ C;.. Milliequivalents 242 (M ⁺⁾ (it) A mixture of the above thiourea (10, 7g, 44 mM) and p-toluenesulfonic acid (10.7 g, 56 mm) was 18h (in refluxing ethanol 80ml) is heated. Then the solution was cooled to 5 ⁰ C. the resulting crystalline precipitate was collected by filtering, thereby i- Cyclohexyl ^ .S-dihydro-e-methyl-thioxo ^ -dHJ-pyrimidinone (3.6g, 36%), mp 240-440 ° C, microanalysis results: C59.1%, H7.3 %, N 12.4%, C _n H ₁₆ N ₂ OD requires: 48.9% C, 7.1% H, 12.5% N. (iii) A mixture of the above thioxo compound (2.96 g , 13.2mM) and methyl iodide (8.8ml, excess) was refluxed in acetonitrile (10ml) for 5 hours The solvent was evaporated and the residue was shaken with a mixture of saturated aqueous sodium carbonate (50ml) and ethyl acetate (50ml). The aqueous phase was further treated with ethyl extracted acetate (3x 50 ml). The bound extracts were dried (MgSO ₄ ) and the solvent was evaporated to give i-cyclohexyl-i-dihydro-e-methyl-methylthio-pyrimidinone as a crude dry substance (3.1 g) which was purified without further purification was used. (A sample of the repeat preparation was recrystallised from ethyl acetate / petrol [60-80 ° C] to a dry substance with mp 184-186 ⁰ C; microanalysis results. C60,5% H7,9% N11,8%; C ₁₂ H ₁₈ H ₂ OS requires: 60.5% C, 7.6% H, 11.8% N.)

(iv) A mixture of the above methylthio compound (3.1 g) and ammonium acetate (15 g) was heated at 1GO ⁰ C (bath temperature) for 2 hours. At intervals of 20 minutes, additional quantities (5 g) of ammonium acetate were added. Then the mixture was cooled and water (50 ml) added. The aqueous mixture was extracted with methylene chloride (8x 30ml) and the bound organic extracts dried (MgSO ₄ ) and the solvent evaporated. The semi-dry residue was dissolved in ethanol (50 ml) and concentrated aqueous sodium hydroxide solution (5 ml). The volatiles were evaporated. The residue was treated with ethanol (50ml) followed by 2M hydrochloric acid to pH <3. Then the solvents were removed from the acid mixture. The dry matter residue was extracted with hot methanol, the extracts were filtered off. The filtrate was evaporated and the residue recrystallized, first from ethanol / propan-2-ol (1: 1 by volume) and then from ethanol. Therefore, 2-amino-1-cyclohexyl-1,4-dihydro-6-methyl-4-pyrimidinone hydrochloride (0.98 g, 30% based on the thioxo compound), mp. 225-226 "C, with a satisfactory microanalysis.

The starting material for Example 7 was prepared as follows:

N- (4-Methoxyphenyl) thiourea (18.2g, 10OmM) and 2,6,6-trimethyl-1,3-dioxin-4-one (21.3g, 15OmM) were heated at 14O ⁰ C (bath temperature) for 30 min , The dry substance was cooled, treated with ethanol (100 ml), boiled for 10 min, cooled and then isolated by filtration. To the above material more dioxinone (21,3g) was added and the mixture was further 20min at 14O ⁰ C heated. Then, ethanol (50 ml) was added to the cooled mixture, which was then heated at reflux for 5 min. The mixture was cooled and the dry matter isolated by filtering to give 2,3-dihydro-1- (4-methoxyphenyl) -6-methyl-2-thioxo-4 (1H) -pyrimidinone (17.9g, yield 72%). ), Mp. 248-249 ° C, microanalysis results: C58.2%, H4.9%, N11.0%; C ₁₂ H ₁₂ N ₂ OS requires 58.1% C, 4.8% H, 11.3% N.

The methylthiopyrimidinones required for the preparation of Examples 4-8 were recovered in an analogous manner to the equivalent starting material for Example 3:

(1) 1,4-Dihydro-6-methyl-2-methylthio-1-phenyl-4-pyrimidinone (required for Examples 4-6 and 8): obtained as a dry substance in 67% yield, m.p. 225 ^° C ( delayed) after trituration with acetone; and

(2) 1,4-Dihydro-6-methyl-1- (4-methoxyphenyl) -2-methylthio-4-pyrimidiation (required for Example 7): obtained as a dry substance in 73% yield, mp 211-213 ° C after recrystallization from acetonitrile.

The required aminopyrimidinones were recovered analogously to the equivalent starting material for Example 3:

(3) M-dihydro-e-methyl ^ -methyl-i-phenyl ^ -Pyrimidinonhydrochlorid (required for Examples 4 and 5): obtained as a dry material, mp 199-200 ⁰ C in 90% yield, RACH purification by Flammensäulenchromatographie. on silica gel (Kieselgel 60) using methylene chloride / methanol (9: 1 by volume) as eluent;

(4) 2-Amino-1,4-dihydro-6-methyl-1-phenyl-4-pyrimidinone acetate (required for Examples 6 and 8): Recovered as dry substance, Fp.269-271 ⁰ C in 42% yield after recrystallization from ether / ethanoic acid; and

(5) 2-Amino-1,4-dihydro-1- (4-methoxyphenyl) -6-methyl-4-Pyrimidinonhydrochlorid (required for Example 7). Obtained as a dry substance, mp 287-289 ⁰ C in 56% yield after recrystallization from ethanol.

Example 9 A mixture of 2-amino-4-N-ethylaniline pyrimidine (2.2 mM), allyl bromide (6.5 mM) and dioxane (1 ml) was stirred at 100 ° C for 1.5 h

heated. The precipitated dry matter was collected by filtration, washed with dioxane and ether and then dried. This gave 1-AHyl-2-amino-4-N-Ethylanilinpyrimidiniodid in 60% yield, m.p. 174-176 ⁰ C, microanalysis and

NMR spectrum satisfactory.

(Note: The quaternization site was confirmed by conventional nuclear Overhauser studies.)

The pyrimidine starting material was prepared as follows:

A mixture of 4-chloro-2-aminopyrimidine (4,63mM) and N-aniline (1.0 mL, 9.2 mm) was heated as a melt for 15 hours at 95-100 ⁰ C. The residue was partitioned between methylene chloride (50 ml) and 2M hydrochloric acid (50 ml) and stirred for 15 min. The organic phase was separated and the aqueous phase extracted again with further amounts of methylene chloride (2 x 20 ml). The bound organic layers were washed successively with saturated sodium bicarbonate solution, water and brine (50 ml each), dried (MgSO ₄ ), then the solution was evaporated. The dry matter residue was triturated with ether and hexane and separated by filtration to give 2-amino-4-N-ethylaniline pyrimidine in 17% yield, mp 188-190 ° C.

Example 10-12

The procedure described in Example 9 was repeated, but using a suitable substituted pyrimidine of the formula III and a suitable alkylating agent of the formula R ¹ .Y, which were heated together for 18 hours. The following compounds of the formula I (Q = phenyl, A = direct bond, R ⁶ = R ⁶ = H) were obtained, all of which were recrystallized from methanol and ether:

example R ² R ¹ R ⁴ Y Fp- ( ⁰ C) Yield (%) 10 11 12 NH ₂ NH ₂ NH ₂ Pr ^c CH ₂ benzyl allyl Et Et Pr Br Cl Br 215-216 254-256 175-177 57 65 »39

Note: (1) · recovered all hydrate (0.25 H] O)

 (2) Prc-CH} = cyclopropylmethyl.

The required starting material 2-amino-4-N-propylaniline pyrimidine for Example 12 was prepared analogously to the analogous intermediate in Example 9 as a dry substance with mp. 82-84 ° C and 89% yield.

Example 13

A solution of 2-amino-4- (indoline-1-yl) pyrimidine (212mg, 1mM) in warm Ν, Ν-dimethylformamide (DMF, 15ml) was treated with ethyl iodide (1ml). The mixture was then left at ambient temperature for 15 hours, the dry matter filtered off and washed with ethyl acetate. Resulting was 1-ethyl-2-amino-4- (indolin-1-yl) pyrimidine iodide (280 mg, 79%), mp> 31O ⁰ C, microanalysis results: C ·, 1.2%, H4.8% , N 15.1%, C ₁₄ H ₁₇ N ₄ I · O · 5H ₂ O requires 44.6% C, 4.8% H, 14.9% N, NMR:

1.2-1.4 (3H, t, CH ₂ CH ₃ ), 3-2-3.4 (2H, t, inddine-SCHj), 3.95-4.1 (2H, q, CH ₂ CH ₃ ), 4.1-4.3 (2H, t, indoline-2 CH ₂ ), 6.55-6.65 (1H, d, pyrimidine-5 H), 7.1-7.4 (3H , complex, aromatic), 8.1-8.2 (1H, d, indoline-7H), 8.25-8.5 (2H, br, NH ₂ ), 8.63-8.73 (1H , d, pyrimidine

The starting material was prepared as follows:

A suspension of 2-amino-4-chloropyrimidine (1.3 g; 1OmM) in dioxane (30ml) was treated with indoline (2.4g; 2OmM) and the mixture for 18 hours at 95-100 ⁰ C heated. The precipitate was filtered from the cooled mixture and suspended in a mixture of propan-2-ol (30 ml) and a solution of potassium hydroxide flakes (6 g) in water (10 ml). This mixture was heated with stirring for one hour at 95-100 ° C. The hot propan-2-ol solution was separated from the aqueous layer and allowed to cool. The dry matter was recrystallized from propan-2-ol to give 2-amino-4- (indolin-1-yl) -pyrimidine as dry solids (1.9 g, 89.6%) mp 177-179 ° C; Microanalysis results: C62,2% H6,2%, N23.8%, C ₁₂ H ₁₂ N ₄ · H ₂ O requires: 62.6% C, 6.1% H, 24.3% N.

Example 14-15

The procedure described in Example 13 was repeated using propyl or heptyl iodide. The following compounds were won:

(Example 14): 2-Amino-4- (indolin-1-yl) -1-propylpyrimidine iodide as a dry substance, mp,> 31O ⁰ C, in 42% yield; and (Example 15): 2-amino-4- (indolin-1-yl) -1-Heptylpyrimidiniodid as dry substance, Fp.219-221 ⁰ C, in 57% yield.

Example 16

A mixture of 2-amino-4- (indol-1-yl) pyrimidine (210 mg, 1 mM) and methyl iodide (1 ml) in dioxane (5ml) for 2 hours at 95-100 ⁰ C was heated. The mixture was cooled and the precipitate filtered off, washed with ethyl acetate and then crystallized from methanol. Therefore, 2-amino-4- (indol-1-yl) -1-methyl-originated Pyrimidiniodid (280 mg; 79.5%), Fp.295-296 ⁰ C (dec.) Microanalysis results: C44,3%, H3.7%, N 15.9%; NMR: 3.71 (H, s, N-CH _3), 6.95-7.05 (1H, d, indole-3H), 7.3-7.45 (3H, complex, aromatic), 7 , 45-7.55 (1H, d, pyrimidine-5H), 7.65-7.75 (1H, complex, indole-7H), 8.15-8.25 (1H, d, indole-2 H), 8.45-8.55 (1H, d, pyrimidine-6H), 8.8-9.5 (2H, brNH ₂ ).

The indole starting material was prepared as follows:

A mixture of 2-amino-4- (indolin-1-yl) pyrimidine (2.6g, 12mM) and 30% (wt%) palladium on charcoal (260mg) in diphenyl ether (15ml) was refluxed for 2 hours , The mixture was cooled, diluted with methylene chloride (100 ml) and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residual oil diluted with hexane (200 ml).

The precipitate was filtered off and washed with hexane. This resulted in 2-amino-i- (indol-1-yl) pyrimidine (2.1 g, 81.5%), mp 163-165 ⁰ C, microanalysis results. C 68.5%, H4,6 %, N2G, 3%, C ₁₂ H ₁₀ N ₄ required: 68.6% C, 4.8% H, 26.7% N.

Example 17-19

The procedure described in Example 16 was repeated using ethyl, propyl or pentyl iodide as the alkylating agent for 18 hours instead of 2 hours. The following compounds of the formula I were formed:

(Example 17): 2-Amino-4- (indol-1-yl) pyrimidine iodide as a dry substance, mp. 248-250 ° C (with decomposition) after recrystallization from methanol and in 59% yield;

(Example 18): 2-Amino-4- (indol-1-yl) -1-propylpyrimidine iodide as a dry substance, mp 256-258 ° C (with decomposition) after recrystallization from methanol / ether and in 32% yield; and

(Example 19): 2-Amino-4- (indol-1-yl) -1-Pentylpyrimidiniodid as a dry substance (isolated as a methanolate), mp 134-136 ⁰ C after recrystallization from methanol / ether and in 25% yield.

Example 20

A mixture of 6-methyl-2-methylamino-4-N-methylanilinepyrimidine (14.01.61.5 mM), methyl iodide (10.7 ml, 172 mM) and dioxane (140 ml) was refluxed for 15 hours. Then the mixture was cooled. The dry matter was filtered off, washed with dioxane (10 ml) and hexane (100 ml) and then recrystallized from propan-2-ol. Were recovered 1,6-dimethyl-2-methylamino-4-N-Methylanilinpyrimidiniodid (15.38g, 67.6% yield), mp. 215-213 ° C, microanalysis: c45.6%, H5.1%, N 15.4%; C ₁₄ H ₁₉ NI required: 45.52% C, 5.17% H, 1F 13% N; NMR: 2.2-2.4 (3H, s, CH _3), 2,85-3,1B (3H, br, NHCH _3), 3.4 (3H, s, N ₄ -CH ₃₎ 3 5- (3 H, s, N-CH _3), 5.7 to 5.85 (1H, br, pyrimidine-H.), 7.35 ->, 6 (5H, complex, aromatic), 8, 1-8.25 (1H, br, NH). (Note: The quaternization site was confirmed by conventional nuclear Overhauser studies). The pyrimidine starting material was prepared as follows: A mixture of 4-chloro-6-methyl-2-methylaminopyrimidine (21.0g, 133mM) (described in British Patent No. 152327) and N-methylaniline (15.69g, 147mM ) was heated as a melt at 95-100 ⁰ C15 hours. The residue was partitioned between methylene chloride (200 ml) and 2 M hydrochloric acid and then stirred for 15 minutes. The organic phase was separated and the aqueous phase extracted again with further quantum methylene chloride (2χ 25 ml). The process was retrieved, then the bound organic layers were dried (MgSO ₄ ) and the solvent evaporated. DiezurückgebliebeneTrockensubstanz was recrystallized from hexane to give 6-methyl-2-methylamino-4-N-Methylanilinpyrirnidin (21.8 g, 72% yield), mp 114-115 ⁰ C. Microanalysis Results: c68.2%, H7.1%, N24.7%; C ₁₃ H ₁₆ N ₄ requires 68.39% C, 7.06% H, 24.54% N.

Example 21-46

The procedure described in Example 20 was repeated using the corresponding substituted pyrimidine

of the formula III and of an alkylating agent of the formula R ¹ .Y. The following compounds of the formula I were formed

NHCH ₃ H, Y "= iodide): QA Rekristallisa melting point yield (R '= Re = CH ₃ , R ⁶ = NHCH ₃ R ⁴ tion medium Mp ( ⁰ C) (%) Example R ² NHCH ₃ phenyl EtOAc / EtOH 158-160 58 NHCH ₃ et phenyl EtOAc / Me ₂ CO 166-167 52 21 NHCH ₃ pr phenyl Me ₂ CO 217-219 59 22 NHCH ₃ Pr ' phenyl EtOAc / EtOH 152-153 50 23 NHCH ₃ allyl phenyl EtOAc 160.5 to 161.5 48 24 NHCH ₃ Bu phenyl EtOAc / EtOH 160-162 51 25 NHCH ₃ pentyl phenyl EtOH 292-293 55 26 NHCH ₃ H 4-chlorophenyl Pr ¹ OH 206-208 68 27 NHCH ₃ me 4-methylphenyl Pr ¹ OH 205-206 44 28 NH ₂ me 2,5-dimethyl-phanyl EtOAc / EtOH 142-145 60 29 NH ₂ allyl 2,5-dimethylphenyl EtOAc 177-178 43 30 NH ₂ pentyl phenyl Pr ¹ OH 250 to 251.5 49 31 NH ₂ me 2-nitriphenyl EtOH / H ₂ O 265-267 36 32 NH ₂ H 4-chlorophenyl EtOH / H ₂ O 278-280 7 33 NH ₂ H 2-carboxyphenyl * · H ₂ O 185-186 38 34 NH ₂ H 3,5-dimethylphenyl EtOH 265-266 46 35 NH ₂ H 3,5-dichlorophenyl EtOAc / EtOH 310-311 * 26 36 NH ₂ H 3.5-dibromophenyl EtOH 276-278 33 37 NMe ₂ H 2,5-dimethylphenyl dioxane 236-237 21 38 NMe ₂ me 3,5-dimethoxyphenyl EtOAc / EtOH 276-277 56 39 NMe ₂ me phenyl EtOH 220-222 46 40 NMe ₂ H 2,5-dimethylphenyl EtOH 230-231 " 28 41 Melting point with decomposition H 3,5 dimethylphenyl EtOH 237-238 48 42 Isolated as p-Toluensulfonatsalz H phenyl Pr ¹ OH 133-133 32 43 H 44 * · *

(Example 45)

Similarly, 1,6-dimethyl-4- (1,2,3,4-tetrahydro-1-quinolyl-amino) -i. Methylaminopyrimidine iodide recovered as Dry substance in 28% yield, mp 128-130 ⁰ C, by reaction of e-methyl- '-. (I ^ .S ^ -tetrahydro-i-quinoiamino) ^ - Methylaminopyrimidine with methyl iodide. The required starting pyrimidino of the formula III (R ⁸ = CH ₃ , R ⁶ = H) was prepared analogously to the preparation of Example 20

prepared starting material and had the following properties:

R ² R ⁴ QA Rekrist. -14- Fp- ( ⁰ C) 297 406 Ill Solutions) yield NHMe et phenyl hexane 125-127 (%) 1 NHMe pr phenyl cyclohexane 140-141 62 2 NHMe Pr ¹ phenyl EtOAc 151-152 43 3 NHMe allyl phenyl - 114-116 34 4 NHMe Bu phenyl hexane 102-104 61 5 NHMe pentyl phenyl - 85-87 21 6 NHMe H phenyl EtOAc 135-136 47 7 NHMe me 4-chlorophenyl hexane 127-129 61 8th NHMe me 4-methylphenyl hexane 128-129 35 9 NHMe allyl 2,5-dimethylphenyl Et ₂ O 95-97 49 10 NHMe pentyl 2,5-dimethylphenyl Et ₂ O / pentane 97-99 53 11 NH ₂ me phenyl hexane / EtOAc 149-150 39 12 NH ₂ H 2-nitrophenyl butanol 188-189 35 13 NH ₂ H 4-clorophenyl butanol 214-217 50 14 NH ₂ H 2-ca'boxyphenyl H ₂ O 303 + (decomp.) 30 15 NH ₂ H 3,5-dimethylphenyl EtOAc / hexane 171-173 60 16 NH ₂ H 3,5-dichlorophenyl acetonitrile 175-176 63 17 NH ₂ H 3,5-dibromophenyl acetonitrile 179-181 61 18 NH ₂ me 2,5-dimethylphenyl ethanol 179-181 · 43 19 NH ₂ H 3,5-dimethoxyphenyl EtOAc / hexane 149-150 21 20 NMe ₂ H phenyl hexane / EtOAc 134-135 31 21 NMe ₂ H 2,5-dimethylphenyl pentane 110-111 35 22 NMe ₂ H 3,5-dimethylphenyl hexane 80-81 48 23 NMe ₂ me phenyl Et ₂ O " 166-167 34 24 78

* Isolated as fumarate salt ** Isolated as dibenzoyl tartrate salt

Similarly, the starting material for Example 45 was prepared, i. 6-Methyl-4- (1,2,3,4-tetrahydro-1-quinolylamino) -2-methylaminopyrimidine, as a dry substance in 41% yield, mp 215-216 "C (hydrochloride salt) by reaction of 4-chloro 6-methyl-2-methylaminopyrimidine with 1,2,3,4-tetrahydroquinoline.

Example 46

When using a method analogous to Example 1 but starting from the known compound (1,6-dimethyl-2-methylaminopyrimidin-4-one (Agai et al., Period. Polytech. Chem. Eng., 1974, 18, 47) which was brought into reaction with phosphorus oxychloride to produce a corresponding reactive quaternary derivative, to give 1,6-dimethyl-2-methylamino-4- (N-methyl-3-phenoxypropylamine) pyrimidine chloride as a dry substance, m.p. 167-169 ⁰ C (recrystallized from acetone / water) in 22% yield (partial hydrate: 0.25 H ₂ O).

Example 47-49

A mixture of 2-amino-4-chloro-1,6-dimethylpyrimidine iodide (1.43g, 5mM), N-allylaniline (0.67g, 5mM), dioxane (15ml) and Ν, Ν-dimethylformamide (15ml) became 15 Hours at 90-100 ° C heated. The volatiles were evaporated and the residue crystallized from ethanol to give 4-N-allylaniline-2-amino-1,6-dimethylpyrimidine iodide, (Example 47), (0.35 g, 15% yield), mp 271-272 ° C ; Microanalysis Results: C46.8%, H5.0%, N 14.9%; C ₁₅ H ₁₈ N ₄ I requires: 47.1% C, 4.97% H, 14.66% N; NMR (200MHz): 2.3 (3H, s, C x CH ₃ ), 3.45 (3H, s, N x CH ₃ ), 4.5-4.6 (2H, d, NCH ₂ ), 5 , 1-5.25 (2H, s + d, CH = CH ₂ ), 5.65-5.8 (1H, br, pyrimidine 5H), 5.8-6.0 (1H, m, CH = CH ₂ ), 7.3-7.6 (5H, complex, aromatic), 8.0-8.4 (2H, br, NH ₂ ).

(Note: Aminochloropyrimidine as the starting material is described in Ainley et al., J. Chem. Soc., 1953, 59-70).

Using a similar procedure, the following compounds of formula I were recovered:

(Example 48): 2-amino-4-N-ethylaniline-1,6-dimethylpyrimidine iodide as dry substance in 25% yield, mp 231-232 ° C (recrystallized from propan-2-ol) using N- Ethylaniline instead of N-allylaniline; and (Example 49): 2-amino-4 (p-methylt-nanoaniline) -1,6-dimethylpyrimidine iodide as a dry substance in 51% yield, m.p. 26O-262 ° C (recrystallized from water using p-methylthioaniline instead of N- allylaniline.

Example 50

When using a similar procedure described in Example 20 1,6-Dimethyl-4- originated (1-indolyl) -2-Methylaminopyrimidiniodid as dry substance in 33% yield, mp. 304-305 ⁰ C, (prepared by reaction of 4-indolyl ) -6-methyl-2-methylaminopyrimidine with methyl iodide.

The starting material was prepared as follows:

A mixture of 4- (indolinyl) -6-methyl-2-methylamino-pyrimidine (2.4 g, 0.01 M), 30% by mass palladium on charcoal (0.24 g) and diphenyl ether (10 ml) was allowed to stand for 1 h Reflux heated in argon atmosphere. The filtrate was then diluted with a quantity of hexane (100 ml). The result was a light yellow dry substance, recrystallized from propan-2-ol to give 4- (1-indolyl) -6-methyl-2-methylaminopyrimidine (1.47 g, 62%), m.p. 160-162 ° C; Microanalysis Results: C 70.5%, H 5.9%, N 23.6%; C ₁₄ H ₁₄ N ₄ requires 70.6% C, 5.9% H, 23.5% N.

Were recovered 4- (1-indolionyl) -6-methyl-2-methylaminopyrimidine in 45% yield as its hydrochloride salt, mp.> 300 ⁰ C using a similar procedure as for the analogous intermediate in Example 20, but by reaction of 4 Chloro-6-methyl-2-methylaminopyrimidine with indoline.

Example 51

A mixture of 2-methyl-6-methylamino-4-N-ethylaniline pyrimidine (0.7g, 2.9mM), methyl iodide (0.54ml, 8.7mM) and dioxane (20ml) was heated at reflux for 15 hours. The mixture was then cooled, the solvent removed in vacuo and the residue syrup crystallized with the addition of acetone. The dry substance was filtered off, washed with acetone and then recrystallized from ethyl acetate to give 1,2-dimethyl-6-methylamino-4-N-Ethylanilinpyrimidiniodid (0.55 g, 50% yield), mp 175-177 ⁰ C. Microanalysis results: c46.8%, H 5.6%, N 14.3%; C ₁₆ H ₂₁ N ₆ I requires: 46.88% C, 5.5% H, 14.58% N; NMR: 1.1-1.2 (3H, t, CH ₂ CH ₃ ), 3.9-4.1 (2H, q, CH ₂ CH ₃ ), 5.15 (1H, s, pyrimidine 5-H ), 7.3-7.65 (5H, complex, aromatic), 7.8-7.95 (IH, br, NH). Note: The quaternization site was confirmed by conventional nuclear Overhauser studies). The pyrimidine starting material was prepared as follows: A mixture of 4-chloro-2-methyl-6-methylaminopyrimidine 2.0g, 12.7mM) and N-ethylaniline (3.06g, 254mM) was melted at 160 for 3 hours ⁰ C heated. The residue was cooled and acetone (1 OmI) added. The resulting dry matter was filtered off and washed with acetone. 2-Methyl-6-methylarnino-4-N-ethylaniline pyrimidine (2.25 g) was recovered as the hydrochloride salt. This salt (2.25 g, 7.9 mM) was dissolved in propan-2-ol (50 ml) and a solution of potassium hydroxide (0.44 g, 7.9 mM) dissolved in a minimum of water was added. The mixture, the solvent was heated 5 min at 9O ⁰ C, removed in vacuo. The resulting dry matter was washed with water (25 ml) is stirred, filtered, washed with water and dried at 100 ⁰ C to 2-methyl-6-methylamino-4-N-Ethylanilinpyrimidin (1.4 g, 46% yield), mp. 144 -145 ° C, microanalysis results: C 69.1%, H 7.5%, N 22.8%; C ₁₄ H ₁₈ N ₄ requires 69.4% C, 7.5% H, 23.1% N.

Example 52-54

The procedure described in Example 51 was repeated using the corresponding substituted pyrimidine

of the formula III and of an alkylating agent of the formula I (A = direct bond, R ¹ = R ³ = CH ₃ , R ⁵ = HY "= iodide):

(Example 52): 1,2-dimethyl-6-methylamino-4-N-Methylanilinpyrimidiniodid as dry substance, mp 195-196 ⁰ C (rekristallisiertaus ethyl acetate), yield 65%;.

(Example 53): 1,2-Dime < ^I > -6-methylamino-4-N-methylanilinpyrimidine iodide as dry substance, mp 198-200 "C (recrystallized from propan-2-o!) ^> Zc / o Yield; and

(Example 54). 1,2-dimethyl-6-ethylamino-4-N-Methylanilinpyrimidiniodid as dry substance, mp 212-213 ⁰ C (rekristallisiertaus acetone) in 49% yield.

The required starting material was prepared in the manner analogous to that described in Example 51 and had the following Properties on:

a. 6-amino-2-methyl-4-N-Ethylanilinpyrimidin as dry substance, mp 126-127 ⁰ C (triturated with ether) in 71% yield.

b. 2-methyl-6-methylamino-4-N-Methylanilinpyrimidin as dry substance, mp 123-124 ⁰ C (triturated with ether) in 60% yield. and

c. 6-E * hylamino-2-methyl-4-N-methylaniline pyrimidine as a dry substance, m.p. 87-89 ⁰ C (triturated with methylene chloride) in 80% yield.

Example 55 Using an analogous procedure described in Example 51, 1,2-dimethyl-4- (1-indolyl) -6- Aminopyrimidiniodid as crystalline dry matter in 27% yield, mp. 286 ⁰ C (with decomposition), (after recrystallization from Methanol) by reaction of 6-amino-4- (1-indolyl) -2-methylpyrimidine with methyl iodide. The starting material was prepared as follows: A mixture of 6-amino-4- (1-indolinyl) -2-methylpyrimidine (4.5 g, 2OmM), 30Ma .-% palladium on charcoal (0.45 g) and Diphenyl ether (15 ml) was refluxed for 1 hour in argon atmosphere. The dry substance was filtered off and

dilute the filtrate with hexane (100 ml) to give 6-amino-4- (1-indolyl) -2-methylpyrimidine (4.25 g, 95%) as a pale yellow dry substance,

Mp 176-177 ⁰ C; Microanalysis results: C 69.5%, H 5.5%, N 24.4%; C ₁₃ H ₁₂ N ₄ requires C 69.64%, H 5.36%, H 25.0%. The 6-amino-4- (1-indolinyl) -2-methylpyrimidine was prepared as a dry substance, m.p. 209-210 ³ C, in a similar amount as

for the analogous intermediate in Example 51 by reaction of 6-amino-4-chloro-2-methylpyrimidine with indoline.

Example 56

A column of quaternary ammonium hydroxide anion exchange resin was prepared from Amberlite ⁺ IRA400 (chloride form) by eluting the resin with sodium hydroxide (1M solution) which was free of chloride ion from the eluate and then washing with deionate (until pH = 7 of the eluate ) and then with 10Ma .-% ethanol / water (500ml). A mixture of 1,2-dimethyl-6-methylamino-4-N-ethylaniline pyrimidine iodide (10.0g) and 10% by weight ethanol / water (200ml) was then poured into the column (approximate resin volume 100ml). The column was eluted with 10% by weight ethanol / water (11). The white solids crystallized from the eluate was filtered off and recrystallized from ethanol / water to give 1,2-dimethyl-6-methylamino-4-N-Ethylanilinpyrimidin (0.93g), mp 82-83 ⁰ C. Microanalysis results: C 70.1%, H 7.8%, N 21.9%, C ₁₆ H ₂₀ N ₄ required: 70.3% C, 7.84% H, 21.86% N; NMR: (200MHz, DMSOd ₈ ): 1.09 (3H, t, -CH ₂ CH ₃ ), 2.38 (3H, s, pyrimidine-2-CH ₃ ), 2.53 (3H, s, = N -CH ₃ ), 3.36 (3 H, s, pyrimidine N (1 J-CH ₃ ), 3.88 (2 H, q, -CH ₂ CH ₃ ), 4.78 (1H, s, pyrimidine 5 -H), 7.22-7.34 (3H, complex, aromatic), 7.40-7.50 (2H, complex, aromatic).

The filtrate was distilled under reduced pressure to reduce the volume to about 400 ml. The pH of the solution was carefully adjusted to 6.65 by addition of M-hydrochloric acid. The mixture was then evaporated to dryness and triturated with ethyl acetate. The white crystalline solids was recrystallized from a mixture of ethyl acetate and propan-2-ol to 1,2-dimethyl-6-methylamino-4-N-Ethylanilinpyrimidinchlorid (4,69g), mp. 201.5 to 202.5 ⁰ C , Microanalysis results: C 61.2%, H 7.3%, N 19.1%; C ₁₆ H ₂ , N <CI needed: 61.5% C, 7.2% H, 19.1% N; NMR (200MHz, DMSOd ₆ ): 1.14 (3H, t, -CH ₂ CH ₃ ), 2.61 (3H, s, pyrimidine-2-CH ₃ ), 4.01 (2H, q, -CH ₂ -CH ₃ ) AIS (IH, s, pyrimidine-5-H), 7.32-7.61 (5 H, complex, aromatic), 8.87 (1H, s, NH)

( ⁺ Amberlit is the trade name owned by Rohm and Haas Co.)

Example 57-76

Using a procedure analogous to that described in Example 20, the following compounds of the formula I were formed (R '= rs = CH ₃ , R ⁵ = H, Y "= iodide):

example R ² R ⁴ QA Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 57 NHMe et 4-methyl- MeOH / 196-199 88 phenyl EtOAc 58 NH · Crotyl H phenyl MeOH / 220-221 14 EtOAc 59 NHMe 2-butynyl phenyl Pr ¹ OH 191-193 47 60 NH ₂ 2-propynyl phenyl Pr ¹ OH 232-234 62 (Dec.) 61 NHEt et phenyl Pr ¹ OH 172-173 39 62 NHEt me phenyl Pr ¹ OH 183-184 39 63 NHEt allyl phenyl EtOAc 104-106 46 64 NHPr ¹ me phenyl Pr ¹ OH / 165-166 37 Et ₂ O 65 NHBu me phenyl Me ₂ CO / 146-147 40 Et ₂ O *

Note: Crotyl is the equivalent of but-2-enyl 'triturated with solvent

The following compounds of formula I (R ⁶ = CH ₃ , R ⁵ = H, Q * A = phenyl, Y "= iodide) arose in a similar manner:

example R ¹ R ² R ⁴ Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 66 et NH ₂ H H ₂ O 263-265 63 (Dec.) 67 et NH ₂ me Pr ¹ OH 213-214 39 68 pr NH ₂ me Me ₂ CO 199-202 13 69 et NHMe et Pr ¹ OH 146-148 58 (Dec.) 70 et NH ₂ et Pr ¹ OH 223-224 39 71 pr NH ₂ et cyclohexane 184-188 31 72 allyl NH ₂ et Pr ¹ OH 202-203 35 73 me piperidino et CH ₂ Cl ₂ * 160-162 17

* Triturated with solvent

(Example 74): 2-amino-1 -ethyl ^ -fS.S-Dimethylanilinl-e-Methylpyrimidiniodid originated in a similar way as a dry substance in 28% yield, mp 226-227 ⁰ C, by reaction of 2-amino-fourth - (3,5-dimethylaniline) -6-methylpyrimidine with ethyl iodide; (Example 75): 2-Amino-1 ö-dimethyl-4- (2-methyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine iodide was similarly prepared as a dry substance in 32% yield, m.p. 216 -218 ° C, by reaction of 2-amino-6-methyl-4- (2-methyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine with methyl iodide; and

(Example 76): 2-Amino-1,6-dimethyl-4- (1-dimethyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine iodide was similarly prepared as a dry substance in 8% yield, m.p. . 140-142 ⁰ C, by reaction of 2-amino-6-methyl-4- (2,4-dimethyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine with methyl iodide.

The required starting pyrimidines of the formula III (R ⁹ = CH ₃ , R ⁶ = H) were formed analogously to the starting material in Example 20 and had the following properties:

(Note: The starting material for Example 60 was formed by alkylating a solution of the starting material for Example 66 in dimethylformamide with propargyl bromide using sodium hydride as the base.)

Ill for Ex. R ² R ⁴ QA Rekrist. Fp ₁ ( ⁰ C) yield Lösgsm. (%) 57 NHMe et 4-methylphenyl Note (a) 138-140 44 58 NH · Crotyl H phenyl Note (a) oil 28 59 NHMe 2-butynyl phenyl EtOAc 141-143 57 60 NH ₂ -CH ₂ -C =CH phenyl cyclohexane 106-108 50 61 NHEt et phenyl Note (a) 91-93 76 62 NHEt me phenyl hexane 89-90 37 63 NHEt allyl phenyl Pr ¹ OH 112-113 61 64 NHPR me phenyl Et ₂ O 77-79 85 65 NHBu me phenyl Note (a) 146-147 54 66 NH ₂ H phenyl EtoAc 161-163 48

Continuation of the table

III R ² R ⁴ QA Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 67.68 NH ₂ me phenyl hexane / 148-150 35 EtOAc 69 NHMe ' et phenyl hexane 125-127 62 70-72 NH ₂ et phenyl Note (a) 113-114 64 73 piperidino et phenyl - oil 99 74 NH ₂ H 3,5-Me ₂ - EtOAc / hexane 117-173 03 phenyl

Note: Crotyl is the equivalent of but-2-enyl

(a): Purified by chromatography on silica gel using ethyl acetate / hexane as eluent.

The starting material 2-butylamino-4-chloro-6-methylpyrimidine required to prepare Compound III for Example 65 was formed as follows:

2-Butylamino-6-methylpyrimidin-4-one (8.4g, 0.046M) was treated with phosphorus oxychloride (5ml). A violent reaction ensued. After fading, the resulting mixture was heated at 90 ° C for 30 minutes. An orange-colored syrup was formed which was cooled and added to the water to decompose the excess phosphorus (V) oxide chloride. The aqueous solution was adjusted to pH 7 using 2M sodium hydroxide solution. The white precipitate was extracted with methylene chloride. The extract was dried (MgSO ₄ ) and the solvent evaporated. This gave 2-butylamino-4-chloro-6-methylpyrimidine (8.1 g) as a dry substance, mp. 35-36 ⁰ C, in 88% yield.

The 4-aniline-2-crotylamino-6-methylpyrimidine starting material for preparing Compound III for Example 58 was prepared as follows:

A mixture of 2-amino-4-aniline-6-methylpyrimidine (1g, 5mrv1), potassium carbonate (0.4g, 5.5mM), crotylbromide (0.61ml) (SmM) and acetone (25ml) became 20h heated to reflux. Then the solvent was evaporated and the residue triturated with methylene chloride. The methylene chloride extracts were bound and the solvent evaporated. The residue syrup was purified by flame chromatography with silica gel Merck 9835 (200 g) and eluted with 5% by weight methanol / methylene chloride. Thus, 4-aniline-2-crotylamino-6-methylpyrimidine was formed as a viscous oil (0.36 g) which was used without labeling.

The 2-amino-6-methyl-4- (2-methyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine as starting material for Example 75 was created as a dry substance in 32% Aubeute, mp. 140-142 ⁰ C, by reaction of 4-chloro-6-methyl-2-methylaminopyrimidine with 2-methyl-1,2,3,4-tetrahydroquinoline. Similarly, the starting material was 2-amino-6-methyl-4- (2,4-dimethyl-1,2,3,4-tetrahydro-1-quinolylamino) pyrimidine for Example 76 as a dry substance in 44% yield, m.p. 144 ~ 146 ° C, by reaction of 4-chloro-6-methyl-2-methyl-aminopyrimidine with the known compound 2,4-dimethyl-1,2,3,4-tetrahydroquinoline (Chemical Abstracts Registry No. 67525-06 -8th).

Example 77-102

The procedure described in Example 20 was repeated using the corresponding substituted pyrimidines of the formula III and an alkylating agent of the formula R ¹ .I.

The following compounds of formula I were obtained

(Q.A = phenyl, R ^s = H, Y "= iodide):

Ex. R ¹ R ² "Sc R " Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 77 me NHY me et MeOH / Et ₂ O 226-230 " 64 78 me NH ₂ me pr dioxane 206-210 " 62 79 me NH ₂ me Bu PrOH / Et ₂ O 173-174 62 80 me NH ₂ me Bu ¹ PrOH / Et ₂ O 167-168 48 81 me NH ₂ me PhCH ₂ CH ₂ Pr'OH / Et ₂ O 175-180 44 82 me NH ₂ me 3-butenyl Pr'OH / Et ₂ O 148-150 53 83 et NH ₂ me et MeOH / Et ₂ O 194-196 " 23 84 et NH ₂ me pr MeOH / Et ₂ 0 199-201 " 18 85 me NHMe me et MeOH / Et ₂ O 208-210 " 26 86 me NH ₂ et et MeOH / Etjo 236-238 " 16 87 me NH ₂ et pr MeOH / Etjo 198-200 " 59 88 me NHY et Bu PrOH / Et ₂ O 147-148 35 89 me NH ₂ et pentyl PrOH / Et ₂ O 164-166 66 90 me NH ₂ et 3-butenyl Pr'OH / Etjo 133-134 39 91 me NH ₂ et EtOCH ₂ PrOWEt ₂ O 208-212 74 92 me NHMe et et MeOH / Et ₂ O 158-160 35 93 me NHMe et pr MeOH / Et ₂ O 143-145 31 04 et NH ₂ et et MeOH / Et ₂ O 190-192 " 38 95 et NH ₂ et pr MeOH / Et ₂ O 196-198 " 51

-18- 297 406 Continuation of the table

Boisp. R ¹ R ² R ⁴ R ^e Rekrist. Mp CC) yield Lösgsm. 1%) 96 me NHEt me et MeOH / Et ₂ O 183-186 " 48 97 me NHEt me pr MeOH / Etjo 168-170 ·· 39 98 me NHEt et et MEOWEt ₂ O 160-163 * 44 99 me NHEt et CH ₂ OEt Pr'OH / Et ₂ O 130-131 58 100 et NHEt et ET MeOH / Et ₂ O 165-167 29

Note: * Melting point with decomposition

** recovered as partial methanolate (0.5 MeOH)

The necessary starting pyrimidines of the formula III

(Q.A = phenyl, R ⁶ = H) were formed analogously to the starting material of Example 20 and had the following properties:

lllfürBeisp. R ² R ⁴ R ^e Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 1 2 3 4 5 6 7 77.83 NH ₂ me et Et ₂ O 105-106 14 78.84 NH ₂ me pr Et ₂ O / hexane 104-106 24 79 NH ₂ me Bu hexane 66-67 65 80 NH ₂ me Bu ' hexane 107-109 78 81 NH ₂ me PhCH ₂ CH ₂ Et ₂ / hexane 110-111 55 82 NH ₂ me But-3-enyl hexane 46-48 46 85 NHMe me et + 84-88 17 86 NH ₂ et et + 115-117 87 87 NH ₂ et pr + 93-95 64 88 NH ₂ et Bu hexane 87-88 44 89 NH ₂ et pentyl hexane 102-103 86 90 NH ₂ et But-3-enyl hexane 79-81 46 91 NH ₂ et EtOCH ₂ + 126-128 32 92 NHCH ₃ et et + 118-122 11 93 NHCH ₃ et pr + 80-82 8th 96 NHEt me et + oil 20 97 NHEt M9 pr + oil 44 98,100 NHEt et et + 68-72 61 99 NHEt et EtOCH ₂ hexane 50-51 55

+ Purified by Rurnmenchromatographleeuf silica gel using 0.5Ma .-% methanol in dichloromethane as the eluent and used without further purification.

The following compounds of the formula I were formed in a similar manner:

(Example 101): 2-Amino-4- (N-ethylaniline) -5,6,7,8-tetrahydro-1-methylquinazoline iodide was formed as a partial hydrate (0.25H ₂ O), m.p.

221-223 ⁰ C (after recrystallization from methanol / ether) in 48% yield by reaction of methyl iodide with 2-amino- (4-N-ethylaniline) -5,6,7,8-tetrahydroquinazoline, (the latter compound as a dry substance , Mp 132-134 ° C, in 11% yield by reaction of 2-amino-4-chloro-5,6,7,8-tetrahydroquinazoline with N-ethylaniline).

(Example 102): 2-Amino-4- (N-ethylaniline) -1-methylquinazoline iodide was similarly produced as a dry substance, mp 252-254 ° C (dec.) (Recrystallized from methanol / ether) in 37% yield by reaction of methyl iodide with 2-amino- (4-N-ethylanilinJ-quinazoline, (the latter compound as a dry substance, mp. 168-170 ⁰ C, 11% yield by reaction of 2-amino-4-chloroquinazoline with N ethylaniline).

Certain chloropyrimidines of formol IV (X = Cl, R ⁵ = H) used as starting material in Example 77-102 are known compounds and can be found in the following references:

(a) R "= H, R ² = NH ₂ ; Tetrahedron, 1968, 24, 3595;

(b) R ⁶ = Et, R ² = NH ₂ ; Belgian Patent No. 657,135,15. Jan. 1965;

(c) R ⁶ = CH ₂ CH ₂ Ph, R ² .NH ₂ ; J. Org. Chem., 27.1717.

The process for preparing the other chloropyrimidines of the formula IV (X = Cl, R ⁵ = H) is illustrated by the following preparation of 4-chloro-2-ethylamino-6-propylpyrimidine:

(a) Ethyl 3-oxo-hexanoate (4.74g, 30mM) and N-ethyl-gluanidine sulfate (4.08g, 30mM) were dissolved in a solution of dissolved sodium (1.4g, 0.65 gram atom) in ethanol (100ml ), then the mixture was heated at reflux in the steam bath for 18 hours. Then, ethanoic acid (5 ml) was added and the cooled mixture was stirred for 10 minutes. Insoluble substances were filtered off and the filtrate was evaporated. The residue was partitioned between water (50 ml) and methylene chloride (50 ml). The aqueous layer was extracted twice with methylene chloride (50 ml). The bound extracts were dried and the solvent evaporated. The residue was crystallized from cyclohexane to give 2-ethylamino-4-hydroxy-6-propylpyrimidine as a dry substance (4.6 g, 85% yield), mp. 108-110 ⁰ C.

(b) A mixture of 2-ethylamino-4-hydroxy-6-propylpyrimidine (1.81 g, 1OmM) and phosphorus (V) oxychloride (15ml) was heated at 100 ⁰ C for 18 hours. The excess of phosphorus oxychloride was removed at reduced pressure and the

Residue decomposed with ice water (50ml). The solution was basified with concentrated ammonia water and extracted with ethyl acetate (3 × 50 ml). The extracts were bound, dried and the solvent evaporated to 4-chloro-2-ethylamino-6-propylpyrimidine (1.79 g, 90% yield) as an oil which was used without further refining.

Other chloropyrimidines of the formula IV (X = Cl, R ⁵ = H) were formed in a similar process from the corresponding hydroxypyrimidines of the formula IV (X = OH, R ^s = H). The latter compounds had the following properties:

No. R ² R " Rekrist. Mp ( ⁰ C) yield l.ösgsm. (%) 1 NH ₂ Bu + 212-216 85 2 NH ₂ Bu ¹ + 231-234 30 3 NHY 3-butenyl + 186-189 83 4 NHY pentyl + 188-191 79 5 NH ₂ EtOCH ₂ + 244-245 69 6 NHMe et EtOAc 204-208 46 7 NHMe pr EtOAc 190-192 54 8th NHEt et cyclohexane 144-146 39 9 NHEt CH ₂ OEt cyclohexane 106-108 54

+ Triturated with ether and used without further purification.

Most chiorpyrimidines of formula IV (X = Cl, R ⁶ = H) were used without labeling, but the following were described:

No. R ² R ^e Rekrist. Lösgsm. Mp ( ⁰ C) Yield (%) 1 2 3 NHj NH ₂ NH ₂ Bu Bu ¹ pentyl EtjO / hexane EtjO / hexane EtjO / hexane 58-59 104-106 58-59 50 33 29

The starting material, the 2-amino-4-chloroquinazoline derivatives (from which the 2-amino-4-N-ethylaniline starting material for Examples 101 and 102 was prepared), was formed in a manner similar to the above chloropyrimidines and was used without purification ,

The 2-amino-4-hydroxyquinazoline derivatives as starting material were obtained as dry substances, mp> 300 ^° C. using methods known in the literature (for example 2-amino-5,6,7,8-tetrahydro-4-one) -Hydroxyquinazoline, Chem. Pharm. Bull.

(Japan), 1986, 34, 4150; 2-amino-4-hydroxyquinazoline: Rec. Trav. chim. Pays. Bas., 7960, 79, 433).

Example 103-109

Using a similar procedure to that described in Example 47, the following compounds of Formula I were prepared (shown below):

Ex. X R ⁴ Rekrist. Mp (X) yield Lösgsm. (%) 103 H pr Me ₂ CO * 250-255 25 104 H But-2-ynyl Me ₂ CO 182-184 47 105 H Bu Pr'OH / Etjo 184-186 25 106 2-MeQ et Pr'0H / Et, 0 267-269 12 107 2-Me et CH ₂ Cl ₂ * 216-217 22 108 4-CI et MeOH / Et ₂ O 244-246 42 109 4-Me et MeOH / Etjo 240-242 32

'Triturated with solvent.

Example 110-112

By analogy with Example 20 procedure, but with output of the corresponding 4- (indol-1yl) -6-methylpyrimidine of the formula 2 (set forth below) and with an alkylating agent of formula R 'I, the following compounds of formula 3 (hereinafter set forth R ⁶ -CH ₃ ):

Ex. rV R ² X B Rekrist. Fa ( ⁰ C) yield Lösgsm. (%) 110 et NHMe H H dioxane · 294-295 6 111 me NHMe H 2-Me EtOH / HaO 301-302 ·· 43 112 me NHMe 5-MeO H EtOH / HaO 304-305 ·· 31 113 me NH ₂ H H EtOH / Etjo 295-296 55 114 et NHY H H EtOH · 28-1-286 7 115 me NHY 5-MeO H H ₂ O / EtOH 297-298 47

-20- 297 406 Continuation of the table

Ex. R ¹ R ² X B Rekrist. Mp CC) yield Lösgsm. (%) 116 me NH ₂ H 2-Me EtOH / H ₂ O 286-288 43 117 me NHY 5-CI H EtOH / H ₂ O 288-290 37 118 me 'NH ₂ 5CN H EtOH 280-282 10 119 me NHY 5-Br H EtOH / HaO 295-298 41 120 me NHY 5-Me H EtOH / H ₂ O 287-288 37 121 me NH ₂ 7-aza H EtOH / HaO 285 ·· 9 122 me NH ₂ 5-F H MeOH 279-281 15

* triturated with solvent ·· with decomposition

The indolyl starting material for Example 110 and 113 was formed similarly as in Example 20 and Example 50 by dehydration of the corresponding 4- {indolin-1-yl) pyrimidine with 30 mass% palladium on charcoal heated under reflux with diphenyl ether in argon atmosphere. The required 2-amino-4- (1-indolinyl) -6-methylpyrimidine as starting material was obtained as a dry substance, mp. 242-244 ° C in 48% yield and similar to the analogous intermediate in Example 13 by reaction of 2-amino 4-Chloro-6-Mylthylpyrimidine with indoline.

The remaining indolyl starting material of formula 2 was formed by alkylation of the corresponding indole with the required chloropyrimidine in dimethylformamide used as the base of a dispersion (60% by mass) of sodium hydride in mineral oil.

The following 4- (indol-1-yl) -6-methylpyrimidine derivatives of the formula 2 (R ⁶ = CH ₃ ) were obtained:

Verb. 2 R ² X B Rekrist. Mp ("C) yield for example Lösgsm. (%) 110 NHMe H H PrOH 160-162 62 111 NHMe H 2-Me cyclohexane 163-165 54 112 NHMe 5-MeO H EtOAc 188-189 47 113,114 NH ₂ H H CH ₂ Cl ₂ * 178-180 56 115 NH ₂ 5-MeO H EtOH 179-180 28 116 NH ₂ H 2-Me EtOAc 186-188 48 117 NH ₂ 5-CI H EtOAc 193-195 42 118 NHY 5-CN H EtOAc 210-212 56 119 NH ₂ 5-Br H Me ₂ CO 194-196 21 120 NH ₂ 5-Me H EtOAc 186-188 33 121 NH ₂ 7-aza H cyclohexane 171-173 35 122 NH ₂ 5-F H EtOAc 198-200 38

* Triturated with solvent

Example 123-125

By a similar procedure as in Example 20, the following compounds of the formula I were obtained:

(Example 123): 1,6-Dimethyl-4- (indolin-1-yl) -2-methylamino-pyrimidinium iodide as dry substance, mp> 300 ° C. (recrystallized from dimethylformamide), in 74% yield, starting from 4- (indolin-1-yl) -6-methyl-2-methylaminopyrimidine (described above in connection with Example 50);

(Example 124). 2-Amino-1,6-dimethyl-4- (indolin-1-yl) Pyrimidiniodid as dry substance, mp 274-276 ⁰ C (recrystallized from ethanol), yield 43%, starting from 2-amino -4- (indolin-1-yl) -6-methylpyrimidine, itself formed in 64% yield as a dry substance, mp. 157-159 ⁰ C (recrystallized from cyclohexane), using a similar procedure as described for the analogous starting material in example 50, however, using 2-methylindoline in place of indoline; and (Example 125). 2-Amino-1,6-dimethyl-4- (2,3-dimethylindolin-1-yl) Pyrimidiniodid as dry substance, mp 279-281 ⁰ C (recrystallized from ethanol), in 55% yield , Output of 2-amino-6-methyl-4- (2,3-dimethylindolin-1-yOPyrimidine, itself produced in 50% yield as a dry substance, mp. 179-181 ⁰ C (recrystallized from ethyl acetate) in a similar procedure as for the analogous starting material in Example 50, but using 2,3-dimethylindoline instead of indoline.

Example 126-130

In a similar procedure as described in Example 51 but starting with the corresponding substituted pyrimidine of Formula III and methyl iodide, the following compounds of Formula I were formed (QA = phenyl, R ¹ = R ² = CH ₃ , _R 6 = H , Y- = iodide):

Ex. R ⁴ R ^e Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 126 me NHY Propane-2-ol 228-230 86 127 allyl NHMe EtOAc / MeOH 68-71 59 128 But-2-ynyl NHMe EtOAc / MeOH syrup 15 129 pr NHMe EtOAc 139-140 38 130 Pr ⁰ · CH ₂ NHMe EtOAc 147-149 47 Note: Pr ¹ = cyclopropyl

The required starting material of the formula III was obtained analogously to the described starting material of Example 51 from the corresponding chloropyrimidines of the formula IV (X = Cl) and had the following properties:

III R ⁴ R ^e Rekrist. Mp ( ⁰ C) yield fürBeisp. Lösgsm. (%) 126 me NH ₂ CH ₂ Cl ₂ 128-130 53 127 allyl NHMe Et ₂ O 98-101 43 128 But-2-ynyl NHMe - syrup 45 129 Pr " NHMe hexane 114 to 114.5 53 130 Pr ⁰ · CH ₂ NHMe hexane 98-100 28

Note: Pr ^c = cyclopropyl * with satisfactory NWR spectrum

Example 131-135

The process described in Example 51b was repeated using the corresponding substituted pyrimidine of Formula III and methyl iodide. It ent stood the following compounds of formula I (QA = phenyl, R ¹ = CHj, R ⁶ = H, R ^e = NHCH ₃₁ Y "= iodide):

Ex. R ⁴ R ² Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 131 me et PrOH / Et ₂ O 173-174 41 132 me H PrOH / Et ₂ O 172-173 81 133 et et EtOAc 146-147 44 134 et pr Me ₂ C0 / Et ₂ 0 127-130 27 135 et Bu MeOH / Et ₂ O 144-146 19

The required starting material of the formula III (QA = phenyl, R ² = CH ₃ , R ⁵ = H) was analogous to the described starting material of Example 51 from the corresponding chloropyrimidine of the formula IV (X = Cl) and had the following properties:

No. R ⁴ R ² levigating Fp- ( ⁰ C) yield medium (%) 131 me et CH ₂ Cl ₂ 98-100 71 132 et H PrOH / Et ₂ O 113-114 44 133 et et CH ₂ Cl ₂ ^ 97-99 63.5 134 et pr CH ₂ Cl ₂ 69-71 22 135 et Bu hexane 75 to 75.5 31

The required chloropyrimidine starting material of formula (IV) was prepared by adding the corresponding 2-substituted-4,6-dichloropyrimidine to an alcoholic solution of the required amine with cooling below 1O ⁰ C. The reaction mixture was then warmed to ambient temperature and the solvent evaporated , The residue was partitioned between water and methylene chloride. The organic phase was dried (MgSO ₄ ) and concentrated in vacuo to give the required compound of formula IV (X = Cl):

(a) 4-Chloro-2-ethyl-6-methylaminopyrimidine as dry substance, mp 80-81 ⁰ C.

(b) 4-chloro-6-methylamino-2-propylpyrimidine as dry substance, mp 30-40 ⁰ C. and

(c) 2-butyl-4-chloro-6-methylaminopyrimidine as an oil.

Example 136-139

The procedure described in Example 51 was repeated using the corresponding substituted pyrimidine of the formula III and an alkylating agent of the formula R 'Y. The following compounds of the formula I were formed (R ⁴ = Et, R ² = CH ₃ , R ⁵ = H , R ^e = NHCH ₃ ): A = direct bond

Ex. QA R ¹ Y Rekrist. Mp ( ⁰ C) yield Lösgsm. (%} 143 p-tolyl me I MeOH / Et ₂ O 188-191 31 147 p-An isy I me I EtOH 211-214 40 148 p-CI-phenyl me I MeOH / Etjo 243-245 60 149 phenyl et BF ₄ EtOAc * 126-128 8th

* Triturated with solvent

The required starting material of the formula IiI was formed analogously to the starting material of Example 51, but using the corresponding N-ethylaniline:

. (a) 4- (N-ethyl-4-methyl aniline) -2-methyl-6-methylaminopyrimidine as dry substance, mp 140-143 ⁰ C, in 70% yield;

(b) 4- (N-ethyl-4-methoxyaniline) -2-methyl-6-methylaminopyrimidine as dry substance, mp 116-118 ⁰ C, in71% yield. and

(c) 4- (N-ethyl-4-chloroaniline) -2-methyl-6-methylaminopyrimidine as dry substance, mp. 133-136 ⁰ C, in 79% yield. Note: The required starting material of Formula III for Example 139 is described in Example 51.

Example 140-144

By a similar procedure to Example 56, the following 1,2-dimethyl-6-methylamino-4-N-ethylaniline pyrimidine salts were formed by reaction of 1,2-dimethyl-6-methylamino-4-N-ethylaniline pyrimidine with the appropriate acid:

Example salt recrystalli- Mp ( ⁰ C) yield sationslüsung (%) 140 fumarate acetonitrile 152-154 80 141 benzoate hexane * 46-47 93 142 bisulfate Pr'OH / Etjo 146-147 58 143 acetate hexane · 43-45 62 144 butyrate Et ₂ O / hexane 52-58 56

Triturated with solvent

Example 145-154

By a similar procedure as in Example 51, but starting from the corresponding substituted 4- (indol-1-y I) -pyrimidine of the formula 2 and of methyl iodide, the following 4- (indol-1-yl) -1,2- Dimethyl 6-methylaminopyrimidine salts of formula 3 (R ¹ = R ² = CH ₃ and R ⁸ = NHCH ₃ with exceptions):

Ex. X B Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 145 H H MeOH 270-272 14 (Decomp.) 146 ⁺ H 3-Me MeOH 276-277 7 147 H 3-Me EtOH / H ₂ O 257-258 24 148 H 3-Et EtOH 259-260 16 149 » H 3-Et EtOH 249-250 24 150 ' H 3-Et EtOH 240-242 21 151 H 3-Pr EtOH 245-247 35 152 H 3-Ph MeOH / H ₂ O 254.5 to 255.5 20 153 H 3-Pr ^! H ₂ O 251-252 4 154 5-MeO H MeOH 309-310 8th

+ R «= NHj * R * = Et ·· R '= NHEt

The starting material, the 4- (indol-1-yl) pyrrole of formula 2 for example 145, 149 and 150, was formed from the corresponding indoline and chloropyrimidine in a manner similar to the analogous starting material in example 55. The preparation of 4- (indole-1 -Y-pyrimidines of the formula 2 as starting material for Example 146.147 and 151-154 is illustrated by the following formulation of the starting material for Example 148:

A mixture of 3-ethylindole (1.45 g, 10 mM), sodium hydride (60% by weight oil dispersion) (0.44 g, 11 mM) and dry dimethylformamide (10 ml) was stirred under argon atmosphere. After completion of the foaming, a mixture of 4-chloro-2-methyl-6-methylaminopyrimidine (1.575 g, 10 mM) and dimethylformamide (15 ml) was added. The mixture was stirred for 20 hours at 11O ⁰ C, cooled, then water was added (10ml) and the solvent evaporated. The residue was dissolved in methylene chloride and purified by flash column chromatography on silica gel (Merck 9385) using ether as eluent to give 4- (3-ethyl-1-indolyl) -2-methyl-6-methylaminopyrimidine as a dry substance (0.64g, 25 %), mp 161-162 ⁰ C (after recrystallization from ethyl acetate). Microanalysis results: C 72.4%, H 6.9%, N 21.1%, C ₁₆ H ₁₈ N ₄ requires 72.18% C, 6.77% H, 21.05% N.

The following are the properties of the various starting materials of formula 2 for example 145-154 in summary:

Verb. 2 X B R ² R ⁹ Rekrist. Mp ( ⁰ C) yield for example Lösgsm. (%) 145 H H me NHMe Et ₂ O 153-154 65 146 H me me NH ₂ EtOAc 183-184 29 147 H me me NHMe EtOAc / hexane 156-157 32 148 H et me NHMe EtOAc 161-162 25 149 H et et NHMe cyclohexane 128-130 58 150 H et me NHEt cyclohexane 117-118 44 151 H pr me NHMe EtOAc * 144-146 31 152 H Ph me NHMe Et ₂ O 151-152 35 153 H pr me NHMe hexane 130-131 40 154 5-MeO H me NH ₂ EtOAc 162-164 31

triturated with solvent

The 4- (indole-1-yl) -6-aminopyrimidines of Formula 4 (set forth below), required as starting material of Formula 2, for Example 145.149 and 150, are similar to the analogous intermediate in Example 51 by reaction of the corresponding substituted indoline with the required chloropyridine and had the following properties:

No. B R ² R ^e Rekrist. Lösgsm. Fp ₁ ( ⁰ C) Yield (%) 1 2 3 H 3-Et Et   Me Et Me NHMe NHMe NHEt Ether / hexane EtOAc MeCN 174-177 168-170 146-148 93 32 17

Example 155-158

By a similar procedure to Example 51, the following indolin-1-yl compounds of formula 5 (set forth below) were prepared by reaction of the corresponding indoline of formula 4 (R ⁶ = NHCH ₃ ) with methyl iodide:

No. B R ² Rekrist. Mp ( ⁰ C) yield Lösgsm. (%) 155 H me EtOH 281-283 »» 50 156 3-Me me EtOH 261-262 51 157 3-Et et ether " 240-241 »» 36 158 3-Et me EtOH 262-263 51

* triturated with solvent ** with decomposition

The starting indolines of formula 4 described above (ie in conjunction with examples 145 and 149) can also be obtained analogously by reaction of the corresponding substituted indoline with the required chloropyrimidine derivative. Thus, the following additional starting materials of the formula 4 were formed (R ⁶ = NHCH ₃ ):

Verb no. B R ² Rekrist. Lösgsm. Mp ( ⁰ C) Yield (%) 4 5 3-Me 3-Et Me Me EtOAc EtOH 164-165 178-180 59 25

Example 159

A mixture of 4-N-ethylaniline-2-methyl-1-phenylpyrimidin-6-one (0.6g, 1.76mM) and phosphorus oxychloride (6ml) was refluxed for 2 hours. The excess of phosphorus oxychloride was evaporated. The residue was dissolved in toluene and the solvent evaporated. The process was repeated and the oily residue (containing the corresponding chloride salt of the dichlorophosphinoyl derivative of the starting pyrimidone) was added slowly to a stirred solution of methylamine in ethanol (10 mL of 33% by mass). After 16 hours, the solvent was evaporated. 1M sodium hydroxide solution (10ml) was added to the residue and the mixture extracted with ether (2 x 10ml). The extracts were dried by filtering through phase separation paper and treated with ethereal hydrogen chloride. The precipitate was filtered off and recrystallized from ethanol / ether to 4-N-ethylaniline-2-methyl-6-methylamino-1-phenylpyrimidinium chloride (0.364 g), m.p.> 330 ° C; Microanalysis results: c 64.8%, H 6.6%, η 15.2%; C ₂₀ H ₂₃ N ₄ Cl · 0.75H ₂ O required: 65.2% C, 6.7% H, 15.2% N, NMR (200MHz): 1.1 (3H, t, CH 3), 2 , 7 (3H, s, CH _3), 3.8 (3H, s, CH _3), 4.0 (2H, q, CH _2), 5.24 (1H, s, CH), 7,1- 7.3 (1OH, complex, aromatic H)

 The starting material was prepared as follows:

(i) A mixture of 2-methyl-1-phenyl-1,4,5,6-tetrahydropyrimidine-4,6-dione (obtained by the method of LB Dashkevich, Dokl. Akad. Nauk, SSSR, 1962, 1445, 333), (2.02 g, 1OmM) and phosphorus (V) oxychloride (10 ml) was heated for 1 hour at 100 ⁰ C. The excess of phosphorus oxychloride was evaporated and the residue was added with stirring to ice-water. Sodium carbonate was added to the stirred mixture until foaming ceased. The mixture was extracted with methylene chloride (2 × 20 ml), the extracts were dried by filtering through phase separation paper, the filtrate was stretched to 250 ml with methylene chloride and subjected to filtration chromatography on silica gel (Merck 7736). 2-methyl -1-Phenylpyrimidm-6-one (1.1 g), mp 109-119 ⁰ C; NMR (200MHz):. 2.28 (3H, s, CH _3), 6.5 (1H, s, CH), 7.15-7.6 (complex, 5 aromatic H).

(ii) A mixture of the above Chlorpyrimidinon (1.1 g, 5OmM) and N-ethylaniline (1.81 g, 15 mM) was heated 18 hours under argon at 180 ⁰ C (external temperature). After cooling, 15 ml of ether was added to the mixture. The precipitate of N-ethylaniline hydrochloride was filtered off. The filtrate was evaporated and the residue was partitioned to 10% sodium carbonate solution and methylene chloride. The organic layer was dried with phase separation paper and evaporated. The residue was purified by flame chromatography on silica gel (Merk 9385) using 3: 1 parts by weight of ethyl acetate and hexane to produce (after re-crystallization of ethyl acetate / hexane) 4-N-ethylaniline-2-methyl-phenylpyrimidine-6- one (0.68 g), Fp.131-132 ^o C; NMR (200MHz): 1.21 (3H, t, CH3), 2.1 (3H, s, CH _3), 3.9 (2H, q , CH2), 5.1 (1H, s, CH), 7.14-7.55 (complex, 10 aromatic H).

Example 160

A mixture of 1,2-dimethyl-4-N-Ethylanilinpyrimidin-6-one (1.13 g, 4,65mM) and phosphorus (V) oxychloride (10 ml) was heated 4 hours at 100 ⁰ C. The excess of phosphorus (V) oxide chloride was evaporated. The residual gum (with the corresponding chloride salt of the dichlorophosphinoyl as a derivative of the starting pyrimidinone) was dissolved in ethanol (10 ml).

To this solution was added dropwise with stirring and ice-cooling an 32% solution of methylamine in ethanol (10ml) was added so that the temperature reached 30 not ^0th The solution was kept at room temperature for 2 hours after completion of the addition. The solvent was evaporated and the residue was partitioned to 10 mass% sodium carbonate solution (20 ml) and ether (20 ml). The aqueous layer was separated and extracted with methylene chloride (4 x 10 ml). The bound organic extracts were dried (MgSO ₄ ) and evaporated to give a gum (1.3 g) which was crystallized from a mixture of acetone and ether to give 1,2-dimethyl-4-N-ethylaniline-6-dothylaminopy imidinchlorid as dry substance (0.81 g), mp. 202-203 ⁰ C.

The starting material was prepared as follows:

(i) 4-chloro-6-hydroxy-2-methylpyrimidine (1.3 g, 1OmM) and N-ethylaniline (5ml) were heated for 4 hours to 200 ⁰ C under argon. The mixture was then cooled to room temperature and treated with ethanol (10ml). The crystalline dry matter thus obtained was isolated by filtration, washed with ethanol and dried to give 4-N-ethylaniline-6-hydroxy-2-methylpyrimidine (1.28g), m.p. 265-266 ° C, NMR (200MHz): 1.0-1.1 (3H, t, CH _3), 2.0 (3H, s, CH _3), 3.9 (2H, q, CH _2), 4.5 (1H, s, CH) , 7.2-7.5 (complex, 5 aromatic H), 11.5-11.64 (1H, br, NH).

(ii) A mixture of the above aniline pyrimidine (1.15 g, 50 mM), methyl iodide (1.9 ml, 0.03 mmol) and potassium hydroxide flakes (0.56 g, 10 mM) in ethanol (50 ml) was refluxed for 4 hours. Further quanta of potassium hydroxide (0.56g) and methyl iodide (1.9ml) were added and the whole heated for a further three hours. The solvent was evaporated and the residue was partitioned between 2M sodium hydroxide (25ml) and ether (25ml). The ethereal layer was deposited, dried (MgSO ₄ ) and the ether evaporated to give 1,2-dimethyl-4-N-ethylanilinopyrimidin-6-one as an oil (1.13g), NMR (200MHz): 1.17 (3H, t, CH _3), 2.45 (3H, s, 6H _3), 3.4 (3H, s, CH _3), 3.92 (2 H, q, CH _2), 5.05 ( 1H, s, CH), 7.1-7.47 (complex, 5 aromatic H).

Example 161-186

The general procedure described in Example 1 was repeated, but starting from the corresponding 1,2-disubstituted-8-methylpyrimidin-1-one of the formula 6 (set out below) for the in-situ generation of the chloride salt of the dichlorophosphinoyl derivative of the starting Pyrimidinone, the latter being brought in reaction with N-ethylaniline or N-methylaniline to give the following compounds of formula I (QA = phenyl, R ^e = CH ₃ , R ⁶ = H, Y "= CD:

Ex. R ¹ R ² R ⁴ Fp ₁ ( ⁰ C) yield Rekrist. (%) Lösgsm. 161 2-MeO-Ph NH ₂ et 267-268 ¹⁺ 30 Me ₂ OVEt ₂ O 162 4-Me-Ph NH ₂ et 215-216 " 29 Me ₂ CO 163 2-Me-Ph NH ₂ et 252-253 19 * EtOH / Et ₂ O 164 3-MeO-Ph NH ₂ et 158-160 34 EtOAc 165 4-MeO-Ph NH ₂ me 218 22 * Me ₂ OVEt ₂ O 166 Bu NH ₂ et 216-217 12 Me ₂ C0 / Et ₂ 0 167 Bu ¹ NH ₂ et 280-282 ^{c +} 19 Me ₂ C0 / Et ₂ 0 168 Bu NH ₂ me 235-237 ' 8th Me ₂ C0 / Et ₂ 0 169 Pr ' NH ₂ et 213-214 26 Me ₂ C0 / Et ₂ 0 170 pentyl NH ₂ Ft 199-200 28 Me ₂ OVEt ₂ O 171 4-MeO-Ph NHEt bt 176-177 " 42 Me ₂ OVEt ₂ O 172 4-MeO-Ph NHMe et 223-225 ⁺ 15 EtOH / Et ₂ O 173 hexyl NHMe et 148-149 45 Me ₂ O / Et ₂ O 174 PhCH ₂ NHMe et 195-196 " 66 Me ₂ C0 / Et ₂ 0 175 Bu ¹ NHMe et 105-108 " 27 Me ₂ OVEt ₂ O 176 Bu NHMe et 142-143 ° 46 EtOAc 177 Pr ¹ NHMe et 1-99-200 37 Me ₂ OVEt ₂ O 178 pr NHMe et 212-214 22 Me ₂ CO 179 4-MeO-Ph NHMe me 226-228 46 Me ₂ CO 180 hexyl NHMe me 156-158 41 Me ₂ C0 / Et ₂ 0 181 Bu ' NHMe me 142-146 " 21 PrOH / Et ₂ O 182 PhCH ₂ NHMe me 208-209 " 62 Me ₂ C0 / Et0AC 183 Bu NHMe me 164-165 " 56 Me ₂ C0 / Et ₂ 0 184 Pr " NHMe me 163-164 47 Me ₂ C0 / Et ₂ 0 185 pr NHMe me 215-217 18 Me ₂ CO 186 et NHMe me 225-227 16 Pr'OH / Etjo Remarks: * characterized as iodide salt + with decomposition a: Analyzes for 0.5 H ₂ O b: Analyzes for 0.25 H ₂ O c: Analyzes for 1.25 H ₂ O d: Analyzes for 0.75 H ₂ O

The starting material, the 1,2-disubstituted-6-methylpyrimidin-4-ones of formula 6 were prepared analogously to the compounds of example 2 described in parts (i) - (iii), i. by reaction of the corresponding 1-substituted-6-methyl-2-methylthiopyrimidin-4-one of formula 7 (below) with methylammonium acetate, ammonium acetate or ethylammonium acetate, the compounds of formula 7 being formed by methylation of the corresponding thiones of formula 8 (listed below) ). The latter thiones were generated in analogous procedures as described in part (i) and (ii) of example 3.

The pyrimidin-4-ones of the formula 6 had the following properties:

Formula 6 for Exp.

R ²

Mp CC)

yield

Rekrist. Lösgsm.

161 2-MeO-Ph NH ₂ 255-257 53 EtOH 162.165 4-Me-Ph NH ₂ 297-298 49 EtOH / hexane 163 2-Me-Ph NH ₂ 125-127 45 EtOH / Etjo 164 3-MeO-Ph NH ₂ 258-260 42 EtOH 166.168. Bu NH ₂ 186-187 38 - 167 Bu ' NH ₂ 276-278 30 EtOH 169 Pr ' NH ₂ 242-243 44 EtOH / Pr'OH 170 pentyl NH ₂ 254-256 40 isolated from EtOH 171 4-MeO-Ph NHEt 220-225 34 EtOAc / EtOH 172 4-MeO-Ph NHMe 243-245 38 EtOH / Et ₂ O 173 hexyl NHMe 135-136 74 Me ₂ C0 / Et ₂ 0 174 PhCH ₂ NHMe 270-271 83 EtOH 175 Bu ¹ NHMe 135-137 53 _ 176 Bu NHMe 224-225 80 washed with Me ₂ CO 177 Pr ' NHMe 53 EtOH / Etjo 178 pr NHMe 202-203 81 MeCN 186 et NHMe 264-266 63 EtOH / Et ₂ O

The methylthio derivatives of formula 7 had the following properties:

Formula 7 for Exp.

R ¹

Mp ( ⁰ C)

yield

Note: + Also required for other biceplels + + hydriodide salt

The thione of formula 8 had the following properties:

Rekrist. Lösgsm.

161 2-MeO-Ph 154-158 68 EtOAc 163 2-Me-Ph 178-179 53 Isolated from CH ₂ CI ₂ 164 3-MeO-Ph 173 62 Iso. of CH ₂ Cl ₂ 166 * Bu 143-146 77 EtOAc 167 * Bu ' 87-89 94 triturated with Et ₂ O 169 * Pr ' 152-155 (Zers.) 85 Iso. from EtOAc 170 pentyl 157-158 ** 68 Iso. from Me ₂ CO 173 * hexyl 144-145 70 Iso. from Me ₂ CO 174 * PhCH ₂ 78-81 58 toluene 178 * pr 85-87 72 Iso. of EtOH / Et ₂ O 186 et 185-187 59 EtOH

Formula 8 for Exp.

Fp ₁ ( ⁰ C)

yield

Rekrist. Lösgsm.

161 2-MeO-Ph 232-234 56 EtOH 163 2-Me-Ph 235-237 83 EtOH 164 3-MeO-Ph 225-227 12 EtOH 165 * Bu 165-166 46 MeOH 166 * Bu ¹ 189-191 35 EtOH / MeOH / H ₂ O 169 * Pr ' 154-157 13 EtOAc 170 pentyl 134-136 44 EtOAc 183 * hexyl 136-137 34 MeOH 184 * PhCH ₂ 210-212 55 EtOH

Note: + Also required for other examples.

The starting thiones of Formula 8 for Example 178 and 186 resulted from Agai et al. As described. Period. Polytech. Chem. Eng., 1974, 18, 47 and Federal German OLS No. 252729 (published on January 8, 1976).

Example 187-188

The general procedure described in Example 1 was repeated, but starting from the known compound 1,6-dimethyl-2-methylamino-pyrimidin-4-one (Agai et al., Period. Polytechn. Chem. Eng., 1974, 18, 47). and phosphorus (V) oxide chloride to form the corresponding reaction derivative, the derivative of which was then reacted with the corresponding amine of formula QA-NHR ⁴ . Thus, the following compounds of the formula I (R ¹ = R ⁶ = CH ₃ ) were formed: (Example 187): 1,6-dimethyl-2-methylamino-4- (N-ethyl-2- (2-methoxy-phenoxyethylamino) Pyrimidine chloride as dry substance, mp 170-171 ° C (recrystallized from acetone) in 40% yield (partial hydrate: 0.5 H ₂ O);

(Example 188). 1,6-Dimethyl-2-methylamino-4- (N-methyl-2-phenylethylanriino) Pyrimidinbromid (mixed with 33% C'.ilorid) as dry substance, mp 219-221 ⁰ C (recrystallized from Propan-2-ol / ether) in 44% yield.

Example 189-190

Following a similar procedure as in Example 47, but using the corresponding amine of the formula QA-NHR ⁴ , the following compounds of the formula I were formed (R '= R ^e = CH ₃ ):

(Example 189): 2-Amino-1,6-dimethyl-4- (N-methyl-2-phenylethylamino) pyrimidine iodide as dry substance, mp 168-169 ⁰ C (recrystallized from propan-2-ol / ether) in 45% yield; (Example 190): 2-Amino-1,6-dimethyl-4- (N-ethyl-2- (2-methoxy-phenoxyethylamino) pyrimidine iodide as dry substance, m.p.

138-14O ⁰ C (recrystallized from acetone / water) in 23% yield; and (Example 191): 2-amino-4- (1,2,3,4-tetrahydroisoquinol-2-yl) -1,6-Dimethylpyrimidinbromid as dry substance, mp 275-276 ⁰ C (recrystallized from ethanol) in Fig.12. % Yield (partial hydrate: 0.25H] O).

Example 192

Following a similar procedure as in Example 160, but using ethylamine instead of methylamine, 1-dimethyl-dimethyldimethylamino-N-ethylaniline pyrimidinium chloride was obtained as a glassy dry substance in 76% yield; NMR (200MHz, de-DMSO): 1.16 (3H, t, CH ₂ CH ₃ ), 2.64 (3H, s, pyrimidine-2-CH ₃ ), 2.8 [6H, s, N (CH ₃ I ₂ ), 3.65 (3H, s, pyrimidine-1-CH ₃ ), 4.06 (2H, q, CH ₂ CH ₃ ), 5.54 (1H, br, s, pyrimidine-5H), 7,3-7,65 (5H, complex, phenyl).

Example 193

An illustration of representative dosage forms of medicaments containing a compound of formula I or an alternative non-toxic salt thereof which can be used therapeutically or prophylactically in humans:

(a) Tablets mg / tablet

Compound X 50

Lactose Ph. Eur 223.75

Croscarmellose is 6.0

Corn starch 15.0

Polyvinylpyrrolidone (5% by volume paste) 2.25

Magnesium stearate 3.0

(b) capsules mg / capsule

Connection X .. 10

Lactose Ph.Eur 488.5

Magnesium Stearate 1.5

"Compound X" means a typical compound of formula I or an alternative non-toxic AIz thereof as described in the preceding examples.

The above compositions can be obtained by conventional methods well known in the pharmaceutical arts. Tablets may be provided with sheaths in a conventional manner, e.g. B. for the purpose of changing the dissolution properties or improving the taste or strength. For example, a cellulosic acetate phthalate shell may be used on tablets to provide a composition that releases the majority of the active ingredients in or near the lower food tract.

Claims (15)

1. An aminopyrimidine derivative of the formula I: Q .. A. characterized in that R ¹ is (C ₁ ^ ₀₎ -alkyl, (C ^ AIkenyl, (C ₄ _ ₇₎ cycloalkyl, phenyl, PhenyKC, ^) and alkyl, or (Q ^ CycloalkyMC ^ -alkyl one of the groups R ² and R ^{6 is} a basic group selected from amino, (C 1-6) alkylamino, dialkylamino having up to eight carbon atoms, pyrrolidine, piperidine and morpholine and the other group of R ² and R ^{6 is} hydrogen, (de) alkyl , (C 3-6) alkenyl, (C 1-4 alkoxy-C 1-4 alkyl, phenyl, phenyl-C 1-6 alkyl, (C 1-6 cycloalkyl or (C 3- e) cycloalkyl- (C 1-8) alkyl or both groups R ² and R ^{6 are} basic groups , are independently selected from the basic groups defined above, and R ^{B is} hydrogen, (Ciw ») alkyl or (Cj-e) alkanyl, or R ² , as defined above, is a basic group, and R ⁵ and R ^{6 are} together (C3_6) alkylene or together with the pendant carbon atoms of the pyridinium ring form a complete benzene ring; R ^{4 is} hydrogen, (Q 1 -cycloalkylMC) cycloalkyl- (C 1 -C ⁴ alkyl, (C 1 -C ⁴ alkyl, (C ₃ )) alkenyl, (C3_6) Alkynyl or phenyKC ^ Al alkyl or R ⁴ is a (C ^ alkylene or (C ₂ -4) alkenylene is bonded to the nitrogen atom of the group QAN-, each linking group, optionally, a (C ^ alkyl, phenyl or phenyl (C ₁ ^) alkyl Substituents and each compound group thereby can form a complete ring with two adjacent carbon atoms of Q, with the carbon atoms of A and with the adjacent nitrogen atom of the group -AN-; A is a direct bond to the the group -N (R ⁴⁾ -, or (C ^ alkylene or oxy (C ₂ _6) alkylene in which the oxy group of at least 2 carbon atoms out of the group -N (R ⁴⁾ - is; Q is a pyridyl, furyl, thionyl or phenyl moiety, Y is a physiologically acceptable anion, and wherein any one or more of said phenyl or benzene moieties may optionally be unsubstituted or have one or more substituents independently selected from halogen , kylamino- (C ^ JAlkyl-, (C ^ AIkenyl-, (C ₁ ^ ₁₎ AI, (C ₁ ^) AlkOXy, cyano, trifluoromethyl, nitro, carboxy, dialkylamino groups having up to six carbon atoms, (C ^ JAlkylthio-, (C ^ alkylsulfinyl, (C ^ alkylsulfonyl and (C ^ Alkylenedioxy groups, but excluding those compounds in which: (a) R ^{1 is} alkyl, R ^{2 is} amino or alkylamino, R ^{4 is} hydrogen or alkyl, R ^{5 is} hydrogen or alkyl, R ^{6 is} hydrogen or phenyl, optionally with an alkyl or alkoxy substituent; (b) R ^{1 is} methyl or ethyl, R ^{2 is} amino, R ⁴ and R ^{5 are} hydrogen, R ^{8 is} methyl and QA- is unsubstituted phenyl; or (c) R ¹ , R ⁵ and R ^{6 are} methyl, R ^{2 is} methylamino, R ^{4 is} hydrogen and QA-3,5-dimethylphenyl, R ^{2 is} methylthio, R ¹ , R ⁴ and R ^{6 are} methyl and wherein in each of these groups Y has the abovementioned meaning. A compound according to claim 1, wherein: R ^{1 is} methyl, ethyl, propyl, butyl, pentyl, heptyl, allyl, but-2-enyl, but-3-enyl, 2-methyl-2-propenyl, pentenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, Benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl or 2- (cyclohexyl) ethyl! is; a group of R ² and R ^{6 is} a basic group selected from amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methylpropylamino, dipropylamino, pyrrolidine, piperidine and morpholine is; and the other group of R ² and R ^{6 is} hydrogen, methyl, ethyl, propyl, butyl, isobutyl, allyl, bui-2-enyl, but-3-enyl, 2-methyl-2-propenyl, pentenyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2- (cyclohexyl) ethyl; or both groups R ² and R ^{6 are} basic groups independently selected from the basic groups defined above; and R ^{5 is} hydrogen, methyl, ethyl, propyl, isopropyl, allyl, but-2-enyl, but-3-enyl or pentenyl; or R ^{2 is} a basic group as defined above and R ⁶ form - and R ^e together are trimethylene, tetramethylene, pentamethylene or a group of the formula -CH ₂ x C (CH _{3) 2} · CH ₂ · CH ₂ - or-CH ₂ x C _(CH3 J ₂ · CH ₂ · CH ₂ and R ⁵ and R ⁶ together with the pendant carbon atoms of the pyrimidine ring complete a benzene ring; R ^{4 is} hydrogen, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2- (cyclohexyl) ethyl, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, secondary butyl, pentyl, allyl, but-2-enyl, but-3-enyl, pentenyl, prop-2-ynyl, but-2-ynyl, benzyl, 1-phenylethyl and 2-phenylethyl or R ^{4 is} methylene, Ethylidene, ethylene, isopropylidene, trimethylene, tetramethylene, vinylene or 1,3-propenylene, attached to the nitrogen atom of the group QAN-, where each linking group is optionally a methyl, ethyl, propyl, butyl, phenyl, benzyl , 1-phenylethyl or 2-phenylethyl substituent and wherein each linking group completes a ring including the two nachba carbon atoms of Q, the carbon atoms of A and the adjacent nitrogen atom of the group -AN-; A is a direct bond to the group -N (R ⁴ ) - or methylene, ethylene, trimethylene, tetramethylene, each group of which may have one more two-methyl substituent, or A is oxyethylene, oxytrimethylene, methylenoxyethylene or ethyleneoxyethylene, each group optionally containing one or two may have two methyl substituents; Q has the meaning defined in claim 1; Y is a physiologically acceptable anion; and wherein one or more of the phenyl or benzene moieties may optionally be unsubstituted or may have one or more substituents independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, allyl, 2- Methyl 2-propenyl, methoxy, ethoxy, propoxy, cyano, trifluoromethyl, nitro, carboxy, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl , Methylsulfonyl, ethylsulfonyl, methylenedioxy and isopropylidenedioxy groups. 3. A compound according to claim 1 or 2, wherein R ^{4 is} (C 1-4) alkyl, A is a direct bond and Q is selected from phenyl, 4-chlorophenyl, 4-methylphenyl, 2-nitrophenyl, 2-methylphenyl, 2-carboxyphenyl, 2 Methoxyphenyl, 4-methylthiophenyl, 2,5-dinitrophenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl, 3,5-dimethoxyphenyl, or the group of the formula QAN ( R ⁴ ) - is selected from 1-indolyl, 3-methyl-1-indolyl, 3-ethyl-1-indolyl, 3-propyl-indolyl, 5-bromo-1-indolyl, 5-chloro-1-indolyl, 5 Fluoro-1-indolyl ₍ 5-methyl-1-indolyl, 5-methoxy-1-indolyl, 1-indolinyl, 3-methyl-1-indolinyl, 3-ethyl-1-indolinyl, 3-isopropyl-1-indolinyl and 1-indolinyl. 4. A compound of formula II: ψ- Μ wherein Ra (d_ ₁₀₎ alkyl, (C ₃ - ^) AIkenyl, phenyl, phenyl (C, ^) alkyl, (Cs-eJCycloalkyl or (Ca- ^ ^ CycloalkyMC JAlkyl is Rb (C ^ ^ JCycloalkyMC JAIkyl, amino, (Ci ^) is alkylamino or dialkylamino having up to 6 carbon atoms; Rc is hydrogen, (Qj-) cycloalkyMC ^ alkyl or Rc is (Ci_4) alkylene or (C ₂ ^) alkenylene attached to the nitrogen atom of the group Qa.AN- wherein each linking group may optionally have a (C 1-6 alkyl, phenyl or phenylC 1-4 alkyl substituent and wherein each linking group completes a ring including the two adjacent carbon atoms of Q, the atoms of A and the nitrogen of the group -Aa.N -; R is hydrogen; Re and Rf are independently selected from hydrogen and (C ^ -alkyl, or together (C ₃ _ $) alkylene form; Qa is phenyl or pyridyl; Aa is a direct bond to the group -NRc-; Y is a is physiologically acceptable anion, and wherein any one or more of said phenyl components is or may be unsubstituted or unsubstituted may have one or more substituents selected from halo, trifluoromethyl, cyano, nitro, (C ^ JAIkyl- and (C ^ AIkoxygruppen. A compound according to claim 4, wherein R a is methyl, ethyl, butyl, phenyl or cyclohexyl, Q a is phenyl optionally substituted as defined in claim 4, R c is methyl or ethyl. 6. A compound of formula II wherein Qa is phenyl; Aa is a direct link to the group -N (Rc) -; Ra (CL ₇ ) AIKyI or (QMjJAlkenyl; Rb (C ₁ ^) AlCl yI; R c is hydrogen, (C 1) alkyl, (C 1) cycloalkylmethyl or (C 1) alkenyl; or R c (C ₂ -4) alkylene or (C ₂ -4) alkenylene is on completion of a ring including the two adjacent carbon atoms of the benzene ring Qa and the nitrogen atom of the group -N (Rc) -; Rd is hydrogen or (C 1-4 alkyl; Y is a physiologically acceptable anion; the benzene ring Qa may optionally be unsubstituted or may have one or two substituents independently selected from halo, (C 1-4 alkyl and (C 1-6) alkoxy groups. A compound according to claim 6, wherein Qa is phenyl; Aa is a direct bond to the group -N (Rc) -, Ra is methyl or ethyl, Rb is methyl, ethyl or propyl, Rc is ethyl, or Rc is ethylene or vinylene upon completion of an indoline or indole ring two adjacent carbon atoms of the benzene ring Qa and the nitrogen atom of the group -N (Rc) -, Rd is hydrogen or methyl, Re is hydrogen and Rf is methyl or ethyl; Y is a physiologically acceptable anion, and wherein the benzene ring Qa may optionally be unsubstituted or have one or two substituents independently selected from fluoro, chloro, bromo, methyl and methoxy groups. 8. A nonionic form of a compound of formula I according to claim 1 having a structure I a or Ib: Y V V N 'χ (or a tautomeric structure thereof when R ^{4 is} hydrogen or when the other group of R ² and R ^{6 is} amino or alkylmino) where "alk" (C, e) is alkyl and R ¹ , R ² , R ⁴ , R ⁵ and R ^{6 have} the meanings defined in claim 1. 9. A nonionic form of a compound of formula II according to claim 4, having the structure Ha: Rd Ha wherein Ra, Rb, Rd, AA and Qa have any of the meanings defined above and "alk" (C ^ AIkyl means. 10. A compound according to claim 1, 4 or 6 wherein Y is selected from halide, sulfate, fluoroborate, phosphate, nitrate, acetate, benzoate, butyrate, citrate, tartrate, dibenzoyl tartrate, fumarate, trifluoroacetate, methosulfate and p-toluenesulfonate. 11. A compound of formula I according to claim 1, wherein Y is a helogenidione and the pyrimidine counter cation is selected from 1,6-dimethyl-2-methylamino-4-N-Methylanilinpyrimidin,
1,2-dimethyl-6-methylamino-4-N-Ethylanilinpyrimidin;
1,2-dimethyl-4- (1-indolyl) -6-methylaminopyrimidine,
1,2-Dimethyl-4- (3-methyl-1-indolyl) -6-methylaminopyrimidine, 1,2-dimethyl-4- (3-ethyl-1-indolyl) -6-methylaminopyrimidine, 2-ethyl-4- (3-ethyl-1-indolyl) -1-methyl-6-methylaminopyrimidine, 1-dimethyl-B-methylamino-1-Si-propyl-N-indoly-pyrimidine, 1,2-dimethyl-4- (3-methyl-1-indolinyl ) -6-Methylaminopyrimidiniodidund 1,2-dimethyl-4- (3-ethyl-1-indolinyl) -6-methylaminopyrimidine. 12. The compound i-dimethyl-G-methylamino-N-ethylaniline pyrimidinium chloride or iodide. A process for the preparation of a compound of formula I according to claim 1 and wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , A, Q and Y have any of the meanings defined in any preceding claim characterized in that: a) an amino compound of the formula III: is reacted with an alkylating agent of the formula R ¹ .Z, where Z is a suitable leaving group; b) a pyrimidine salt of the formula V: P? wherein X is a suitable leaving group, is reacted with an amine of the formula QAN (R ⁴ ) H, or c) for the compounds in which R ^{6 is} an amino, (C 1-4) alkylamino group having up to 6 carbon atoms, a pyrrolidine, piperidine or morpholine group, a pyrimidine salt of the formula VI: Vl wherein X is a suitable leaving group, is reacted with a suitable amine selected from ammonia, (C 1-6) alkylamine, dialkylamine of up to 6 carbon atoms, pyrrolidine, piperidine and morpholine, or a set of these compounds having a (C ₁ -j ) Alkanoic acid, whereafter, when a different counteranion Y is required, the compound of formula I is reacted with a suitable metal salt having the desired counter anion or ion exchanged with a basic resin in the form of its salt with the desired counter anion becomes. 14. A process for the preparation of a nonionic form of a compound of formula I having a structure I a or II a (or tautomeric structure thereof) according to claim 8, characterized in that a compound of formula I is reacted, wherein a group of R ³ or R ^{6 is} an amino or (C 1-6 alkylamino group and the other group of R ² and R ⁶ and R ¹ , R ⁴ , R ⁵ , Q, A and Y have any of the corresponding meanings according to claim 1, and treated with a strong base such as a quaternary ammonium hydroxide (and especially one in a macroreticular resin form) to the corresponding nonionic anhydrobase forms of the formula I a or I b. 15. A novel aminopyrimidine of the formula III: wherein R ² , R ⁴ , R ⁵ , R ⁸ , A and Q have any of the meanings for novel compounds according to claim 1. 16. A pharmaceutical composition, characterized in that it contains an active substance selected from a compound of formula I according to claim 1, a nonionic form thereof having formula I a and I b (or a tautomeric form) according to claim 8 and a nonionic form of said formula I compound of formula IIa, together with or in admixture with a pharmaceutically acceptable excipient or carrier. Field of the invention The invention relates to novel heterocyclic compounds, and in particular to novel aminopyrimidine derivatives having a beneficial effect on the cardiovascular system (and in particular having a beneficial effect via the Keith-Flack sinus node) and pharmaceutical compositions containing such a derivative as active ingredient, and further Process for the preparation and medical use of these derivatives. Initial situation of the invention Although numerous compounds with medically beneficial effects on the cardiovascular system are known, there has hitherto been no satisfactory means of influencing the function of the Keith Flack sinus node in warm-blooded animals, including humans, in a beneficial, selective and medically meaningful manner, so that the agents used to treat cardiovascular disorders resulted in an unduly high heart rate (ie, bradycardia effect) and also had little effect on other hemodynamic parameters such as blood pressure and cardiac output. An object of the invention is to make possible a means which, inter alia, has bradycardic properties. Pyrimidine derivatives have been extensively studied in research for new drug agents. A number of aminopyrimidine derivatives have been described as having cardiotonic properties (U.S. Patent No. 4,725,600). Various 4-aminopyrimidine salts have been reported as fungicidal and antibacterial agents (U.S. Patent No. 4,339,453). The present invention is based on surprising and sine knot-inducing effects of a novel series of aminopyrimidine derivatives of Formula I defined below. Presentation of the invention The invention provides an aminopyrimidine derivative of the formula I (set out below together with other chemical formulas occurring here), in which: R ^{1 is} - (C, ₁₀ ) alkyl, (C ₃ ) alkenyl, (C 1 -C 12) cycloalkyl, phenyl, phenyl (C 1 -C 4) alkyl or (C 1 -C 6 -cycloalkyl-C 1 -C 4 alkyl; one of R ² and R ⁶ a basic group selected from amino, (C, ^) alkylamino, dialkylamino of up to eight carbon atoms, pyrrolidine, piperidine and morpholine; and the other of R ² and R ^e is hydrogen, (C _e.) alkyl, (Cj_e) Alkenyl, (Ci ^) alkoxy (C, _4) alkyl, phenyl, phenyl (Ci-4) alkyl, ((^! Cycloalkyl or (C _M ) cycloalkyl- (Ci_4) alkyl; or both of R ² and R ⁹ basic groups independently selected from the basic groups described above, and R ^B is hydrogen, (C 1-6 alkyl or (C _M ) alkenyl; or R ² is a basic group as described above, and R ⁶ and R ⁵ together form (C alkylene or together with the pendant carbons of the pyrimidine ring complete a benzene ring; R ⁴ is hydrogen, (C ₃ e) alkynyl or phenyl (Ci-4) alkyl; or R ⁴ is a (C 1) alkylene or (C ₂ _ «) Alkenylene, bound to the nitrogen atom of the G QAN-, wherein each linking group optionally has a (C _1-4 ) AllCyI, phenyl or phenyl (C, ^) alkyl substituent, and each linking group has one ring including the two vicinal carbon atoms of Q, the carbon atoms of A and the adjacent one Nitrogen atom of the group -AN- complete; A is a direct bond to the group-N (R ⁴ ) -or is (C 1) alkylene or is (C ₂ -) alkylene in which the oxy group has at least 2 carbon atoms separated from the group -N (R ⁴ Q is a pyridyl, furyl, thienyl or phenyl component; Y is a physiologically acceptable anion; and wherein any one or more of said phenyl or benzene moieties may optionally be unsubstituted or have one or more substituents independently selected from halogen, (C 1 -C 4 alkyl, (C 1 -C 4) alkenyl, (C 1 -C 6) alkoxy, cyano, trifluoromethyl, nitro, carboxy, (C 1 -C 6) alkylamino, dialkylamino having up to six carbon atoms, (C 1 -C 4 alkylthio, (C 1 -C 4) alkylsulphinyl, (C, _ ^) alkylsulphonyl and (C 1 -C 1) alkylenedioxy; but excluding those compounds in which: