CA2235994A1 - Novel piperazinylalkylthiopyrimidine derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the novel compounds - Google Patents

Abstract

The invention refers to novel piperazinylalkylthiopyrimidine derivatives of formula (I) being suitable for the treatment of diseases due to pathological alterations of the central nervous system, pharmaceutical compositions containing the above derivatives, and a process for the preparation of the novel compounds.

Description

- -CA 02235994 l998-04-27 Novel piperazinylalkylthiopyrimicline derivatives, pharmaceutical compositions containin~ the same and a process for the preparation of the novel compounds The invention refers to novel piperazinyl-alkylthiopyrimidine derivatives, pharmaceutical compositions containing the above deriv2tives, a ~cthocl for the treatment of diseases of especially the central nervous system, and a process for the preparation of the novel compounds.
Specifically. the invention refers to compounds of the formula (CH2)m N N -(CH)- S 1 ~N
~(CH~)n wherein Rl and R3 represent, independently, a hydrosen. a Cl 4 alk~l group, an amino group. a (Cl 4 alkanoyl) amino ~roup, or a phenyl group optionally bearing 1 to 3 substituents selected from the CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 group consisting of, independently, a halo, a Cl 4 alkoxy group, a di(Cl_4 alkyl)amino group or a benzyloxy group, R stands for a hydrogen, a cyano group, a furylmethyl group, a (C5 7 cycloalkyl)methyl group, a (Cl 4 alkoxy)carbonyl group, a hydroxy(Cl_4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a Cl 4 alkyl group, a Cl 4 alkoxy group, a trifluoro methyl group, a hydroxy group, a benzyloxy group or a di(Cl_4 alkyl)amino group, R means hydrogen, or R3 forms with R an oxygen atom, R5 is hydrogen, or R forms with R5 a valence bond, R represents a halo, a cyano group, a nitro group, a Cl_4 alkyl group, a Cl_4 alkoxy group or a trifluoromethyl group, m has a value of O or 1, n has a value of 1 or 2, p is an integer between 2 to 11, and k has a value of 0, 1, 2 or 3, and pharmaceutically acceptable acid addition salts thereof.

CA 0223~994 1998-04-27 The novel piperazinylalkylthiopyrimidine derivatives can be employed, in the first place, for the treatment of diseases due to pathological alterations of the central nervous system.
Pyrimidine derivatives connected with a piperazine ring and used for the t~eatment of urination disorders are described by Japanese Patent Application No. J 3 090 027.
Uracil compounds of similar type are known from DE-P No. 1 942 405. One of the known uracil compounds is urapidil, a blood pressure lowering drug. However, in case of the above compounds, the two heterorings are connected through an alkylamino group.
Pyrimidine derivatives bonded to a piperazine ring through an alkoxy group and having sedative and hypotensive activity are described by BE-P Nr. 756 127.
It was found that the novel compounds of the formula I, wherein the heterorings containing nitrogen atoms are connected through an alkylthio group, have excel~ent biological activity influencing the serotonerg system.
In the description, a Cl 4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, sec.-butyl, tert.-butyl, n-butyl or isobutyl group. Preferably, Cl 4 alkyl is methyl.
A Cl 4 alkanoyl group is a formyl, acetyl, n-propanoyl, n-butanoyl etc. group, CA 0223~994 1998-04-27 preferably an acetyl group.
In general, a halo is a fluoro, chloro or bromo, preferably chloro or bromo.
A Cl 4 alkoxy group is generally a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group.
The pharmaceutically acceptable acid addition salts of the compounds of the formula I are acid addition salts of the compounds formed with pharmaceutically acceptable inorganic or organic acids. Preferred acid addition salts are hydrogen haloids such as hydrochlorides or hydrobromides, carbonates, hydrogen carbonates, sulfates, phosphates, acetates, fumarates, maleates, citrates and ascorbates.
A preferred sub-group of the compounds of the invention consists of the compounds of the formula I, wherein Rl and R3 represent, independently, a hydrogen, a methyl group, an amino group, an acetylamino group or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro group, a methoxy group, a dimethylamino group or a benzyloxy group, R stands for a hydrogen, a cyano group, a furylmethyl group, a cyclohexylmethyl group, an ethoxycarbonyl group, a hydroxyethyl group or a benzyl group -CA 02235994 l998-04-27 optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro, a fluoro, a Cl 3 alkyl group, a methoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a dimethylamino group, R4 means a hydrogen, or R forms with R an oxygen atom, R is a hydrogen, or R4 forms with R5 a valence bond, R represents a chloro, a fluoro, a cyano group, a nitro group, a methyl group, a methoxy group or a trifluoro methyl group, m has à value of O or 1, n has a value of 1 or 2, p has a value of 2 or 11, and k has a value of 0, 1, 2 or 3, and pharmaceutically acceptable acid addition salts thereof.
A specifically preferred sub-group of the compounds of the invention consists of the compounds of the formula I, wherein R and R represent an amino group, R2 stands for a hydrogen or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a fluoro, a chloro, a .methoxy group and a dimethylamino group, ~ R4 forms with R5 a valence bond, R means a fluoro, a chloro, a nitro group, CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 a cyano group, a methyl group, a methoxy group or a trifluoromethyl group, k has a value of 1, m has a value of 1, n has a value of 1, and p has a.value of 2, and pharmaceutically acceptable acid addition salts thereof.
The piperazinylalkylthiopyrimidine derivatives of the invention are prepared by reacting a 2-mercaptopyrimidine of the formula ~ N ~ R2 II

i Rl R2 R3 R4 and R5 are as defined above, or an alkali metal salt thereof with a haloalkylpiperazine derivative of the formula (R6)k (CH~n III

CA 0223~994 1998-04-27 wherein R6, m, n, p and k are as stated above, Hlg stands for chloro or bromo, or an acid addition salt thereof, and, if desired, transforming an obtained compound of the formula I into a pharmaceutically acceptable acid addition salt or liberating the base from the acid addition salt.
The process of the invention is performed in a solvent or solvent mixture that is indifferent from the point of view of the reactants. For example aliphatic alcohols such as methanol, ethanol, isopropanol;
dialkylamides preferably dimethylformamide;
dialkyl sulfoxides preferably dimethyl f sulfoxide; or the mixtures thereof can be used. It is especially preferred to react the reactants in methanol, dimethylformamide or a mixture of methanol and dimethyl-formamide.
The reaction of the 2-mercaptopyrimidine of the formula II with haloalkylpiperazine derivative of the formula III can be performed in the presçnce of an acid binding agent.
Preferred acid binding agents are alkali metal carbonates such as sodium carbonate, alkali metal hydrocarbonates such as sodium or potassium hydrocarbonate, alkali metal hydroxides such as sodium or potassium hydroxide, alkali earth metal hydroxides such as calcium hydroxide or tertiary amines such as pyridine, triethylamine or other CA 0223~994 1998-04-27 W ~ 97/16429 PCTAHU96/00061 trialkylamines. Preferably, potassium carbonate or sodium carbonate is employed as the acid binding agent.
Optionally, a catalyst is used to accelerate the reaction. In general, alkali metal halides or alkali earth metal halides such as potassium iodide, potassium fluoride, sodium bromide or calcium chloride are employed as the catalyst. The reaction is preferably performed in the presence of potassium iodide catalyst.
Depending on the reactivity of the starting compounds, the reaction proceeds at a temperature between room temperature and the boiling point of the reaction mixture.
It is preferred to react the reactants at 60 to 80 ~C.
The reaction time is 1 to 10 hours depending on the reactivity of the reactants and the reaction temperature used.
The starting compounds of the formulae II and III can be employed in an equimolar amount, or the haloalkylpiperazine derivative of the formula III is used up to 10 per cent excess, at the most. The acid binding agent is used in an equimolar quantity referring to the amount of the haloalkylpiperazine derivative of the formula III.
The catalyst is employed in 0.1 to 0.2 molar, preferably in 0.1 molar quantity for each mole of the starting compounds.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96100061 The reaction mixture is worked up in a manner known per se. Preferably, the product is separated as follows: the inorganic salts precipitated are filtered, the filtrate is distilled off in vacuo, and the residue is dissolved in water or an organic solvent to crystallize the product; or the product separated is filtered together with the inorganic salts, then the inorganic salts are removed by dissolution in water. A further alternative is to pour the reaction mixture into water in order to dissolve the inorganic salts, and filtering the product precipitated.

If desired, the reaction product is purified by known purification methods such as recrystallization or chromatography.
The compounds of the formula I can be also separated in the form of pharmaceutically acceptable acid addition salts mentioned above, or a compound of the formula I obtained as a base can be converted to acid~addition salt in a subsequent step by reaction with the suitable acid in an indifferent solvent.
From the acid addition salt, the base can be repeatedly liberated and optionally converted to another acid addition salt.
v A large part of the starting compounds of the formula II is known from the literature or is commercially available. These known compounds can be prepared by the modified CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Traube's synthesis /W. Traube, Ann., 331, 64 (1904)/ or by the method of José et al.
/Heterocycles, 19 (2), 305-311 (1982)/.
However, the compounds of the formula II, wherein R is an amino group, R represents a nitrile group, R stands for a 4-bromophenyl, 2- or 4-chlorophenyl, 2- or 4-methoxyphenyl, 4-dimethylaminophenyl, 4-benzyloxy-3-methoxyphenyl or 3,4,5-trimethoxyphenyl group, R and R5 mean hydrogen, as well as the compounds of the formula II, wherein R and R stand for an amino group, R is a 2-furylmethyl, cyclohexylmethyl, benzyl or mono-, di- or trisubstituted benzyl group, R4 forms together with R5 a valence bond, are novel, that are not described in the literature. They can be prepared by the synthesis methods of the known compounds (e.g. European Patent Application No. 465 323).
A part of the haloalkylpiperazine derivatives of the formula III is also known from the literature. They can be prepared by means of the method described by e.g.
C.B. Pollard et al. /J. Org. Chem., 24, 764-767 (1959)/ or Sidney D. Ross et al.
/J. Am. Chem. Soc., 85 (24), 3999-4003 (1963)/. The starting compounds of the formula III, wherein R represents a 2-nitro, 3-chloro, 3-nitrile, 3-trifluoromethyl, 4-methoxy or 4-methyl group, m has a value CA 0223~994 1998-04-27 -of 1, n has a value of 1 or 2, p has a value of 2, and Hlg is chloro or bromo, or R6 stands for a 2,6-dinitro-4-trifluoromethyl or 2-nitro-4-trifluoromethyl group, m has a value of 0, n has a value of 1 or 2, p has a value of 2, and Hlg is a chloro or bromo, are novel compounds that can be prepared by the methods given in connection with the known compounds.
Compounds of the formula I have valuable biological activity.
Our studies revealed that the compounds of the invention bind strongly to different serotonin receptor subtypes, and inhibit serotonin-evoked smooth muscle contractions of the rat gastric fundus and the rabbit aorta. The chemical name of serotonin is 3-(2-aminoethyl)-lH-indol-5-ol.

5-HT2A and 5-HT2C receptor binding studies 5-HT2A and 5-HT2C receptor binding was measured according to the methods described by Leysen et al. /Mol. Pharmacol., 21, 301 (1981)/ and Pazos et al. /Eur. J. Pharmacol., 106, 539 (1985)t, respectively. 5-HT2A
receptor binding was measured in rat brain frontal cortex membrane preparation using tritiated ketanserine /3-/2-(4-fluorobenzoyl)--l-piperidinyl/ethyl-2,4-(lH,3H)-quinazoline-dione/ (60-90 Ci/mmole) as ligand. 5-HT2C

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 receptor binding was measured in pig brain choroid plexus membrane preparation using tritiated mesulergine /N'-/(8)-1,6-dimethyl-ergoline-8-yl/-N,N-dimethylsulfamide t70-85 Ci/mmole) as the ligand. Non-specific binding to 5-HT2A and 5-HT2C receptors were determined in the presence of 10 micro M cyproheptadine /4-(5H-dibenzo/a,d/cycloheptene-5-ylidene)-1--methylpiperidine/ and 1 micro M mianserine /1,2,3,4;10,14b-hexahydro-2-methyldibenzo-/c,f/pyrazino/1,2-a/azepine/, respectively.
The final incubation volumes were 250 and 1000 microlitres. Samples were incubated for 15 and 30 minutes at 37 ~C. Incubation was stopped by adding 9 ml of ice-cold 50 mM tris(hydroxymethyl)-aminomethane hydrochloride (pEI = 7.7) to the reaction mixture. The samples were rapidly filtered through Whatman GF/B glass fiber filters using reduced pressure. Before use, the filters were soaked in a 0.05 % poly-ethyleneimine solution for 2 to 3 hours.
Radioactivity of the filters was determined by a scintillation spectrometer.
The results obtained are shown in Table I.

Table I
Effect of the compounds examined on 5-HT2A
and 5-HT2C receptors CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Compound Inhibition of receptor binding (Example of the radioactive ligand No.)5-HT2C 5-HT2A
(Ki in nm/l) 3 >100 58 12 47 ~100 14 >100 78 19 >100 48 20 >100 203 21 39 ~100 22 >100 56 23 >100 20 25 ~100 20 26 ~45 48 28 50 >100 31 21 >100 34 >100 71 69 ~100 36 18 ~100 39 27 not tested 40 ~100 21 44 >100 93 47 33 ~100 53 >100 15 CA 0223~994 1998-04-27 Table I
(continued) Compound Inhibition of receptor binding (Example of the radioactive ligand No.) 5-HT2C 5-HT2A
(Ki in nm/l) 57 42 >lOO

66 >loo 61 67 8.6 4.6 68 hoo 21 lOl 24 16 From Table I it can be seen that the compounds of the formula I have considerable affinity for 5-HT2A and 5-HT2C receptors.

Inhibition of serotonin-induced contractions of rat stomach fundus smooth muscle The experiments were performed on male Wistar rats weighing 350 to 400 g. The animals were fasted for 2 4 hours before the experiments, however, they were allowed to drink tap water ad libitum. The method used was a modified version of Vane et al. /J.
Pharmac. Chemother., 12, 344 (1957)/. The CA 0223~994 l998-04-27 W O 97/16429 PCTAnU96/00061 rats were killed by decapitation and their stomach was removed, and 3 mm wide and 20 to 30 mm long strips were cut in parallel with the greatest curvature of the stomach.
The strips were incubated for 60 minutes in a 6 ml Lucite chamber filled with Tyrode solution (NaCl 136.9 mM, KCl 2.7 mM, CaC12 1.8 mM, MgC12 1.0 mM, NaHC03 11.9 mM, glucose 5.6 mM, NaH2P04 0.4 mM) warmed to 37 C and bubbled with a gas consisting of 95 % of oxygen and 5 ~ of carbon dioxide. The strips were stretched with 0.5 g during the 60 minutes equilibration time and were washed every 20 minutes. The tension was measured isometrically by a strain gauge (Hugo Sachs) and was recorded on a Graphtech Mark VII
3101 polygraph.
Experimental protocol:
- Three control contractions were evoked by 5-HT added to the bath in 10 M
concentration (Cl, C2, C3).
- If peak tension did not differ more than by 10 ~ between C2 and C3, a threshold concentration of the compound to be tested was added to the bath and the strip was contracted by 5-HT (10 M) in its presence (Tl)-- The effects of the test compounds were determined in 5 increasing concentrations - (T2, T3, T4, T5, and T6). After determining the effect of two concentrations of the test CA 0223~994 1998-04-27 WO 97/16429 PCT~HU96/00061 compounds, the control 5-HT response was checked after each test measurement.
Results and evaluation:
IC50 was calculated by nonlinear curve fitting of the inhibitory effect of increasing concentrations of the test compound.
The compounds of the invention inhibit the 5-HT-evoked contractions of the isolated rat stomach fundus smooth muscle strips.
The results obtained are shown in Table II.

Table II
Inhibition of 5-HT-evoked contractions of isolated rat stomach fundus Compound Inhibition, (Example No.) IC50 (micro M/l) 0.56 22 0.32 48 O. 42 57 0.89 64 0.68 Determination of 5-HT2A receptor antagonistic effect on isolated rabbit aorta New-Zealand, male, white rabbits weighing 2.0 to 2.5 kg were killed by a blow on the head. The thoracic aorta segment after the CA 0223~994 l998-04-27 aortic arch was removed and placed into a Krebs' solution (NaCl 118 mM, KCl 4.6 mM, NaHC03 25 mM, glucose 10.5 mM, Mg3(S04)2 1 mM, KH2P04 1 mM, CaC12 2.6 mM). The aorta was carefully cleaned from fat and connective tissue, and was cut into 3 mm wide and 30 mm long helical strips. Four strips were obtained from each rabbit. The strips were equilibrated at 37 ~C for 60 minutes in an organ chamber filled with Krebs' solution.
The strips were also oxygenated by bubbling carbogen gas (5 % of carbon dioxide and 95 % of oxygen) through the solution. The strips were stretched by 1 g tension.
The contractions were measured by a Hugo Sachs K-30 type strain gauge, and were registered on a Multicorder type polygraph.
During the last 40 minutes of the equilibration, the MA0 enzym inhibitor tranylcypramine (10 M) /chemical name:
(-)-trans-2-phenylcyclopropylamine/ was also added to the bath.
Any alpha-adrenergic effects of the test compounds were eliminated by 10 8 M
of phenoxybenzamine /N-(2-chloroethyl)-N--(l-methyl-2-phenoxyethyl)benzylamine/ /Clancy et al., J. Pharm. Exp. Ther., 233, 761 (1985).
Testing of the serotonergic antagonistic effect was started at the 90th minute of - incubation. The stability and reproducibility of the contractile response of the aortic CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 strips to serotonin was tested by two consecutive application and wash-out procedures of 10 6 M concentration of 5-HT, 40 minutes apart. Measurements were continued only in the case if peak tensions in the above test did not differ by more than 10 %. 30 minutes after the second testing, a preset concentration of the test compound was added to the bath, and, after a 10 minutes incubation time, the response to 10 6 M of 5-HT was determined in the presence of the compound to be tested.
Two different concentrations of a given compound were tested on each aortic strip by the above method. Reproducibility of the control 5-HT-evoked response was checked between testing the two concentrations of the compound. The second concentration was tested only if the 5-HT-evoked tension did not di~fer by more than +10 ~ from the original control response.
IC50 was calculated by nonlinear curve fitting of the inhibitory effect of increasing concentrations of the test compound. The results obtained are shown in Table III.

Table III
Inhibition of 5-HT-evoked contractions on isolated rabbit aortic strips CA 0223~994 l998-04-27 W O 97/16429 PCT~HU96/00061 Compound Inhibition, (Example No.) IC50 (micro M/l) 3 0.96 0.25 13 0.12 14 6.0 1.5 22 0.42 23 0.67 24 0.24 0.28 26 0.26 27 0.9 31 0.73 39 0.3 44 0.65 0.43 53 0.47 54 0.57 56 0.9 57 0.89 0.17 67 0.039 68 0.78 69 0.096 72 0.084 Based on the results presented in Table III, it can be stated that the compounds CA 0223~994 1998-04-27 W'D97/16429 PCTnHU96/00061 of the invention effectively inhibit the serotonin-evoked contractions of the isolated rabbit aortic preparation.
Based on the results of the above studies, the novel compounds of the formula I can be applied for the treatment of various disorders due to pathological alterations of the central nervous system.
The compounds of the formula I
demonstrated inhibitory activity primarily at 5-HT2A and 5-HT2C serotonergic receptor subtypes. Based on literature data, these receptors play a fundamental role in the pathomechanism of anxiety disorders, schizophrenia and migraine. The 5-HT2C
receptor agonist m-chlorophenylpiperazine /Conn et al., Proc. Natl. Acad. Sci. USA, 83, 4086 (1986)/ induces anxiety both in rats /Kennett et al., Eur. J. Pharmacol., 164, 455 t1989)/ and human beings /Kahn and Weltzer, Biol. Psychiat., 30, 1139 (1991)/.
Based on studies performed in rats, the anxiogenic effect of m-chlorophenylpiperazine can be attributed to the activation of 5-HT2C
(formerly 5-HTlC) receptors /Kennett et al., Eur. J. Pharmacol., 164, 455 (1989)/.
Compounds with antagonistic effect at the 5-HT2A~2C receptors have been shown to be anxiolytic in animal experiments /Kennett, Psychopharmacol., I07, 379 (1992)/.
The 5-HT2A/2c receptor antagonistic -compound ritanserin /chemical name: 6-C 2-/4--bis(4-fluorophenyl)methylene/-1-piperidinyl-ethyl ~-7-methyl-5H-thiazolo/3,2-a/pirimidine--5-one/ has been proved to be effective for the treatment of different forms of human anxiety /Ceulemans et al., Pharmacopsychiat., 18, 303 (1985)/. Usefulness of 5-HT2A receptor antagonists for neuroleptic indication is proved by the fact that a basic role is attributed to the 5-HT2A antagonistic effect in the therapeutic efficacy of clozapine /chemical name: 8-chloro-11-(4-methyl-l-piperazinyl)-5H-dibenzo/b,e//1,4/-diazepine/, a widely used neuroleptic compound /Meltzer, J. Clin. Psychiatry, 55 Suppl.
B, 47 (1994)/.
Usefulness of the compounds of -the invention for prophylactic treatment of migraine is supported by both the 5-HT2A/2C
receptor antagonistic properties of the compounds /Sleight et al. in Serotonin Receptor Subtypes: Basic and Clinical Aspects, ed. Peroutka, S.J., pp. 211, Wiley-Liss Inc., (1991)/ and their activity exhibited in rat stomach fundus test.
Besides central nervous system disorders, the compounds of the invention can be useful for the treatment of ischemic heart disease.
Results of the rabbit aorta test make it probable that the compounds can have 5-HT2 antagonistic effect also on the heart vessels CA 0223~994 1998-04-27 and the myocardium. It is known that 5-HT2 receptor antagonists play a role in the development of heart disease. 5-HT2 receptor antagonistic compounds also improve contractility and accelerate regeneration of the myocardium after an ischemic insult /Grover et al., J. Cardiovasc. Pharmacol., 22, 664 (1993)/.
A role of serotonergic receptors is assumed in the regulation of food consumption and body temperature as well as development of depression, addiction to drugs and alcohol, some other gastroenterologic and circulatory disorders, and in the pathomechanism of pain /Sleight et al. in Serotonin Receptor Subtypes: Basic and Clinical Aspects, ed.
Peroutka, S.J., pp. 211, Wiley-Liss Inc., (1991); Kennett, Drugs, 125 (1993)/.
Due to the above test results, the novel compounds of the formula I or pharmaceutically acceptable acid addition salts thereof can be used as active ingredients of pharmaceutical compositions. The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof and one or more conventional carrier(s).
The pharmaceutical compositions of the invention are suitable for peroral, parenteral CA 0223~994 1998-04-27 or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethyleneglycol), silica etc.; wetting agents such as sodium laurylsulfate etc.
as the carrier.
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.;
emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration consist of steril solutions of the active ingredient, in general.
Dosage forms listed above as well as - other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 18th Edition, Mack Publishing Co., Easton, USA tl990).
The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof. A typical dose for adult patients amounts to 0.1 to 20 mg of the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, daily. The above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g.
Remington's Pharmaceutical Sciences.
Suitably, the pharmaceutical compositions of the invention contain a compound of the formula I, wherein Rl and R3 represent, independently, a hydrogen, a methyl group, an amino group, an acetylamino group or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, CA 0223~994 1998-04-27 WO 97/16429 PCTnIU96/00061 .

independently, a chloro~ a methoxy group.
a dimethylamino group or a benzyloxy group, R stands for a hydrogen, a cyano group, a furylmethyl group. a cyclohexylmethyl group, an ethoxycarbonyl group, a hydroxyethyl group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro, a fluoro, a Cl 3 alkyl groupr a methoxy group ! a trifluoro~
methyl group. a hydroxy group, a benzyloxy group or a dimethylamino group R4 means a hydrogen, or R forms with R an oxygen atom, R is a hydrogen, or R forms with R5 2 valence bond, R represents a chloro, a fluoro, a cyano group, a nitro sroup! a methyl group.
a methoxy group or a trifluoro methyl group, m has a value of o or 1, n has a value of 1 or 2, p has a value of 2 or 11, and k has a value of o ! 1~ 2 or 3, and pharmaceutically acceptable acid addition salts thereof ~s the active ingredient.
Preferably! the pharmaceutical compositions of the invention contain a compound of the formula I. wherein R and R represent an amino group, -CA 0223~994 1998-04-27 R stands for a hydrogen or a benzyl ~roup optionally bearins 1 to 3 substituents selected from the group consisting of, independently, a fluoro, a chloro, a methoxy group and a dimethylamino groupS
R4 forms with R5 a valence bond, R means a fluoro, a chloro a nitro group a cyano sroup, a methyl group, a methoxy group or a trifluoromethyl group, k has a value of 1, ' m has a value of 1, n has a value of 1, and p has a value of 2, and pharmaceutically acceptable acid addition salts thereof as the active ingredient.
Furthermore, the invention refers to a method for the treatment of diseases especially due to patholosical alterations of the central nervous system. The method of the invention comprises administering an effective non-toxic dose of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof to a patient sufferins from said diseases.
The invention also refers to the use of a compound of the formula I or a pharma-ceutically acceptable acid addition salt thereof for the prepzration of a pharma-ceutical composition.
The invention is further elucidated b~ means of the following Examples.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 General method for preparing compounds of the formula I

0.05 moles of a mercaptopyrimidine of the formula II or an alkali metal salt thereof, 6.9 g (0.05 moles) of potassium carbonate and 0.83 g (0.005 moles) of potassium iodide are stirred in 300 ml of solvent at room temperature for 15 minutes, and, to the mixture obtained, 0.05 moles of haloalkylpiperazine of the formula III
or an acid addition salt thereof are added.
If the solvent consists of methanol or ethanol, the reaction mixture is boiled under reflux, while if the solvent is dimethyl-formamide, the reaction mixture is heated at 65 to 70 ~C for the time given in the Examples. After the lapse of the reaction time, the mixture is worked up by one of the folIowing methods.
Method "A":
The inorganic salts separated are ~iltered, then the filtrate is evaporated under reduced pressure.
Method "B":
The reaction product separated is filtered together with the inorganic salt, then latter is removed by washing with water.
Method "C":
- The reaction mixture is poured onto 300 ml of water to dissolve the inorganic salts, CA 0223~994 1998-04-27 WO 97/16429 PCT~HU96/00061 then the product separated is filtered.
The reaction product obtained by any of the above methods is purified as indicated in the Examples.
Using the above general method, the following compounds of the formula I were prepared:

Example 1 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by flash chromatography using a mixture of chloroform and methanol in a ratio of 99:1 as the eluent.
Yield: 4 g (23 %).
Melting point: oil.
Analysis for C17H21ClN4S (348.90) calculated: C 58.53 %, H 6.07 %, Cl 10.16%, N 16.06 %, S 9.18%;
found: C 58.13 %, H 6.25 %, Cl 9.97%, N 15.73 %, S 8.98%.

Example 2 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4,6--diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.

CA 0223~994 l998-04-27 W O 97/16429 PCT~HU96/00061 The reaction mixture is worked up by method "B".
Yield: 11. 2 g ( 65 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 167-169 ~C.
Analysis for C17H42N6S (344.485) calculated: C 59.27 %, H 7.02 %, N 24.40%, S 9.31 %;
found: C 58.78 %, H 6.85 %, N 24.20%, S 9.31 %~

Example 3 2-~ 2-/4-(4-Fluorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 8.2 g (45 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 179-182 C.
Analysis for C17H23FN6S (362.475) calculated: C 56.25 %, H 6.32 %, N 23.19%, S 8.93 %;
found: C 56.33 %, H 6.40 %, N 23.19%, S 8.84 %.-CA 0223~994 1998-04-27 Example 4 2-~ 2-/4-(4-Chlorobenzyl)l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 17.5 g (92 %).
Purification: recrystallization from aqueous methanol.
Melting point: 192-194 C.
Analysis for C17H23ClN6S (378.930) calculated: C 53.89 %, H 6.12 ~, Cl 9.36%, N 22.18 %, S 8.46%;
found: C 53.45 %, H 6.25 ~, Cl 9.26%, N 22.35 %, S 8.59%.

Example 5 2-C 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 9.5 g (50 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 150-153 C.
Analysis for C17H23ClN6S (378.930) CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 .

calculated: C 53.89 %, H 6.12 %, Cl 9.36%, N 22.18 %, S 8.46%;
found: C 53.45 %, H 6.25 %, Cl 9.50~, N 22.18 %, S 8.41%.

Example 6 2-C 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 17.5 g (90 %).
Purification: recrystallization from methanol.
Melting point: 218-219 C.
Analysis for C17H23N7 2 calculated: C 52.43 %, H 5.95 %, N 25.17%, S 8.23 %i found: C 52.10 %, H 6.17 ~, N 24.54%, S 8.04 %.

Example 7 2-~ 2-/4-(2-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 8.6 g (44 %)~

CA 0223~994 1998-04-27 Purification: recrystallization from aqueous ethanol.
Melting point: 165-169 C.
Analysis for C17H23N702S
calculated: C 52.43 %, H 5.95 %, N 25.17%, S 8.23 %;
found: C 52.19 %, H 5.94 %, N 24.33%, S 8.07 %.

Example 8 2-~ 3-/4-(4-Nitrobenzyl)-l-piperazinyl/-propylthio ~-4,6-diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 6.5 g (32 %).
Purification: recrystallization from aqueous dimethylformamide.
Melting point: 186-188 C.
Analysis for C18H25N702S
calculated: C 53.38 %, H 6.25 %, N 24.30%, S 7.95 %;
found: C 54.01 %, H 6.26 %, N 23.62%, S 7.72 %.

Example 9 2-~ 2-/4-(2,4-Dinitrophenyl)-l-piperazinyl/-ethylthio ~-4,6-diaminopyrimidine CA 0223~994 l998-04-27 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "C" .
Yield: 17.2 g (82 %).
Purification: treatment with water. acetone, then chloroform.
Melting point: 235-237 ~C.
Analysis for C16~l20N8~4 calculated: C 45.71 %, H 4.79 %, N 26.65%, S 7.63 %;
found: C 45.75 ~. H 4.59 %, N 27.71%, S 7.29 %.

Example 10 2-C 2-/4-(4-Tri~1uoromethyl-2,6-dinitro-phenyl)-l-piperazinyl/ethylthio ~-4~6--diaminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked Up by method " C " . .' Yield: 20.3 g (83 ~).
Purification: recrystallization from ethanol.
Melting point: 195-196 ~C.
Analysis for C17HlgF3N804S (488.451) calculated: C 41.80 %, H 3.93 %~ F 11.67%, N 22.94 %, S 6.56%;
found: C 41.08 %, ll 4.10 ~, F 11.37%, N 22.53 %! S 6.76%.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Example 11 2-C 2-/4-(4-nitrobenzyl)-1-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-furylmethyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 14 a ( 50 %).
Purification: chromato~raphy on a column filled with Kiesel~el 60 and elution with acetone, then recrystallization from ethanol.
MeltinS point: 157-159 ~C.
Analysis for C22H27N703S (469.6) calculated: C 56.27 %, H 5.80 ~, N 20.88~, S 6.83 %;
found: C 54.26 %, ~I 5.81 %, N 20.18~.
S 6.69 %.

Example 12 2-r 2-/4-(3-Me'hoxybenzyl)-l-piperazinyl/-ethylthio ~-4 6-diamino-5-benzylpyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method " i'~ "
Yield: 12.6 ~ (54 %).
Purification: recrystallizat~on from aqueous CA 0223~994 l998-04-27 W O 97/16429 PCTAnU96/00061 ethanol.
- Melting point: 143-145 C.
Analysis for C25H32N60S (464.637) calculated: C 64.49 %, H 7.14 %, N 18.05%, S 6.89 %;
found: C 64.67 %, H 6.98 %, N 17.84%, S 6.95 %~

Example 13 2-L 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-benzylpyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 14.5 g (62 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 177-180 ~C.
Analysis for C24H29ClN6S (469.056) calculated: C 61.46 %, 1l 6.23 %, Cl 7.55~, N 17.92 ~, S 6.83%;
found: C 60.85 ~, H 6.20 %, Cl 7.54%, N 17.46 %, S 6.56%.

Example 14 2-r 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-benzylpyrimidine Solvent employed in the reaction: methanol.

CA 0223~994 l998-04-27 Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 17.5 g (73 ~).
Melting point: 188-191 ~C.
Analysis for C24H29N702S (479.608) calculated: C 60.10 %, H 6.10 %, N 20.44%, S 6.68 %;
found: C 59.25 %, H 6.10 %, N 19.92%, S 6.43 %

Example 15 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l--piperazinyl/ethylthio ~-4,6-diamino--5-benzylpyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 20.6 g (82 ~).
Purification: recrystallization from aqueous ethanol.
Melting point: 179-180 C.
Analysis for C25H29F3N6S (502.609) calculated: C 59.62 %, H 6.00 %, N 16.69~, S 6.37 %;
found: C 59.72 %, H 5.57 %, N 17.01%, S 6.23 ~.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Example 16 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5-benzylpyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 13 g (45 %).
Purification: chromatography on a column filled with Kieselgel 60 and elution with ethyl acetate.
Melting point: 159-163 C.
Analysis for C24H25F3N804S (578.577) calculated: C 49.82 ~, H 4.36 %, N 19.37%, S 5.54 %, F 9.85~;
found: C 49.36 %, H 4.33 %, N 18.54%, S 5.76 %~ F 9.85%.

Example 17 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(cyclohexylmethyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
- The reaction mixture is worked up by method "A".
Yield: 9.7 g (40 %).
Purification: chromatography on a column CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 filled with Kieselgel 60 and elution with acetone, then recrystallization from ethanol.
Melting point: 160-162 ~C.
Analysis for C24E135N702S
calculated: C 59.36 %, H 7.26 %, N 20.19%, S 6.60 %;
found: . C 59.65 ~, H 7.20 %, N 19.90%, S 6.57 %.

Example 18 2-~ 2-/4-t2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio 7-4,6-diamino-5-(cyclohexylmethyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "C" .
Yield: 11.1 g (38 %).
Purification: chromatography on a column filled with Kieselgel 60 and elution with ethyl acetate.
Melting point: 176-178 ~C.
Analysis for C24H31F3N8 4 calculated: C 49.31 %, H 5.34 %, N 19.17%, S 5.48 %, F 9.75~;
found: C 48.80 %, H 5.28 %, N 18.80%, S 5.60 %, F 10.19%.

CA 0223~994 1998-04-27 Example 19 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-hydroxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 9.9 g (40 %).
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 8:2 as the eluent.
Melting point: 195-199 ~C.
Analysis for C24E~29N703S (495.608) calculated: C 58.16 %, H 5.90 ~, N 19.78%, S 6.47 ~;
found: C 60.26 %, H 6.08 %, N 19.97%, S 6.55 %~

Example 20 2-[ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-fluorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 5.5 g (47 %).
Purification: recrystallization from aqueous CA 0223~994 1998-04-27 W ~ 97/16429 PCTAHU96/00061 ethanol.
Melting point: 201-203 ~C.
Y 24 28 7 2 ~ ) calculated: C 57.93 %, H 5.67 %, N 19.70%, S 6.44 %;
found: C 57.53 %, H 5.66 %, N 19.55%, S 6.60 %.

Example 21 2-C 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5--(4-fluorobenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 20.6 g (79 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 162-164 ~C.
Analysis for C25H28F4N6S
calculated: C 57.68 %, H 5.42 %, N 16.14%, S 6.16 %;
found: C 57.08 %, H 5.34 %, N 16.36%, S 6.11 %.

Example 22 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4,6--diamino-5-(4-methoxybenzyl)pyrimidine CA 0223~994 l998-04-27 WO 97/16429 PCT~HU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 21.8 g (94 %).
Melting point: 152-154 ~C.
Analysis for C25H32N60S (464.637) calculated: C 64.63 %, H 6.94 %, N 18.09%, S 6.90 %;
found: C 63.11 %, H 6.86 %, N 17.77%, S 6.76 %~

Example 23 2-r 2-/4-(4-Methylbenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 16.3 g (68 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 183-185 ~C.

calculated: C 65.24 %, H 7.16 %, N 17.56%, S 6.70 %;
found: C 64.52 %, H 6.95 %, N 17.70%, S 6.49 %.

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Example 24 2- L 2-/4-(2-Methylbenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 18.4 g (77 %)~
Purification: recrystallization from aqueous ethanol.
Melting point: 166-168 ~C.

calculated: C 65.24 %, H 7.16 %, N 17.56%, S 6.70 %;
found: C 64.63 %, H 7.30 %, N 17.47%, S 6.90 %.

Example 25 2-L 2-/4-(2-Fluorobenzyl)-l-piperazinyl/-ethylt~io 7-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 20.5 g (85 %).
Purification: recrystallization from aqueous ethanol.

CA 0223~994 l998-04-27 Melting point: 162-164 ~C.
Analysis for C25H31FN6~S (482-628) calculated: C 62.22 %, H 6.47 %, N 17.41%, S 6.64 %;
found: C 62.17 %, H 6.68 %, N 17.42%, S 6.64 %.

Example 26 2-C 2-/4-(3-Cyanobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 21.3 g (87 %)~
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 9:1 as the eluent.
Melting point: 142-144 ~C.
Analysis for C26H31N70S (489.647) calculated: C 63.78 %, H 6.38 %, N 20.02%, S 6.55 %;
found: C 63.32 %, H 6.31 %, N 20.34%, S 6.43 %

Example 27 2-~ 2-/4-(2-Cyanobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 21.3 g (87 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 150-153 ~C.
Analysis for C26H31N70S (489.647) calculated: C 64.36 %, H 6.43 %, N 20.08%, S 6.57 %;
found: C 63.78 ~, H 6.38 %, N 20.02~, S 6.55 %~

Example 28 2-[ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 18.8 g (76 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 150-152 ~C.
Analysis for C26H34N602 calculated: C 63.13 %, H 6.93 %, N 16.99%, S 6.48 %;
found: C 62.86 %, H 6.98 %, N 17.15%, CA 0223~994 l998-04-27 W O 97/16429 PCTnHU96/00061 S 6.68 ~.

Example 29 2-~ 2-t4-(4-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 17.8 g (72 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 156-158 ~C.
Analysis,for C26H34N602 calculated: C 63.13 %l H 6.93 %, N 16.99~, S 6.48 %;
found: C 63.50 %t H 7.23 %, N 16.31%, S 6.66 %~

Example 30 2-r 2-/4-(4-Methoxybenzyl)-l-piperazinyl/-ethylthio J-4,6-diamino-5-(2-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 20.0 g (81 %)~

CA 0223~994 1998-04-27 Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 9:1 as the eluent.
Melting point: 149-152 ~C.
Analysis for C26H34N602 calculated: C 63.13 %, H 6.93 %, N 16.99%, S 6.48 %;
found: C 60.83 %, H 6.74 %, N 16.55%, S 6.16 %~

Example 31 2-~ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 22 g (89 %).
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 9:1 as the eluent.
Melting point: 118-120 ~C.
Analysis for C26H34N602 calculated: C 63.13 %, H 6.93 %, N 16.99%, S 6.48 %;
found: C 61.89 %, H 6.84 %, N 17.17~, S 6.26 %.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Example 32 2-~ 2-/4-(4-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 11.5 g (46 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 185-187 ~C.
Analysis for C25H31ClN60S (499.082) calculated: C 60.17 %, H 6.26 %, Cl 7.10%, N 16.84 %, S 6.42%;
found: C 58.32 %, H 6.19 %, Cl 6.95%, N 17.10 %, S 6.42%.

Example 33 2-r 2-/4 (4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 25.2 g (99 %).
Purification: recrystallization from aqueous acetone.

CA 0223~994 1998-04-27 W O 97/16429 PCT~nU96/00061 Melting point: 191-193 ~C.
y for C25H31N703s (509.635) calculated: C 58.92 %, H 6.13 %, N 19.24%, S 6.29 %;
found: C 58.20 %, H 6.08 %, N 18.65%, S 6.14 %.

Example 34 2-L 2-/4-(4-Nitrobenzyl)-1-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-methoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 12.2 g (48 %).
Purification: flash chromatography using a mixture of acetonitrile and methanol in a ratio of 8:2 as the eluent.
Melting point: 99-104 ~C.
Ana ys 25 31 7 3 calculated: C 58.91 %, H 6.13 %, N 19.24%, S 6.29 %;
found: C 57.51 %, H 6.25 %, N 19.49%, S 6.22 %.

Example 35 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/-ethyl-thio ~-4,6-diamino-5-(4-methoxybenzyl)pyrimidine CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96100061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A'l .
Yield: 17.8 g (67 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 164-165 ~C.
Analysis for C26H31F3N6 calculated: C 58.63 %, H 5.87 %, N 15.78%, S 6.02 %;
found: C 58.16 %, H 5.76 %, N 15.28%, S 5.93 %.

Example 36 2- L 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5--(2-methoxybenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 14.7 g (55 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 140-144 C.
Analysis for C26H31F3N60 ~ calculated: C 58.63 %, H 5.87 %, N 15.78%, S 6.02 %;

_ CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 found: C 56.51 %, H 5.88 %, N 15.47%, S 5.81 %.

Example 37 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5-(4-methoxybenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 13.4 g (44 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 178-180 C.
Analysis for C2sH27F3N8 5 calculated: C 49.34 %, H 4.47 %, N 18.41%, S 5.27 %;
found: C 48.69 %, H 4.29 %, N 18.35%, S 5.48 %.

Example 38 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4,6-diamino-5-(4-chlorobenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 14.1 g (60 %).

CA 0223~994 1998-04-27 Melting point: 182-184 ~C.
Analysis for C24H29ClN6S (469.056~
calculated: C 61.46 ~, H 6.23 %, Cl 7.56%, N 17.92 %, S 6.84%;
found: C 59.31 %, H 6.25 %, C1 7.40%, N 17.58 %, S 6.63%.

Example 39 2-L 2-/4-(2-Methylbenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(2-chloro-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 22.5 g (93 ~).
Purification: recrystallization from aqueous ethanol.
Melting point: 146-148 ~C.
Analysis for C2SH31ClN6S (483.083) calculated: C 62.16 %, H 6.46 %, Cl 7.34%, N 17.40 ~, S 6.64%;
found: C 62.06 %, H 6.47 %, Cl 7.35%
N 17.30 %, S 6.75~.

Exam,ple 40 2-L 2-/4-(4-Methylbenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chlorobenzyl)-- pyrimidine CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 19.3 g (80 %).
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 95:5 as the eluent or recrystallization from aqueous ethanol.
Melting point: 166-168 ~C.
Y 25 31 6S (483.0,83) calculated: C 62.16 %, H 6.46 %, Cl 7.34%, N 17.40 %, S 6.64%;
found: C 62.55 %, H 6.56 %, Cl 7.67%, N 16.86 %, S 6.46%.

Example 41 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4-(2-chlorophenyl)-5-cyano-6-aminopyrimidine Solvent employed in the reaction:
dimethylformamide.
Reaction time: 30 hours.
The reaction mixture is worked up by method "B".
Yield: 5.9 g (25 %).
Purification: recrystallization from ethanol.
Melting point: 177-178 ~C.
Y 24 25 6 ( 5.017) calculated: C 61.99 %, H 5.42 %, Cl 7.62%, N 18.07 %, S 6.89%;

CA 0223~994 l998-04-27 W O 97/16429 PCTnlU96/00061 found: C 61.45 %, H 5.50 %, Cl 7.54%, N 17.90 %, S 6.69%.

Example 42 2-L 2-/4-(2-Cyanobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(2-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 22.2 g (90 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 170-173 C.
Analysis for C25H28ClN7S (494.066) calculated: C 60.78 %, H 5.71 ~, Cl 7.18%, N 19.84 %, S 6.49%;
found: C 61.11 %, H 5.86 %, Cl 7.04%, N 19.09 %, S 6.56%.

Example 43 2-~ 2-/4-(4-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Yield: 22.2 g (89 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 181-184 ~C.
Analysis for C25H31ClN60S (499.082) calculated: C 60.17 %, H 6.26 %, Cl 7.10%, N 16.84 %, S 6.42%;
found: C 58.89 %, H 6.07 %, Cl 6.80%, N 16.15 %, S 6.49%.

Example 44 2-~ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 22.2 g (89 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 151-153 ~C.
Analysis for C25H31ClN60S (499.082) calculated: C 60.17 %, H 6.26 %, Cl 7.10%, N 16.84 %, S 6.42~;
found: C 60.57 %, H 6.16 %, Cl 7.02%, N 16.64 %, S 6.46%.

CA 0223~994 l998-04-27 W O 97/16429 PCTnHU96/00061 Example 45 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 10.8 g (43 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 178-183 ~C.
Ana ysi or C24ll28C 2 6S ( ~ ~ ) calculated: C 57.25 %, H 5.61 %, Cl 14.08%, N 16.69 %, S 6.37%;
found: C 57.45 %, H 5.36 ~, Cl 13.59%, N 16.80 %, S 6.14%.

Example 46 2-C 2-/4-(4 Chlorobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(2-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A"
Yield: 10.82 g (43 %).
Puri~ication: recrystallization from aqueous ethanol.

CA 0223~994 1998-04-27 W097/16429 PCT~U96/00061 Melting point: 173-175 C.
Ana y s fo C24 28C 2 6 calculated: C 57.25 %, H 5.61 %, Cl 14.08%, N 16.69 %, S 6.37%;
found: C 56.48 %, H 5.53 %, Cl 13.59%, N 16.38 %, S 6.11%.

Example 47 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction.time: 24 hours.
The reaction mixture is worked up by method "B".
Yield: 15.1 g (60 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 190-191 C.
Analysis for C24H28C12N6S (503.501) calculated: C 57.25 %, H 5.61 %, Cl 14.08%, N 16.69 %, S 6.37%;
found: C 56.42 %, H 5.67 %, Cl 14.14%, N 16.25 %, S 6.27%.

Example 48 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio J-4,6-diamino-5-(4-chlorobenzyl)-pyrimidine CA 0223~994 1998-04-27 W O 97/16429 PCTm U96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 25.4 g (99 %).
Purification: recrystallization from aqueous acetone.
Melting point: 133-135 C.
Analysis for C24H28ClN702S (514.053) calculated: C 56.08 %, H 5.49 %, Cl 6.90%, N 19.07 ~, S 6.24%;
found: C 56.55 ~, H 5.58 %, Cl 6.76%, N 18.77 ~, S 6.15~.

Example 49 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chlorobenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 12.1 g (47 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 201-203 ~C.
Analysis for C24H28ClN702S (514.053) calculated: C 56.08 %, H 5.49 %, Cl 6.90%, N 19.07 ~, S 6.24%;
found: C 56.05 %, H 5.57 %, Cl 6.69%, CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 N 18.96 %, S 6.17%.

Example 50 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5--(2-chlorobenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 15.3 g (57 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 121-123 ~C.
Analysis for C25H28ClF3N6S (537.054) calculated: C 55.81 %, l~ 5.43 ~, Cl 6.59~, N 15.62 %~ S 5.96%;
found: C 53.98 %, H 5.65 %, Cl 6.47%, N 15.31 %, S 5.79%.

Example 51 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4,6-diamino-5-(4-isopropylbenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 7 hours.
The reaction mixture is worked up by method "B".
Yield: 14.5 g (61 %).
Purification: recrystallization from aqueous CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 ethanol.
Melting point: 154-155 ~C.
Analysis for C27H36N6S (476.692) calculated: C 68.03 %, H 7.61 %, N 17.63%, S 6 73 %, found: C 66.63 %, H 7.57 %, N 17.14%, S 6.96 %.

~ xample 52 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-isopropylbenzyl)-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 20.8 g (80 %).
Purification: flash chromatography using a mixture of chloroform and acetone in a ratio of 2:8 as the eluent.
Melting point: 175-176 ~C.
Analysis for C27H35N7~2 calculated: C 62.16 %, H 6.76 %, N 18.79%, S 6.15 %;
found: C 62.38 %, H 6.87 %, N 18.40%, S 6.06 ~.

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Example 53 2-L 2-/4-(2-Fluorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 15.12 g (61 ~).
Purification: recrystallization from aqueous ethanol.
Melting point: 182-184 ~C.
Analysis for C26H34FN7S (495.670) calculated: C 63.00 %l H 6.91 %, N 19.78%, S 6.47 %;
found: C 62.86 %, H 7.23 %, N 19.73%, S 6.52 %.

Example 54 2-C 2-/4-(2-Cyanobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B"
Yield: 23.1 g (92 %).
Purification: recrystallization from aqueous ethanol.

CA 0223~994 l998-04-27 W 0 97/16429 PCTtHU96tO0061 Melting point: 170-173 ~C.
Analysis for C27H34N8S (502.690) calculated: C 64.51 %, H 6.82 %, N 22.29%, S 6.38 %, found: C 64.25 %, H 6.95 %, N 21.78%, S 6.12 %.

Example 55 2-[ 2-/4-(4-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 21.8 g (86 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 192-195 ~C.
Analysis for C27H37N70S (507.706) calculated: C 63.88 %, H 7.35 %, N 19.31%, S 6.31 %;
found: C 63.93 %, H 7.13 %, N 19.12%, S 6.51 %.

Example 56 2-~ 2-/4-(3-Chlorobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine CA 0223~994 1998-04-27 WO 97/16429 PCT~HU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 16.60 g (65 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 179-182 ~C.

calculated: C 60.98 %, H 6.69 %, Cl 6.92%, N 19.15 %, S 6.26%;
found: C 60.81 %, H 6.56 %, Cl 6.85%, N 19.00 ~, S 6.38%.

Example 57 2-C 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,~-dlamino-5-(4-dimethyl~mino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 11 g (42 %).
Purification: recrystallization from aqueous dimethylformamide.
Melting point: 219-220 ~C.
Analysis for C26H34N802 calculated: C 59.75 %, H 6.56 %, N 21.44%, S 6.13 %;
found: C 58.03 %, H 6.32 %, N 21.08%, CA 0223~994 l998-04-27 W O 97/16429 PCTnlU96/00061 S 5.94 %.
Example 58 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/ethylthio J-4,6-diamino-5-(4--dimethylaminobenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 11.50 g (42 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 185-189 ~C.
Ana ys 27 34 3 7 calculated: C 59.32 %, H 6.45 %, N 17.94%, S 5.86 %;
found: C 58.44 %, H 6.35 %, N 18.01%, S 5.79 %.

Example 59 2-~ 2-/4-(4-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chloro-6-fluoro-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
- The reaction mixture is worked up by method "B".
Yield: 11.7 g (45 %).
Purification: recrystallization from aqueous CA 0223~994 1998-04-27 ethanol.
Melting point: 202-206 ~C.
Analysis for C24H27C12FN6 calculated: C 55.28 %, H 5.22 %, Cl 13.60%, N 16.12 ~, S 6.15%;
found: C 54.78 %, H 5.20 %, Cl 13.40%, N 16.22 %, S 6.30%.

Example 60 2-r 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(2-chloro-6-fluoro-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 17.8 g (48 %).
Purification: recrystallization from acetone.
Melting point: 202-204 ~C.
Analysis for C24H27ClFN7~2 calculated: C 54.18 ~, H 5.12 %, Cl 6.66%, N 18.43 %, S 6.03%;
found: C 53.97 %, H 5.04 %, Cl 6.61%, N 17.73 %, S 6.05%.

Example 61 2-C 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4,6-diamino--5-(2-chloro-6-fluorobenzyl)pyrimidine CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 15.8 g (50 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 185-192 ~C.
Analysis for C24ll23ClF4N804 calculated: C 45.68 %, H 3.67 %, Cl 5.62%, N 17.76 %, S 5.08%;
found: C 45.56 %, H 3.62 %, Cl 5.49%, N 17.14 %, S 5.25%.

Example 62 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-trifluoromethyl-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 12.6 g (46 %).
Purification: recrystallization from aqueous dimethylformamide.
Melting point: 164-166 C.
Analysis for C25H28F3N702 calculated: C 54.83 %, H 5.15 %, N 17.90%, S 5.86 %;
found: C 54.00 %, H 5.18 %, N 17.50%, CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 S 6.06 %.

Example 63 2-C 2-/4-(3-Trifluoromethylbenzyl)-l-piperazinyl/ethylthio ~-4,6-diamino-5-(4-trifluoromethylbenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 14 g (49 %).
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 9:1 as the eluent.
Melting point: 127-129 ~C.
Analysis for C26~l28F6N6S
calculated: C 54.73 %, H 4.95 %, N 14.73%, S 5.62 %;
found: C 54.79 %, H 4.80 %, N 14.46%, S 5.74 %.

Example 64 2-~ 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-bromo-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".

W O 97/16429 PCTnHU96/00061 Yield: 12.9 g (46 %).
Purification: recrystallization from aqueous acetone.
Melting point: 169-173 ~C.
Analysis for C24H28BrN702S (558.509) calculated: C 51.61 %, H 5.05 %, Br 14.31%, N 17.56 ~, S 5.74%;
found: C 51.45 %, H 5.04 %, Br 13.94%, N 17.44 %, S 5.50%.

Example 65 2-~ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(3,4,5-trimethoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 17.2 g (62 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 137-138 ~C.

calculated: C 60.63 %, H 6.91 %, N 15.15%, S 5.78 %;
found: C 58.32 ~, H 7.05 %, N 14.95%, S 5.62 %~

CA 0223~994 1998-04-27 W ~ 97/16429 PCTnHU96/00061 Example 66 2-C 2-/4-(4-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(3,4,5-trimethoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 23.6 g (85 %).
Purification: flash chromatography using a mixture of chloroform and methanol in a ratio of 9:1 as the eluent.
Melting point: 152-154 ~C.

calculated: C 60.63 %, H 6.90 %, N 15.15~, S 5.78 %;
found: C 61.99 %, H 6.89 %, N 14.45%, S 5.52 %~

Example 67 2-r 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(3,4,5-trimethoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 22.4 g (80 %).
Purification: recrystallization from aqueous CA 0223~994 1998-04-27 ethanol.
Melting point: 170-172 ~C.
Analysis for C27H35ClN603S (559.135) calculated: C 58.00 %, H 6.31 %, Cl 6.34%, N 15.03 %, S 5.73;
found: C 57.30 %, H 6.30 %, Cl 6.27%, N 14.80 %, S 5.74%.

Example 68 2-L 2-/4-(4 Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(3,4,5-trimethoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 11.7 g (41 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 130-132 ~C.

calculated: C 56.93 %, H 6.19 %, N 17.21%, S 5.63 %;
found: C 56.67 ~, H 6.22 %, N 17.38%, S 5.54 %.

A Example 69 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l--piperazinyl/ethylthio 7-4,6-diamino-5--(3,4,5-trimethoxybenzyl)pyrimidine -CA 0223~994 1998-04-27 WO 97/16429 PCT~HU96/00061 Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 13 g (44 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 159-162 ~C.
Analysis for C28H35F3N6 3 calculated: C 56.74 %, H 5.95 %, N 14.18%, S 5.41 %;
found: C 56.90 %, H 6.04 %, N 14.06%, S 5.62 %.

Example 70 2-C 2-/4-(4-Nitrobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-benzyloxy-3--methoxybenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 14.5 g (47 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 171-173 ~C.
Analysis for C32 37 7 4 calculated: C 62.42 ~, H 6.06 %, N 15.92~, S 5.21 %;
found: C 61.23 ~, H 5.83 %, N 15.85~, CA 0223~994 l998-04-27 S 5.22 %.

Example 71 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio J7-4,6-diamino-5--(4-methoxybenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 2.5 hours.
The reaction mixture is worked up by method "B".
Yield: 23.1 g (82 %).
Melting point: 181-182 C.
Analysis for C25H28F3N7~3S (563.607) calculated: C 53.28 ~, H 5.01 %, N 17.40~, S 5.69 %;
found: C S2.65 %, H 4.89 %, N 17.05~, S 5.91 ~, Example 72 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-methoxy-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 4 hours.
The reaction mixture is worked up by method "B".
Yield: 16.0 g (64 %).
- Purification: recrystallization from aqueous ethanol.

CA 0223~994 1998-04-27 WO 97/16429 PCTnHU96/00061 Melting point: 173 ~C.
Analysis for C25H31ClN6~S (499 075) calculated: C 60.17 %, H 6.26 %, Cl 7.10%, N 16.84 %, S 6.42%;
found: C 59.95 %, H 6.22 %, Cl 6.99%, N 16.55 %, S 6.50%.

Example 73 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-benzyloxy-3--methoxybenzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 82 hours.
The reaction mixture is worked up by method "B".
Yield: 25.7 g (85 %).
Purification: recrystallization from benzene.
Melting point: 158-160 ~C.
Analysis for C32H37ClN6~2S
calculated: C 63.51 %, H 6.16 %, Cl 5.86%, N 13.89 %, S 5.30%;
found: C 63.16 %, H 6.12 %, Cl 5.84%, N 13.84 %, S 5.33%.

Example 74 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(4-isopropyl-benzyl)pyrimidine Solvent employed in the reaction: methanol.

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 16.1 g (63 %).
Purification: recrystallization from ethanol.
Melting point: 138-140 ~C.
Analysis for C27H35ClN6S (511.130) calculated: C 63.45 %, H 6.90 %, Cl 6.94%, N 16.44 %, S 6.27%;
found: C 63.32 %, H 7.00 ~, Cl 6.76%, N 16.34 ~, S 6.30%.

Example 75 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4,6-diamino-5-(4-benzyloxy-3-methoxybenzyl)-pyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 7.5 hours.
The reaction mixture is worked up by method "C" .
Yield: 26.6 g (~3 %).
Purification: recrystallization from methanol.
Melting point: 166-167 ~C.

calculated: C 67.34 %, H 6.71 %, N 14.72%, S 5.62 %;
found: C 66.52 %, H 6.68 ~, N 14.36%, S 5.55 %.

CA 0223~994 l998-04-27 W O 97/16429 PCTnHU96/00061 Example 76 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4-methyl--5-(2-hydroxyethyl)uracil Solvent employed in the reaction: methanol.
Reaction time: 1.5 hours.
The reaction mixture is worked up by method "B".
Yield: 13.8 g (52 %).
Purification: stirring in ethyl acetate.
Melting point: 196-197 ~C.
Analysis for C20H23F3N6 6 calculated: C 45.11 %, H 4.35 %, N 15.78%, S 6.02 %;
found: C 46.30 %, H 4.35 %, N 15.55%, S 6.29 %, Example 77 2-C 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/-ethylthio 7-4-methyl-5--(2-hydroxyethyl)uracil Solvent employed in the reaction: ethanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "A".
Yield: 17.6 g (72 %).
Purification: stirring in hexane.
Melting point: 133-135 ~C.
Analysis for C20H24F3N5~4S (487.506) CA 0223~994 1998-04-27 W O 97/16429 PCTlHnU96/00061 calculated: C 49.28 %, Il 4.96 %, N 14.37%, S 6.58 %;
found: C 48.05 %, H 4.75 %, N 14.38%, S 6.56 %.

Example 78 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio~-4-methyl-uracil Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 11 g (45 %)~
Purification: recrystallization from ethanol.
Melting point: 226-228 C.
Analysis for C18H19F3N6~5S (488.45) calculated: C 44.26 %, II 3.92 %, F 11.67%, N 17.21 %, S 6.56~;
found: C 44.04 ~, H 4.07 %, F 12.07%, N 16.76 %, S 6.56%.

Example 79 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio J-4-amino-uracil Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 "B".
Yield: 17.6 g (72 %).
Purification: flash chromatography using a mexture of chloroform and methanol in a ratio of 9:1 as the eluent, then recrystallization from aqueous ethanol.
Melting point: 257-259 ~C.

calculated: C 41.72 %, H 3.71 %, F 11.65%, N 20.03 %, S 6.55%;
found: C 42.10 %, H 3.64 %, F 11.66~, N 20.23 %, S 6.66%.

~ xample ~0 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ~-4-(4-methoxy-phenyl)-5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: methanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 20.6 g (73.4 %).
Melting point: 225-226 ~C.
Analysis o 25 26 3 7 3 calculated: C 53.47 %, H 4.67 %, N 17.46%, S 5.71 %;
found: C 53.54 %, H 4.69 %, N 17.18%, S 5.89 %.

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Example 81 2-C 2-/4-~2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio 7-4-(2-methoxy-phenyl)-5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: methanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 24.8 g (88 %).
Melting point: 213-215 ~C.

calculated: C 53.47 %, H 4.67 ~, N 17.46%, S 5.71 ~;
found: C 53.67 ~, l1 4.74 ~, N 17.27~, S 5.95 %.

Example 82 2-~ 2-/4 (2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ,7-4-(4-chlorophenyl)--5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: ethanol.
Reaction t-me: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 24.9 q (87.9 ~).
Meltin~ point: 217-219 ~C.
Analysis for C24H23ClF3N7~2 calculated: C 50.93 %, H 4.10 ~, Cl 6.26~, N 17.32 %, S 5.66%;

CA 0223~994 1998-04-27 W O 97/16429 PCT~HU96/00061 found: C 50.09 %, H 4.02 %, Cl 6.32%, N 16.51 %, S 5.65%.

Example 83 2-L 2-/4-(2-Nitro-4-.rifluoromethylphenyl)--l-piperazinyl/ethylthio ~-4-~2-chlorophenyl)--5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 45 minutes.
The reaction mixture is worked up by method "8".
Yield: 25.7 g (90.8 %).
Melting point: 235-236 ~C.
Analysis for C24H23ClF3N7~2S
calculated: C 50.93 %~ H 4.10 ~, Cl 6.26%, N 17.32 %, S 5.66~;
found: C 50.55 %, H 4.11 %, Cl 6.19~, N 17.20 %, S 5.72%.

Example 8 4 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ~-4-(4-dimethyl-aminophenyl)-5-cyano-6-amino-3,4-dihydro-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 1.5 hours.
The reaction mixture is worked up by method "B".
Yield: 25.8 g (89.8 %).

CA 0223~994 l998-04-27 W O 97/16429 PCT~HU96/00061 Purification: recrystallization from aqueous acetone.
Melting point: 221-223 ~C.
Analysis for C26H29F3N8~2S (574.634) calculated: C 54.35 %, H 5.09 ~; N 19.50%, S 5.58 %;
found: C 54.48 %, H 5.11 %, N 19.32% r S 5.72 %.

Example 85 2-C 2-/4-(2-Nitro-4-trifluoromethylphenyl)_ -1-piperazinyl/ethylthio ~-4-phenyl-5-cyano--6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 0.5 hours.
The reaction mixture is worked up by method "B".
Yield: 24 g (90.3 %).
Melting point: 240-242 ~C.
Ana ysi r C24H24F3 7 2S
calculated: C 54.23 %, H 4.55 %, N 18.44~, S 6.03 %;
found: C 53.63 %, H 4.49 %, N 18.08%, S 6.21 %.

Example 86 2-C 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-pipera7inyl/ethylthio ~-4-(4--methoxyphenyl)-5-cyano-6-aminopyrimidine CA 0223~994 1998-04-27 Solvent employed in the reaction: methanol.
Reaction time: 20 minutes.
The reaction mixture is worked up by method "C" .
Yield: 15.7 g (51.7 ~).
Purification: recrystallization from a mixture of ethanol and acetone.
Melting point: 245-247 ~C.

calculated: C 49.67 %, H 3.83 %, N 18.53%, S 5.30 ~;
found: C 49.16 %, H 4.05 %, N 18.30~, S 5.38 %.

Example 87 2-L 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio J-4-(4-bromophenyl--5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 1 hour.
The reaction mixture ic worked up by method "B".
Yield: 26.4 g (86.4 %).
Melting point: 220-222 ~C.
Analysis for C24H23BrF3N7~2 calculated: C 47.22 ~, ll 3.80 %, Br 13.09~, N 16.06 %, S 5.25%;
found: C 46.50 %, H 3.73 %, Br 13.26%, N 15.99 %, S 5.20%.

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Example 88 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ,7-4-(4-benzyloxy--3-methoxyphenyl-5-cyano-6-amino-3,4--dihydropyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 27.7 g (83.0 %).
Purification: recrystallization from ethyl acetate.
Melting point: 162-164 C.
~nalysis for C32~l32F3N7~4S (667.717) calculated: C 57.56 %, H 4.83 %, N 14.68%, S 4.80 %;
found: C 57.10 ~, H 4.76 %, N 14.46%, S 4.99 ~, Example 89 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ~-4-(3 ! 4,5--trimethoxyphenyl)-5-cyano-6-amino-3,4--dihydropyrimidine Solvent cmploycd in thc rcaction: ct}lanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 26.2 g (84.4 %).

CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Melting point: 204-206 ~C.
Ana ys s f C27 30 3 7 5 calculated: C 52.17 %, H 4.86 %, N 15.77%, S 5.16 %i found: C 52.16 %, H 4.72 %, N 15.98%, S 5.32 %.

Example 90 2-C 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)piperazinyl/ethylthio ~-4-(2-methoxy-phenyl)-5-cyano-6-aminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "B".
Yield: 10.7 g (35.4 ~).
Purification: recrystallization from aqueous ethanol.
Melting point: 194-195 ~C.
Analysis for C2sH23F3N805S (604.573) calculated: C 49.67 ~, H 3.83 %, N 18.53~, S 5.30 %;
found: C 48.27 %, H 3.85 %, N 18.29%, S 5.26 %.

Example 91 2-~ 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio 7-4-methyl-5-ethoxy-carbonyl-6-phenyl-3,4-dihydropyrimidine CA 0223~994 1998-04-27 Solvent employed in the reaction: methanol.
Reaction time: 1.5 hours.
The reaction mixture is worked up by method "A".
Yield: 12.2 g (42.1 %).
Purification: recrystallization from a mixture of methanol and hexane.
Melting point: 110-112 C.

calculated: C 56.14 ~, H 5.23 %, N 12.12%, S 5.55 %;
found: C 54.41 %, H 4.91 %, N 12.24%, S 5.63 %.

Example 92 2-t 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4-(4-chloro-phenyl)-5-cyano-6-aminopyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 15.2 g (50.9 %).
Purification: recrystallization from ethyl acetate. Melting point: 247-249 C.
Analysis for C23~20ClF3N804S
calculated: C 46.28 %, H 3.38 %, Cl 5.94%, N 18.77 %, S 5.37~;
found: C 46.94 %, 1l 3.27 %t Cl 5.84%, N 18.37 ~, S 5.23%.

CA 0223~994 1998-04-27 Example 93 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4--(4-methoxyphenyl)-5-cyano-6-aminopyrimidine Solvent employed in the reaction: methanol.
Reaction time: 3 hours.
The reaction mixture is worked up by method "A".
Yield: 13.1 g (55.5 %).
Melting point: 156-158 ~C.
Analysis for C25H30N60S (462.617) calculated: C 64.91 %, H 6.54 %, N 18.17%, S 6.93 %;
found: C 64.87 %, H 6.59 %, N 17.86%, S 6.98 %.

Example 94 2-~ 2-/4-(2,6-Dinitro-4-trifluoromethyl-phenyl)-l-piperazinyl/ethylthio ~-4-(4-benzyloxy-3-methoxyphenyl)-5-cyano--6-aminopyrimidine Solvent employed in the reaction: ethanol.
Reaction time: 1 hour.
The reaction mixture is worked up by method "B".
Yield: 25.0 g (70.2 ~).
Puri~ication: recrystallization from ethyl acetate.
Melting point: 201-203 ~C.
Analysis for C32H29F3N806 CA 0223~994 l998-04-27 W O 97/16429 PCT~HU96/00061 calculated: C 54.08 %, H 4.11 %, N 15.77%, S 4.51 %;
found: C 53.49 %, H 3.99 %, N 15.70%, S 4.38 %.

Example 95 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4--(2-chlorophenyl)-5-cyano-6-amino-3,4--dihydropyrimidine Solvent employed in the reaction: methanol.
Reaction time: 14 hours.
The reaction mixture is worked up by method "C" .
Yield: 15.9 g (67.9 %).
Melting point: 183-184 ~C.
~nalysis for C24~l27ClN6S (467.033) calculated: C 61.72 %, H 5.83 %, Cl 7.59%, N 17.99 %, S 6.86%;
found: C 62.20 %, H 5.76 %, Cl 7.85%, N 18.13 %, S 7.04%.

Example 96 2-/2-(4-Benzyl-l-piperazinyl)ethylthio/-4--phenyl-5-cyano-6-amino-3,4-dihydropyrimidine Solvent employed in the reaction: methanol.
Reaction time: 2.5 hours.
The reaction mixture is worked up by method "B"
Yield: 11.9 g (55.1 %).

CA 0223~994 1998-04-27 Purification: recrystallization from ethanol.
Melting point: 175-176 C.
Analysis for C24H28N6S (432.591) calculated: C 66.64 %, H 6.52 %, N 19.43%, S 7.41 %;
found: C 66.59 %, H 6.50 %, N 19.28%, S 7.29 %.

Example 97 2-~ 2-/4-(2-Nitrobenzyl)-l-piperazinyl/-ethylthio 7-4-phenyl-5-cyano-6-amino-3,4--dihydropyrimidine Solvent employed in the reaction:
dimethylformamide.
Reaction time: 3 hours.
The reaction mixture is worked up by method "C" .
Yield: 13.8 g (57.6 %).
Melting point: 198-199 ~C.
Y 24 27 7 2 ( . 89) calculated: C 60.36 %, H 5.70 %, N 20.53%, S 6.71 %;
found: C 59.61 %, H 5.53 %, N 20.52%, S 6.63 %..

Example 98 2-L 2-(4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/etllylthio ~-4-phenyl-5-cyano--6-aminopyrimidine CA 0223~994 l998-04-27 W O 97/16429 PCTnHU96/00061 Solvent employed in the reaction:
dimethylformamide.
Reaction time: 10 hours.
The reaction mixture is worked up by method "B".
Yield: 20.3 g (76.8 %).
Purification: recrystallization from ethanol, then from benzene.
Melting point: 189-190 ~C.
Analysis for C24H22F3N702S (529.549) calculated: C 54.44 %, H 4.19 %, N 18.52%, S 6.05 %;
found: C 55.59 %, H 4.33 %, N 18.02%, S 5.92 %.

Example 99 2-C 2-/4-(2-Nitro-4-trifluoromethylphenyl)--l-piperazinyl/ethylthio ~-4-(2-methoxy-phenyl)-5-cyano-6-aminopyrimidine Solvent employed in the reaction:
dimethylformamide.
Reaction time: 35 hours.
The reaction mixture is worked up by method "B".
Yield: 20.6 g (73.6 ~).
Purification: recrystallization ~rom benzene, then the crystals are suspended in kerosene.
Meltiny point: 145-147 ~C.
Y 25 24 3 7 3 ( 9~5 calculated: C 53.66 %, H 4.32 %, N 17.52%, CA 0223~994 1998-04-27 W O 97/16429 PCTnIU96/00061 S 5.73 %;
found: C 54.04 %, H 4.36 %, N 17.13%, S 5.94 %.

Example 100 2-~ 2-/4-(3-Trifluoromethylbenzyl)-l--piperazinyl/ethylthio 7-4-(2-chlorophenyl)--5-cyano-6-aminopyrimidine Solvent empl-oyed in the reaction:
dimethylformamide.
Reaction time: 5 hours.
The reaction mixture is worked up by method "A".
Yield: 16.7 g (63.5 %).
Purification: recrystallization from ethanol.
Meltin~ point: 166-167 ~C.
y C25H24ClF3N6s (533.02) calculated: C 56.34 %, H 4.54 %, Cl 6.65%, N 15.77 %, S 6.01%;
found: C 55.78 %, H 4.42 %, Cl 6.68%, N 15.81 ~, S 6.20%.

Example 101 2-~ 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 40 hours.
The reaction mixture is worked up by method CA 0223~994 l998-04-27 " }'. "
Yield: 5.85 g (22.9 %).
Purification: recrystallization ~rom aqueous acetone.
Melting point: 156.4-156.6 ~C.
Analysis for C26H34ClN7S (512.13) calculated: C 60.98 %, H 6.69 %, Cl 6.92%, N 19.15 %, S 6.26%;
found: C 60.80 %, H 6.67 %, Cl 6.83%, N 18.85 %, S 6.11%.

Example 102 2-L 2-/4-(2-Chlorobenzyl)-l-piperazinyl/-ethylthio 7-4,6-diamino-5-(4-dimethylamino-benzyl)pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 40 hours.
The reaction mixture is worked up by method "A".
Yield: 5.30 g (26.5 %).
Purification: recrystallization from aqueous acetone.
Melting point: 90-93 ~C.
Analysis for C26H34ClN7S (512.13) calculated: C 62.97 %, H 8.05 %, N 20.98%, S 8.00 %;
found: C 62.36 %, H 7.92 %, N 20.34%, S 7.86 %.

CA 0223~994 1998-04-27 W ~ 97/16429 PCTAHU96/00061 Example 103 2-/11-(4-Benzyl-l-piperazinyl)undecylthio/--4,6-diaminopyrimidine x MeOH

Solvent employed in the reaction: methanol.
Reaction time: 12 hours.
The reaction mixture is worked up by method "A".
Yield: 18.50 g (78.0 %).
Purification: recrystallization from aqueous ethanol.
Melting point: 109-111 ~C.
Analysis for C27~l46N6 calculated: C 64.50 ~, H 9.22 %, N 16.72%~
S 6.38 %;
~ound: C 62.57 %, H 8.90 %, N 16.43~, S 6.36 ~.

Example 104 2_L 11-/4-(4-Nitrobenzyl)-l-homopiperazinyl/-l-undecylthio 7-4~6-diamino-pyrimidine Solvent employed in the reaction: methanol.
Reaction time: 12 hours.
The reaction mixture is worked up by method "A".
Yield: 18.2 g (68.0 %).
Purification: recrystallization from a mixture of chloroform and methanol.
Melting point: 185-187 ~C.
Analysis for C27 43 7 2 CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 calculated: C 61.22 %, H 8.18 ~, N 8.51 %~
S 6.05 %;
found: C 61.05 %. H 8.10 %, N 8.60 %, S 6.09 %.

Preparation of the acid addition salts The pharmaceutically acceptable acid addition salts of the compounds of the formula I are prepared according to the following general method:

0.05 moles of the compound of the formula I are dissolved in 1000 ml of ethanol, and, to the solution obtained, 250 ml of ethanol containing 25 per cent of hydrochlorid acid are added. The reaction mixture is stirred at reflux temperature for 2 hours, then the solvent is removed under reduced pressure.
The solid residue is purified by suspending it in 100 ml of anhydrous ethanol, stirring the suspension for 20 minutes, then removing the solvent under reduced pressure. The purification procedures are repeated three times, and the product is dried in a drying oven until a constant weight is attained.

Example 105 2-[ 2-/4-(2-Methylbenzyl)-l-piperazinyl/-ethylthio J-4,6-diamino-5-(2-chloro-benzyl)pyrimidine trihydrochloride CA 0223~994 1998-04-27 W O 97/16429 PCTnHU96/00061 Yield: 27 ~ (91 %).
Melting point: 179-186 C.
Analysis for C25~34C14N6S ( calculated: C 50.68 %, H 5.78 %, Cl 23.94%, N 14.18 % S 5.41 %;
found: C 49.75 %, H 5.75 %, Cl 23.46%, N 14.02 ~, S 5.45 %.

Example 106 2-~ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4,6-diamino-5-(3 4,5-trimethoxy-benzyl)pyrimidine trihydrochloride Yield: 30 ~ (39 %).
Melting point: 171-179 C.
Analysis for C28l541C13N604S (664.100) calculated: C 50.64 %, ll 6.22 %, Cl 16.02~, N 12.65 %, S 4.83 %;
found: C 50.07 %, H 6.52 %, Cl 15.79%, N 12.20 %~ S 4.64 %.

Example 107 2-~ 2-/4-(2-Cyanobenzyl)-l-piperazinyl/-ethylthio ~-4.6-diamino-5-(4-methoxy-benzyl)pyrimidine trihydrochloride Yield: 28 ~ (92 %).
Melting point: 199-210 ~C.
~nalysis for C261l34C13W70S (599.030) calculated: C 52.13 % H 5.72 %, Cl 17.76%, N 16.37 %~ S 5.35 %;

CA 0223~994 l998-04-27 found: C 51.76 %, El 5.65 %, C1 17.57%, N 16.06 %, S 5.45 %.

Example 108 2-C 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio ~-4 r 6-diamino-5-benzylpyrimidine trihydrochloride Yield: 25 g (87 %).
Melting point: 163-174 ~C.
Analysis for C25E~35C13N6~S (574-020) calculated: C 52.31 %, H 6.15 % Cl 18.53%, N 14.64 %, S 5.59 %;
found: C 51.29 %! H 6.17 %, Cl 19.08%, N 14.26 %, S 5.80 %.

Example lo9 2-~ 2-/4-(3-Trifluoromethylbenz~l)-l--piperazinyl/ethylthio ~-4;6-diamino-5--(3,4,5-trimethoxybenzyl)pyrimidine trihydrochloride Yield: 30 g (85 %).
Meltins point: 162-165 ~C.
Analysis for C28H38C13F3N6~3 calculated: C 47.90 %, H 5.46 % Cl 15.15%, N 11.97 %, S 4.57 %;
found: C 45.84 %, H 5.60 %r Cl 14.51%, N 11.40 %, S 4.63 %~

W O 97/16429 PCTnHU96/00061 Example 110 2-/ 2-/4-(3-Methoxybenzyl)-l-piperazinyl/-ethylthio /-4,G-di~mino-5-(4-methoxy-benzyl)pyrimidine trihydrochloride Yield: 26 g (86 ~).
Melting point: 172-182 ~C.
.~nalysis for C26H37C13N6~2 calculated: C 51.70 %, El 6.17 %. Cl 17.61%, N 13.91 %! S 5.31 %;
found: C 50.01 ~, H 6.27 %, Cl 16.94%, N 13.29 %, S 5.24 %.

Claims (11)

Claims

1. A piperazinylalkylthiopyrimidine derivative of the formula wherein R1 and R3 represent, independently, a hydrogen, a C1-4 alkyl group, an amino group, a (C1-4 alkanoyl)-amino group, or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group or a benzyloxy group, R2 stands for a hydrogen, a cyano group, a furylmethyl group, a (C5-7 cycloalkyl)methyl group , a (C1-4 alkoxy)carbonyl group, a hydroxy-(C1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group, a hydroxy group , a benzyloxy group or a di-(C1-4 alkyl)amino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom, R5 is a hydrogen , or R4 forms with R5 a valence bond, R6 represents a halo, a cyano group, a nitro group, a C1-4 alkyl group, a C1-4 alkoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p is an integer between 2 to 11, and k has a value of 0, 1, 2 or 3, and a pharmaceutically acceptable acid addition salt thereof.

2. A compound of the formula I as claimed in Claim 1 wherein R1 and R3 represent, independently, a hydrogen, a methyl group, an amino group, an acetylamino group or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of independently, a chloro, a methoxy group, a dimethylamino group or a benzyloxy group;

R2 stands for a hydrogen, a cyano group, a furylmethyl group, a cyclohexylmethyl group, an ethoxycarbonyl group , a hydroxyethyl group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently , a chloro, a C1-3 alkyl group, a fluoro, a methoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a dimethylamino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom, R5 is a hydrogen , or R4 forms with R5 a valence bond, R6 represents a chloro, a fluoro. a cyano group, a nitro group, a methyl group, a methoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p has a value of 2 or 11, and k has a value of 0, 1, 2 or 3, and a pharmaceutically acceptable acid addition salt thereof.

3. A compound of the formula I as claimed in Claim 1 or 2 , wherein R1 and R3 represent an amino group, R2 stands for a hydrogen or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently.
a fluoro, a chloro, a methoxy group and a dimethylamino group, R4 forms with R5 a valence bond, R6 means a fluoro, a chloro, a nitro group, a cyano group, a methyl group, a methoxy group or a trifluoromethyl group, k has a value of 1, m has a value of 1, n has a value of 1, and p has a value of 2, and a pharmaceutically acceptable acid addition salt thereof.

4. 2-[ 2-/4-(4-Nitrobenzyl)-1--piperazinyl/ethylthio ]-4,6-diamino--5-benzylpyrimidine and a pharmaceutically acceptable acid addition salt thereof.

5. A process for preparing a piperazinyl-alkylthiopyrimidine derivative of the formula wherein R1 and R3 represent independently; a hydrogen, a C1-4 alkyl group, an amino group, a (C1-4 alkanoyl)-amino group, or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of independently, a halo, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group or a benzyloxy group, R2 stands for a hydrogen, a cyano group, a furylmethyl group, a (C5-7 cycloalkyl)methyl group, a (C1-4 alkoxy)carbonyl group. a hydroxy-(C1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a di-(C1-4 alkyl)amino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom.
R5 is a hydrogen, or R4 forms with R5 a valence bond, R6 represents a halo, a cyano group, a nitro group, a C1-4 alkyl group, a C1-4 alkoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2.
p is an integer between 2 to 11 , and k has a value of 0, 1, 2 or 3, and a pharmaceutically acceptable acid addition salt thereof, in which a 2-mercaptopyrimidine of the formula wherein R1, R2, R3, R4 and R5 are as defined above. or an alkali metal salt thereof is reacted with a haloalkylpiperazine derivative of the formula wherein R6, m, n, p and k are as stated above, H1g stands for chloro or bromo, or an acid addition salt thereof and, if desired an obtained compound of the formula I is transformed into a pharmaceutically acceptable acid addition salt or the base of the formula I is liberated from the acid addition salt.

6. A pharmaceutical composition comprising a piperazinylalkylthiopyrimidine derivative of the formula wherein R1 and R3 represent. independently; a hydrogen, a C1-4 alkyl group. an amino group, a (C1-4 alkanoyl)-amino group, or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of; independently, a halo, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group or a benzyloxy group, R2 stands for a hydrogen, a cyano group, a furylmethyl group, a (C5-7 cycloalkyl)methyl group, a (C1-4 alkoxy)carbonyl group, a hydroxy-(C1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a di-(C1-4 alkyl)amino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom;
R5 is a hydrogen, or R4 forms with R5 a valence bond, R6 represents a halo; a cyano group. a nitro group, a C1-4 alkyl group, a C1-4 alkoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p is an integer between 2 to 11, and k has a value of 0, 1, 2 or 3, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient and one or more usual carrier(s) .

7. A pharmaceutical composition as claimed in Claim 6 in which the piperazinyl-alkylthiopyrimidine derivative is a compound of the formula I wherein R1 and R3 represent, independently, a hydrogen, a methyl group, an amino group, an acetylamino group or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a chloro, a methoxy group, a dimethylamino group or a benzyloxy group, R2 stands for a hydrogen, a cyano group, a furylmethyl group, a cyclohexylmethyl group an ethoxycarbonyl group, a hydroxyethyl group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, 2 chloro, a C1-3 alkyl group, a fluoro, a methoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a dimethylamino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom.
R5 is a hydrogen, or R4 forms with R5 a valence bond, R6 represents a chloro, a fluoro, a cyano group, a nitro group, a methyl group, a methoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p has a value of 2 or 11, and k has a value of 0, 1. 2 or 3, or a pharmaceutically acceptable acid addition addition salt thereof.

8. A pharmaceutical composition as claimed in Claim 6 or 7 in which the piperazinylalkylthiopyrimidine derivative is a compound of the formula I wherein R1 and R3 represent an amino group, R2 stands for a hydrogen or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a fluoro, a chloro, a methoxy group and a dimethylamino group, R4 forms with R5 a valence bond, R6 means a fluoro, a chloro a nitro group, a cyano group, a methyl group, a methoxy group or a trifluoromethyl group, k has a value of 1, m has a value of 1, n has a value of 1, and p has a value of 2, or a pharmaceutically acceptable acid addition salt thereof.

9. A pharmaceutical composition as claimed in any of Claims 6 to 8 in which the piperazinylalkylthiopyrimidine derivative of the formula I is 2-[ 2-/4-(4-nitrobenzyl)--1-piperazinyl/ethylthio ]-4 6-diamino-5--benzylpyrimidine or a pharmaceutically acceptable acid addition salt thereof.

10. A method for the treatment of diseases especially due to pathological alterations of the central nervous system which comprises administering an effective non-toxic dose of a piperazinylalkylthio-pyrimidine derivative of the formula wherein R1 and R3 represent, independently, a hydrogen, a C1-4 alkyl group, an amino group, a (C1-4 alkanoyl)-amino group, or a phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group or a benzyloxy group, R2 stands for a hydrogen. a cyano group, a furylmethyl group, a (C5-7 cycloalkyl)methyl group, a (C1-4 alkoxy)carbonyl group. a hydroxy-(C1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkyl-group, a C1-4 alkoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a di-(C1-4 alkyl)amino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom, R5 is a hydrogen, or R4 forms with R5 a valence bond, R6 represents a halo, a cyano group, a nitro group, a C1-4 alkyl group, a C1-4 alkoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p is an integer between 2 to 11, and k has a value of 0, 1, 2 or 3, or a pharmaceutically acceptable acid addition salt thereof to a patient suffering from said diseases.

11. The use of a piperazinylalkylthio-pyrimidine derivative of the formula wherein R1 and R3 represent, independently, a hydrogen. a C1-4 alkyl group, an amino group, a (C1-4 alkanoyl)-amino group, or 2 phenyl group optionally bearing 1 to 3 substituents selected from the group consisting of, independently, a halo, a C1-4 alkoxy group, a di(C1-4 alkyl)amino group or a benzyloxy group, R2 stands for a hydrogen, a cyano group, a furylmethyl group, a (C5-7 cycloalkyl)methyl group. a (C1-4 alkoxy)carbonyl group, a hydroxy-(C1-4 alkyl) group or a benzyl group optionally bearing 1 to 3 substituents selected from the group consisting of independently, a halo, a C1-4 alkyl group, a C1-4 alkoxy group, a trifluoromethyl group, a hydroxy group, a benzyloxy group or a di-(C1-4 alkyl)amino group, R4 means a hydrogen, or R3 forms with R4 an oxygen atom, R5 is a hydrogen, or R4 forms with R5 a valence bond, R6 represents a halo, a cyano group, a nitro group, a C1-4 alkyl group, a C1-4 alkoxy group or a trifluoromethyl group, m has a value of 0 or 1, n has a value of 1 or 2, p is an integer between 2 to 11 and k has a value of 0, 1, 2 or 3, or a pharmaceutically acceptable acid addition salt thereof, optionally in admixture with one or more carrier(s) commonly used in pharmaceutical compositions, for preparing medicaments having an activity in the treatment of diseases especially due to pathological alterations of the central nervous system.