HU227402B1 - Novel piperazinyl alkylthio pyrimidinyl derivatives, pharmaceutical compositions containing such active ingredients and process for producing the active ingredients - Google Patents

Abstract

Piperazinyl-alkylthiopyramidines (I), useful for treating central nervous system diseases, are new. Piperazinyl-alkylthiopyramidines (I) and their acid addition salts are new: [Image] R 1hydrogen (H), 1-4C alkyl, 1-4C alkanoyl or di(1-4C alkyl)amino(1-4C alkyl); R 2H or benzyl substituted with 1-3 groups from 1-4C alkyl, 1-4C alkoxy, di(1-4C alkyl)amino, hydroxy or halo; and n : 2-4. Independent claims are made for: (1) pharmaceutical compositions comprising (I) or their acid addition salts and one or more conventional carriers; and (2) a process for making (I). ACTIVITY : Anxiolytic; neuroprotective. SPRD Male rats were subjected to an elevated plus-maze test to compare the anxiolytic effects of oral 6 diamino-2-[2-(1-piperazinyl)ethylthio]-5-(4-fluorobenzyl)-pyrimidine trihydrochloride hydrate (Ia) (a compound of (I)). The minimum effective doses were (Ia) 0.01 mg/kg and diazepam 1 mg/kg. MECHANISM OF ACTION : None stated.

Description

The present invention relates to novel piperazine H-alkyl-pyridine derivatives, to pharmaceutical compositions containing such an active ingredient, and to a process for the manufacture of the active ingredient. The novel compounds are particularly useful in the treatment of diseases caused by pathological disorders of the central nervous system.

More particularly, the present invention relates to a piperazinyl alkyl pyrimidine derivative of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein

R ¹

FT is hydrogen, C 1-4 alkyl. C 1 -C 4 alkanoyl or C 1 -C 4 alkylamino-C 1 -C 4 alkyl, which is a benzyl group substituted with 1 to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, di (may be 1 and / or halogen, having a value of 2, 3 or 4 carbon atoms)

From the patent application WO 97/16429, plperazinyl-alkyldio-pyrmyldldine derivatives in which the 4-position nitrogen atom of the plperazine is substituted with a phenyl or benzyl group are known. The known compounds are useful, inter alia, for the treatment of diseases of the central nervous system, for example, they have an outstanding anxiolytic effect. The essential feature is that the serotonin receptors (His-HTsa, 5-HT ₂ c} occur. A significant disadvantage, however, that the best anxiolytic effect of compounds suffer a very rapid mefabolítikus decomposition process with the EIO body, Consequently, the bioavailability is low, and it inhibits the their development into medicine.

ΦΦ φ * φ φ φ φ * * «* φ φ

4ΧX »** *» φ Φ »« *

It is an object of the present invention to provide novel effective compounds within the above range of activity which are metabolically more stable than the known compounds.

It has been found that the above object is achieved by the novel piperazinyl-alkylmipinnidine derivatives of formula (I), which are anxiolytic, but do not act on the serotonin receptors and their metabolism is not rapid.

As used herein, C 1-4 alkyl is methyl. is meant ethyl, n-propyl, isopropyl, η-butyl, sec-butyl, tert-butyl or isobufyl. Preferably, C 1-4 alkyl is methyl or isopropyl.

C 1-4 -alkoxy is primarily mefoxyl, ethoxy, n-propoxy or n-butoxy, preferably methoxy.

The halogen atom is generally fluorine, chlorine or bromine, preferably chlorine or fluorine.

C 1-4 alkanoyl groups include formyl, acetyl, η-propanoyl, n-butanol, etc., preferably acetyl.

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) include the acid addition salts of the compounds with pharmaceutically acceptable inorganic or organic acids. Preferred acid addition salts are hydrogen halides, such as hydrochlorides or hydrobromides, carbonates, hydrogenates, sulfates, phosphates, acetates, fumarates, maleates, citrates, ascorbate and benzoates with organic sulfonic acids, e.g.

A preferred subgroup of the compounds of the invention are the compounds of formula I and their pharmaceutically acceptable acid addition salts wherein * X φ * * · ♦ * * »* # <χ

Φ X φ φ φ *> * X φ · χ> X> '

R ^! is hydrogen, dimethylamine (C1-C4 alkyl) or (C1-C4) alkenoyl,

Po is as defined for formula (I), n is 2 or 3.

Particularly preferred piperazinylalkylthiopinnidine derivatives of formula I are those wherein

R ¹ is hydrogen or C 1 -C 4 alkyl

R ² is benzyl substituted with C 1-4 alkoxy or fluoro, n is 2, and their pharmaceutically acceptable acid addition salts.

In the meaning of R ² , it is preferred that the C 1-4 alkoxy group is ortho.

The compounds of the present invention are prepared by reacting a 2-mercaptopinyldldine of formula (II) wherein R ² is as defined above or an alkali metal salt thereof with a haloalkylpiperazine of formula (hl) wherein R ¹ and n are as defined above. When diluted, it is halogen, preferably chlorine or bromine, or an acid addition salt thereof, and the resulting compound of formula (I) is optionally converted into a pharmaceutically acceptable acid addition salt thereof.

If desired, one compound of formula I can be converted to another compound of formula I. These subsequent conversions may be carried out in a manner known per se. For example, a resulting compound of formula I wherein R ¹ is hydrogen may be alkylated to form a compound of formula I wherein R 1 is C 1 -C 4 alkyl. But just as ex post φ φ · V φφφ

Φ φ

X Φ · X * * φ Φ- »φ ** φφ φ conversion (by subconversion or acylation) gives R ^! Compounds of formula (I) containing a dialkylaminoethyl group or an alkanoyl group. Another example of the post-conversion is the preparation of a compound of formula (I) containing an alkoxybenzyl group of R ^{2 by} alkylation from a compound of formula (I) wherein R ' ^: ' is hydroxybenzyl; or when a (I) compound wherein ^R! H is prepared by hydrolysis to remove formyl from a compound of formula (I) wherein R 'is a formyl group.

The process of the invention may be carried out in an organic solvent or mixture of solvents which is inert to the reactants, such as aliphatic alcohols, such as methyl alcohol, isopropyl alcohol, dialkyl amides, preferably dimethylformamide, water or a mixture of these solvents. The reaction of the compounds of formula (II) and (III) may be carried out either starting from the alkali metal salt of 2-mercaptopyrimidine (II) or may be carried out in the presence of an acid scavenger, preferably alkali metal carbonates, e.g. alkali metal hydrogencarbonates such as sodium or potassium hydrogencarbonate, alkali metal hydroxides such as sodium or potassium hydroxide, fatty earth metal hydroxides such as calcium hydroxide, or tertiary amines such as pyridine amines, e.g. or other trialkylamines. Preferably, potassium hydroxide, potassium carbonate or sodium carbonate may act as an acid scavenger.

Optionally, a catalyst may be used to accelerate the reaction. The catalysts used are in particular alkali metal halides or alkaline earth metal halides (e.g., potassium iodide, potassium fluoride, sodium bromide or calcium chloride). Preferably, the reaction is carried out in the presence of a potassium iodide catalyst.

φ ΦΦ φ χ X *

Φ Φ>

Φ ♦ Φ Φ X * ♦ * «Αφ X * * ♦

ΦΦ Φ φ * φ

Φ φ φ Φ Α Φ φ

Ο * X Φ Α

Depending on the reactivity of the starting materials, the reaction is carried out at room temperature to the reflux temperature of the reaction mixture. Aqueous solution is preferably at room temperature, otherwise it is preferably carried out at temperatures ranging from 60 ^° C to 80 ° C, the reaction time depending on the temperature and reactivity of the starting materials from 2 to 20 hours.

The starting materials (0) and (III) may be used in equimolar amounts, or a maximum of 10% excess of the haloalkylpiperazine (III) may be added to the reaction mixture. When starting from the salt of the mercapto compound, generally less acid binding agent is required. The catalyst is generally employed in an amount of from 0.1 to 0.2 mole, but preferably in the presence of 0.1 mole of catalyst.

For each mole of 2-mercapto-pyridine, the reaction mixture is worked up in a manner known per se. The product is preferably isolated by filtration from the precipitated inorganic salts, distilled off the filtrate in vacuo and crystallized with water or an organic solvent. The precipitated product and the inorganic salts are simultaneously filtered off from the reaction mixture and then washed with water to remove the inorganic salts, but it is also possible to remove the precipitated inorganic salts by water-blowing the reaction mixture and then filtering off the precipitated product. If desired, the product is purified by known purification procedures such as recrystallization or chromatography.

The compounds of formula (I) may also be isolated in the form of the aforementioned pharmaceutically acceptable acid addition salts, or the compounds of formula (I) obtained as the base may be converted into the acid addition salt in a subsequent step by reaction with an appropriate acid in an inert solvent. From these, the base can be liberated again and optionally converted to another salt form,

The starting compounds of formula (II) are known in the art and are prepared according to WO-87/18429. in U.S. Pat. The (hl) halcgén alkyl plperezinok formula are also known, except for the compound in which ^R1 is iso-propyl. They may be prepared, for example, as described in U.S. Patent No. 2,851,458. The halogen compound represented by R ¹ in the form of a formyl group is Arzneim. Forsch., 12, 1962, 937-942, and the halogen bearing the acetyl group can be prepared as described in Belgian Patent No. 645,802.

The compounds of formula (I) have commercially available central nervous system (CNS) effects, in particular valuable psychotropic effects.

The activity of the compounds of the invention was demonstrated by the following assays;

1, Elevated plus-maze ”

The tests were performed on 8-10 male SPRD rats weighing 220-280 g per group. The test substance or vehicle (0.4% solution of distilled water or cellulose) was dissolved or suspended in the test animals in a volume of 5 ml / kg. received 60 minutes before the start of the measurement. A wooden floor cross with raised arms 50 cm high and 100 cm long and 15 cm wide was used for the study. The two balustrade arms of the cross are fenced off on two longitudinal sides and at the end with a 40 cm high wall, open only to the central 15 cm x 15 cm of the cross (closed arms), The other two opposing arms have no wall (open arms), The essence of the method is that animals spend more time in closed arms than in open arms as a result of their natural fear of open space and height. Anxiolytic compounds significantly increase the length of stay in open arms as well as the number of open arms. The average values of these two parameters were calculated, and then the minimum effective dose (Pelow, S., Chopin, P. _s filet, SE, Briley, M. (1985) vegyületenkéni determined after statistical analysis: Validation of open, closed arm entries in ars elevafed plus-maze as a measure of anxiety in tbe rat. d. Neurosci. Methods. 14: 14-9-187.)

The results obtained were used with dlazepamol fZ-chloro.

t is given in Table I. Reference substance «S-dlhldre-1-methyl'S-phenylSH-tethe benzodiazepin-S-one»

X X

The A

A X A A

The A

A AAA * X A A X * A

A A A AAA A X A

The A

A * A A *

Compound (example number) "table

Minimum effective dose (mg / kg po) (besilate) (metal price)

8?

12

18

diazepam

0.03 <1

0 _: 01

0.3

Table I shows that the compounds of the present invention exhibit an anxiolytic effect equal to or better than that of diazepam, in some cases by an order of magnitude higher in the assay.

Ί!

φφ φ

φ φφ * * Φ φ X φ Φ Φ * Φ φ X Φ φ χ »φ (» φ Φ Φ φ φ * φ

Χ-Χ ΧΦ ΦΦ *

2. Measurement of spontaneous motor activity

For each experiment, 10 male NMRI mice weighing 20-25 g per treatment group were used. Test substance Or vehicle (0.4% methylcellulose solution) suspended in oral volume of 20 ml / kg Test animals received 60 minutes prior to commencement of measurement. This method provides general information on how the test substance alone influences the animal's natural movement as sedative. In the case of anxiolytics, the judgment of anxiolytic effect is crucially influenced by the presence or absence of a sedative effect (the latter being desirable). The experiment was carried out with a 10-well Digitammotimeter. The movement of the animals was signaled by the interruption of three parallel infrared beams recorded by the device. The activity of one animal per well was determined in the apparatus. From the measurement results, ΙΟ _δ (50% inhibition dose) was calculated (Bersy, I. Csanyl, £ ,, Lazar, Larcb. Int. Pharmaeodyn. 124: 180-190, 1960; Stille, G ,,). Leuener, H, and Eichenberger, E _.; II Farmaco Ed. Pr., 28, 603-625 (1971) J. The data obtained are shown in Table II using diazepam as reference material.

ΦΦ φ

ΦΦφφ Φφφ * φ * ΦΦ * Φ φΦΦ X φΦΦ * χ Φ ΦΦΦ: ΦΦ * $ - * * Φ * <·

Φ XX ΦΦ ί & * V * Φ

Compound (example number) ID50 (mg / kg po) 1 (besylate) > 80 1 (fumarate) > 100 2 > 100 4 32.8 5 > 100 6 > 100 7 > 100 8 > 100 18 > 100 17 > 100 18 > 100 18 > 100 26 > 100 diazepam 8.9

It is clear from Table IL that the compounds of the invention do not affect the spontaneous motor activity of mice at a dose greater than fourteen times the ID50 of the reference diazepam.

In summary, the compounds of the present invention exhibit a very significant anxiolytic effect, while sedative side effects are not observed at orders of magnitude higher than the anxiolytic dose.

The results of the studies indicate that the anxiolytic effect of the novel plperazinyl •• alkyl-fi O'-pyrimidine derivatives is more beneficial than the therapeutic φ X Φ *

χ. X * χ Φ X Φ Φ

ΦΦ X Φ Φ Φ XX

Φ *

Φ Α Φ Φ # Φ

Φ X * is currently widely used in practice for benzodiazepine anxiolytics, which are characterized by strong sedative side effects,

Accordingly, the piperazinylalkyltromopyrimidine derivatives of formula I can be used as active ingredients in pharmaceutical compositions.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, in addition to one or more conventional carriers.

The pharmaceutical compositions of the present invention may be solid or liquid compositions suitable for oral, parenteral or rectal administration or topical administration.

Solid pharmaceutical compositions for oral administration may be in the form of powders, capsules, tablets, lozenges, microcapsules, etc., and may contain excipients such as gelatin, sorbitol, polyvinylpyrrolidone, etc .; fillers such as lactose glucose, starch, calcium phosphate, etc .; tableting excipients such as magnesium stearate, talc, PC (ethylene glycol) -f, silica, etc .: wetting agents such as sodium lauryl sulfate, etc .;

Liquid pharmaceutical compositions for oral administration include solutions, suspensions, or emulsions which contain, for example, a carrier such as a suspending agent such as gelatin, carboxymethylcellulose, etc .; an emulsifier such as sorbitan monooleate, etc .; solvent such as water, oils, glycerol, propylene glycol, ethanol; preservatives such as methyl p-hydroxybenzoic acid and the like. They contain.

Pharmaceutical compositions for parenteral administration generally comprise a sterile solution of the active ingredient.

• φ φ φ φ φ

X * * * Φ φ Φ X

ΦυΦ 4 Φ *

The above exemplified and other dosage forms are known per se, see, for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Pubshing Co., Easton USA (1990).

The pharmaceutical compositions of the present invention will generally contain from 0.1 to 95.0% by weight of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. A typical daily dose for an adult patient is 0.1 to 1000 mg of a compound of formula (I) or an acid addition salt thereof, which may be administered in one or more administrations orally or parenterally. The actual dose will depend on many factors and will be determined by your doctor.

The pharmaceutical compositions of the present invention are prepared by admixing an active compound consisting of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof with a carrier (s) and converting the resulting mixture into a pharmaceutical composition in a manner known per se. Applicable methods are known in the art, such as the above-mentioned Remington's Pharmaceutical Sciences.

Preferably, the pharmaceutical compositions of the present invention comprise a piperazinyl-alkylmio-pyrimidine number formula (I) or a suitable acid addition salt thereof, wherein

R

R 'is hydrogen, dremephylamino- (C 1 -C 4) alkyl or C 1-4 -alkanoyl; C 4 -C 4 alkoxy, di (C 1-4 -alkylamino) and / or halogen, having a value of 2, 3 or 4.

Α-ΧΧν ΑΑΑΧ Α * ΑΑ

A A A A A A X

JA X Α φ A X A Α Μ Α

AAA * * Α Α * αχ *

Particularly preferably, the pharmaceutical compositions of the present invention contain a piporazinylalkylthiopyrimidyl derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, wherein it is hydrogen or dimethylamino-C 1-4 alkyl; is a C 1 -C 4 alkoxy group or a (benzyl substituted benzyl group with a value of 2,

The invention also encompasses a method of treating a patient, particularly a patient suffering from a central nervous system disorder, by administering a non-toxic amount of a pipefazinylalkylmopinimidine derivative of the formula (I) or a suitable acid addition salt thereof.

The invention will now be described in more detail by the following examples.

Example 1

4,6 'diamino ~ δ- (2-methoxy ~ benzyl} -2 ~ [2- (1-piperazinyl) ethyl · tío'j> pínmsclín

5.71 g (19 mmol) of 4,6-dimethylamino-2-mercapto-6- (2-mephoxybenzyl) pplidine,

To a solution of potassium hydroxide (8.73 g, 120 mmol) in water (120 mL) was added dropwise a solution of 1- (4-chloroethylhypperazin-dihydrochloride) (4.43 g, 20 mmol) in water (20 mL) at 25 ° C. After stirring at room temperature for 3 hours, water (140 ml) and methanol (200 ml) were added. After heating to reflux, the mixture is filtered hot, and the filtrate is crystallized by CAC. The material thus obtained is chromatographed on a 130 g Kieselgel 60 column with a 1: 1 mixture of methyl alcohol and toluene. The mixture was refluxed from 100 ml of a 1: 1 mixture of ethanol and water at 30 [deg.] C. over calcium. vacuum dried,

4.69 g (60%) of the title product are obtained.

»X '* * *» * X *

X # X »

X A

X * $ * * »* £ ·« · * ** '

Fumarate training

Ealemanalysis calculated:

because:

The base (4.64 g, 12.4 mmol) was suspended in ethyl alcohol (75 mL). Boil and add a solution of fumaric acid (1.47 g, 12.8 mmol) in ethyl alcohol (80 mL). Crystallization at room temperature gave the fumaric acid salt of the title compound (8.02 g, 80%).

198 'C (decomposes)

C 5 H 8 N 5 O 5 S (498.59) requires 0 53.88%, H8.18%. N, 17.13%, $ 8.54%:

C, 63.64%, H8.06%, N, 18.97%, $ 8.55%.

Formation of a benzoic acid salt

The base (1.0 g, 2.87 mmol) was suspended in ethyl alcohol (28 mL) and a solution of benzenesulfonic acid (8.42 g, 2.87 mmol) in ethyl alcohol (2 mL) was added dropwise at 0 ° C. Stir at room temperature for 6 hours, then

1.25 g (88%) of the besylate salt of the title compound are obtained.

Melting point; 173-174'C

Elemental Analysis: -? Found: C, 54.12; H, 8.06; H, 15.78; H, 12.04; Found: C, 54.01; H, 8.15; N, 16.69; 27%

Example 2

4,6-Dlamini-5- (2-ethoxy 'benzyl) -2- [2- (1-piperazinyl) -ebl-> thio] -pyrimidine fumarate

2.99 g of (S, 5 mmol) of _4-t 8 ~ diaminö'2 merkapfo-5- suspended 3,37g (80 mmol) of potassium hydroxide in 89 ml of water a solution of (2-ethoxy ~ benzl0-pirsmldis'st and 25 A solution of 1.22-chloroethylpiperazine dihydrochloride (2.22g, 10mmol) in water (10ml) was added dropwise at C. The mixture was stirred at room temperature for 2 hours, then water (50ml) and methanol (100ml) were added. After heating and filtering hot, the filtrate is crystallized at 0 [deg.] C. The material thus obtained is 130 g of Kieselgel on a column of 80 x x x Φ * * '*> · # φ ♦ ·> ♦. **'

ΦΧ ΦΧ \ * ^V * νχ * ***** · chromatographed on a 2: 3 mixture of methanol and toluene. The resulting crystalline material was recrystallized from a mixture of methanol (20 mL) and water (20 mL). 2.20 g of the dihydrate of the base are obtained. This is dissolved in 40 ml of ethyl alcohol and added to a solution of 0.64 g of fumaric acid in 15 ml of ethyl alcohol. Crystallization at room temperature gave 2.56 g (53%) of the title product.

Olva Eíemanalizís calculated:

because:

187-189

C23H32N.SO5S (604.61): C, 54.75; H, 8.39; N, 16.65; C, 54.72%, H6.37%, H 16.93%, δ 6.33%.

Example 3

4 _i 6-Diamino-2- [3- (4-methyl-1-piperazinyl) propyl-thio ~ ~ 5- (2-methoxy-benziS) pyrimidine trihydrochloride · -pírl

_4> 8-diamino-2-mercapto-5- (2-methoxybenzyl) pyrimidine potassium salt (20 mmol) of potassium carbonate and 2.76 g (0.33 g, 2 (6.0 g, 20 mmol) To a suspension of cadmium iodide (100 mmol) in methanol (100 mL) was added 1- (3-chloroform) -4-methylpiperazine (5.0 g, 20 mmol) dihydrochloride and the reaction mixture was refluxed for 20 hours. After allowing to cool to room temperature, the inorganic salts are filtered off, the filtrate is evaporated in vacuo, the resulting oil is crystallized with water, the crystals are filtered off and dried. In ethyl alcohol, isopropyl alcohol containing 3 equivalents of hydrochloric acid isopropyl alcohol. 5.5 g (53,779) of product are obtained.

M.p.> 2 ° C

Elemental Analysis: Calculated for C¢ ^H¼¼Cl $N NOS (511.95): C, 46.92; H, 6.60; N, 16.42; 3, 6.23; Cl (Ion) 20.76; Found: C 46.31%, SN, 54%, N 16.14%, δ 6.28%, Cl (ion) 20.44%.

4 _} 6-Diamino-2- [2- (4-methyl-1-piperazinyl) -ethylmio] -5- (2-methoxy-benzyl) -pinnidine trihydrochloride hydrate

X _W X Α * *: ♦ *. · * **>

, X Φ <λ V 'χ5 s Φ <«· · .. ·. ·' ** * * '

8.0 g (20 mmol) of potassium salt of 4- _} e-dibasino-2-mercaptO-5- (2-methoxybenz-2-yl) -pinmldine, 5.52 g (40 mmol) of potassium carbonate and 8.68 g (4 mmol) in 50 ml of dimethylformamide Jedid szuszpenzíéjéhoz 4.71 g (20 mmol) of 1- (2-chloroethyl) "-methyl 4" piρerazin dihydrochloride was added and the reaction stirred at 80 ^c C for 10 hours . After cooling, it is poured into 100 ml of water, the precipitated crystals are filtered off and dried. The resulting material was chromatographed on a Kieselgel 80 column using methyl alcohol. and dichloromethane (1: 8), and the pure material is converted into a salt with hydrochloric acid isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol. Yield: 8.84 g (65.9%). Melting point: 241-243 * 0

Calcd for C ^ H ₃₃ ChhUOsS (515.94) Analysis: Elemental analysis C 44.23%, H: 6.4596; N, 18.29% 8 8.21%, Cl (ion) 20.81% Found: C 44.32%, H8.35%, N 18.37%, δ 8.22%, Cl (ion) 20.92%.

Example 5

4,8 <-Diamino ~ 2 "-2- (4-flavorpropyl-1" piperazinyl) -ethylthio] -5- (2-methoxybenzyl) -pyrimidinium dihydrochloride hydrate

8.0 g (20 mmol) of potassium salt of 4,8-diamino-2-mercapto-8- (2-mephoxybenzyl) proline, 5.52 g (40 mmol) of potassium carbonate, 0.86 g of potassium iodide (6.2 mmol) and 1- (2-chloroethyl) -4-iso-propyl-piperazine dihydrochloride (5.27 g, 20 mmol) in methanol (150 mL) was heated to reflux for 20 hours. The reaction mixture was worked up as in Example 3, but salt formation was carried out from the oil obtained after evaporation.

Yield: 8.83 g (81.1%).

Melting point: 253-26 ° C

Elemental Analysis: Calculated for C 21 H 37 CUN 8 O 5 S (643.99): O 48.37, H 8.88, N 15.45, S 5.8996, Cl (Ion) 19.55; Found: 0 45.98%, H8.78%, N 15.03%, S 5.78%, Cl fion) 19.81%.

* φφ «φ

Example 6

4,8-Diamino-2- (244- (2-dimethylaminoethyl) -1'-piperazinyl) -ethylthio] -5- (2-ethoxybenzyl) -plimimidine-tetrabenzylclondihydrate

1.0 g (3 mmol) of potassium salt of 4,5-diamino-2-mercapto-5-> (2-methoxybenzyl) pinnidine, _1S 85 g (12 mmol) of potassium carbonate, 0.1 g (0.6 mmol) of potassium iodide and 1.1 g (3 mmol) of 1- (2-chloroethyl) -4- (2'-dimethylamino) -N-plperazine trihydrochloride hydrochloride in 20 ml of methanol. The reaction mixture was worked up as in Example 3, and after evaporation, the oily material was purified by column chromatography according to Example 4, but with a 1: 1 mixture of methanol and dichloromethane, followed by salt formation with 4 equivalents of hydrochloric acid. propyl alcohol to give 0.82 g (41.2%) of the title compound.

Melting point; 254-2S7 C

Etemanalfzis: CUN CzsK® 0 _s S Calcd (627.51) Analysis: C 42.11%, H6,91%, N 15.62%, 86.11%, Cl (Ion) 22.60%? Found: C 42.75%, H6.86%, N 15.38%, 3 6.26%, Cl (Ion) 22.18%.

4.8 ~ Diamlno-2- {3- (4-formyl-1-plperezlnil) propyl-thio-5- (2-ethoxy ~ benzyl) -plrlmidin

3.14 g (10 mmol) of potassium salt of 4,6-diamine O2-mercaptol (2-efoxybenzyl) pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) of mmol) jodldot and 1-formyl-4 9.1 g (10 mmol) of (3-chloro-propyl) ~ piperazlnt stirred in 30 ml of dimethyl formamide ^and 80 ° C for 9 hours. After filtration of the inorganic compounds, the solution was evaporated and the resulting product was chromatographed on a silica gel 60 column using a 8: 1 mixture of dichloromethane and methyl alcohol. 1.63 g (42.5%) of crystalline title product are obtained. Melting point: 154-156 ° C

Elemanalfzi; Calcd. For C21H13N3O2S (430.68): 058.58%, H7.02%, N 19.52%, δ 7.48%;

Found: C 58.10%, H 6.99%, hl 10.39%, δ 7.33%.

Example 8

4,3-Diamino-2- (444-methyl-1-plperazinyl) -butylthio-5- (2-methoxybenzyl) -pyrimidinium trihydrochloride hd.

2.8 g (8.8 mmol) of potassium salt of 4,8-diamino-2-markapto-5- (2-methoxybenzyl) -pinnimidine, 2.4 g (17 mmol) of potassium carbonate (0.15 g). 0.9 mmol) of potassium iodide and 2.28 g (8.8 mmol) of 1-metii'4 ~ (4-chloro-butyl) piperazine dihydrochloride in 40 ml of dimethylformamide Leiden Example 7 140 ^° C for 20 hours. The reaction mixture is also worked up as described in Example 7 and then salted with 3 equivalents of hydrochloric acid in Isepropol alcohol in ethyl alcohol. 1.65 g (39.9%) of the title compound are obtained. Mp 202 ° C

Elemental Analysis: Found C, 46.37; H, 8.88; N, 15.45; S, 5.89; Cl, Cl, 19.55; mode: C 48.82%, H 6.82%, N 15.38%, S 5.74%, Cl (Ion) 19.35%,

9 am

4,8-Diamino-2- [3- (4-formyl-1-piperazinyl) propyl-thio-5- (2-methoxybenzyl) "

-oirímidin

3.94 g (13 mmol) of potassium salt of 4,8-diamino-2-mercapto-5- (2-methoxybenzyl) pyrimidine, 1.8 g (13 mmol) of potassium carbonate, 0.22 g (3 mmol) of potassium iodide and 2.5 g (13 mmol) of 1-formyl-4- (3-chloropropyl) -pyrazine in 50 ml of dimethylformamide were reacted as described in Example 7 for 7 hours. The product obtained after the heparia was crystallized with 150 ml of ice water, filtered and dried. 4.8 g (88.8%) of the title product are obtained.

Melting point: 174-178 ° C Lemanalysis: CaOHxsNsOaS (418.55)

C 57.67%, R 8.78%, 14 20.18%, S 7.70%;

C 57.23%, H8.81%, N 19.88%, S 7.64%.

because;

ΦΦ * φ ♦ φ *

ΦΦ φ *> 0

Example 10

Method (a)

4,6-Diemino-2- (3 ' (1 piperaz.iníl) -p? Opil4ícj-5- (2-methoxy ~ benzyl) -píurnidin trihydrochloride

2.3 g (5.0 mmol) of 4 ₎ 8-diamino-2- [3- (4-formyl-1-piperazinyl) -propylthio] -6- (2-n-ethoxybenzyl) p-imidine was added to the reaction mixture. To a slurry of ethyl alcohol (4 ml) was added isopropyl alcohol (4 equivalents of hydrochloric acid) and the reaction mixture was refluxed for 2.5 h. After cooling, the solid was filtered off, washed with diisopropyl ether (1.89 g, 66.8%). yielding the title compound.

Melting point: 188 C ^rí

Anal calcd CwHai CBN ₆ OS (497.92) Analysis: C 45.83%, H8,28%, N 18.88%, 8 6.44%, Cl (ion) 21.36%; Found: C 45.41%, H 6.34%, N 16.38%, 66.33% Cl (ion) 21.89%.

3.0 g (10 mmol) of potassium salt of 4,5-phenylmino-2-mercapto-5- (2-methoxybenzyl) pipimidine, 2.78 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) of potassium iodide and 1- (3-chloro-propH) -piperazine dihydrochloride (2.36 g, 18 mmol) in dimethylformamide (30 mL) were reacted for 5 hours as in Example 7. After evaporation, the product was crystallized with ice-water (120 mL). the crude product was purified on silica gel using a 80 column column, Eluens: dichloromethane: methanol = 8: 2. The resulting pure base is salted with 2-equivalents of isopropyl alcohol in ethyl alcohol.

2.1 g (42.2%) of the title compound are obtained.

187-198%)

H, 6.26; K, 16.88; S8.44; Cl (ion) 21.38. Found: C, 45.38%, Found: C, 45.38; H, 6.30%, N, 16.43%, δ 8.3233 Cl (Ion) 21.30%.

X X

Example 11

4,6 ~ diamino-2- [2- (1-piperazinyl) -ethyl-thio-5- (2-butoxy-benzyl) ~ pirímldln fdhidrokloríd-hydrate

Methyl sodium (0.25 g, 11 mmol) was dissolved in ethyl alcohol (50 mL) followed by 3.8 g (1 mmol) of 4,8-diamino-2- (2- (1-piperazinyl) ethyl) -5- ( A solution of 2-hydroxybenzyl) -pyrimidine in 80 ml of ethyl alcohol is added and after 20 minutes stirring is added to the reaction mixture.

1.37 g (10 mmol) of n-butyl bromide are added dropwise and the solution is stirred at reflux for 12 hours. methanol: methyl alcohol = 8: 2 to give the pure base obtained isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol to give 2.54 g (45.2%) of the title compound, m.p.

Melting point: 180 ^c C

Ephemanalysis; H, 6.99; N, 14.95; S, 5.71; Cl (ion), 18.92; C ;HHss CC C -HMgOOsS (562.01) requires C, 44.88; Found: C 45.00%, H 7.04%, N 14.81%, δ 5.82%, Cl (ion) 1676%.

Example 12

4,6-Diamino-2- (3- (4-acefil-1-piperazinyl) ~ fio propyl] -5- (2-methoxybenzyl) pyridin ~

2.06 g (10 mmol) of 1-acetyl-4- (3-chloropropyl) piperazine 2.85 g (9.5 mmol) of 4,8-diamino-2-mercapto-5- (2-methoxyl) benzyl) p-pimimidine potassium salt is refluxed in 10 ml of ethyl alcohol for 2 hours. After cooling, it is poured onto 40 ml of water, the precipitate is nailed, washed with water, dried and chromatographed on a Kieselgel 60 column with methanol: toluene (1: 9). The crude product is recrystallized from mefilic alcohol.

1.34 g (33.0%!) Of compound compound dm are obtained,

Melting point: 203 ~ 209 * C φφ * φ χφ »*» · **

Elemanahzis calculated:

because:

H, 7.02; N, 19.52; S, 7.45; C21HH30,5OSS (430.58) requires C, 58.58; C 58.95%, H 6.88%, H 19.42%, δ 7.51%.

4,6-Diamino-2- [4- (4-mephyl-1-piperazinyl) -ethyl] -5- (2-ethoxyl-benzyl) -plimmonine dihydrochloride hydrate

Potassium salt of 4- _t 6-diamino-2-mercapto-5- (2-efoxybenzyl) pyrimidine, 3.14 g (10 mmol), 2.78 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) potassium iodide and

1-Methyl- (2-chloroethyl) -plperazine diborochloride (2.38 g, 10 mmol) in methyl alcohol (25 mL) was reacted as in Example 3 for 28 ohms. After evaporation the product is crystallized with ice water and the crude product is chromatographed on a silica gel 80 column with dichloromethane and methanol 3; 2 ratio. The resulting base is salted with isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol. 1.93 g (36.4%) of the title compound are obtained.

melting point

Elemanahzis calculated:

because:

121 ° C.

Cgo 8Hss CCbHeOjS (529.964) C 45.33%, H 8.68%, Cl (ion) 20.97%, N 15.88%, C 44.99%, H 8.75%, Cl (ion) 19.57%, N 15.78%,

S 8.06%, S 5.96%,

Example 14

4.6 ~ Dlamini "2 [3» (1 plperazinll) ~ propyl-tloj-5- (2-ethoxy-benzyl) -pyrimidin-trihydrochloride tnhidrát

4.73 g (16 mmol) of potassium salt of 4,6-diamino-2-mercapto-5- (2-ethoxybenzyl) pyrimidine, 2.08 g (15 mmol) of potassium carbonate, 0.25 g of Potassium iodide (1.5 mmol) and 1- (3-chloropropyl) piperazine dihydrochloride (3.57 g, 16 mmol) in dimethylformamide (50 mL) were stirred at 120-125 ° C for 20 h. Work up in the same manner as in Example 1, and the resulting oil was chromatographed on a Kieselgel 80 column using dichloromethane: methanol 8: 2 φ φ ν Λ Φ Φ X Φ * Φ φ φ φ φ * * * φφ φ-> φ * * of the pure product obtained, 3 equivalents of hydrochloric acid in ethyl alcohol

3.92 g (46.1734) of the title compound are obtained.

Melting point; 116 ^° C

H, 6.95; Cl, Ion 18.79; N, 14.85; δ 5.87; Found: C, 42.48; %, H 7.04%, Cl (ion) 19.60%, N 14.74%, S 5.77%.

15

4,6-6ΐ3ηΊΐηο ~ 2- [3- (1-ρΙρβΓθζ.ΙηΙΙ) ~ ρΓορΙΜίο) -δ '(3,4,51πΓηο1οχΙ 6οηζΙΙ ~) ~ ρΙπϊηΙ <1Ιη-trihldroklond trihydrate

3.6 g (10 mmol) of 4,8-Dlamini ~ 2 m8rkapto-5- _(3! 4 _i 5trimetoxi-benzyl) -pyrimidin potassium salt, 2.78 g (20 mmol) of potassium carbonate, 0.33 g of ( Potassium iodide (2 mmol) and 1- (3-chloropropyl) piperazine dihydrochloride (2.36 g, 10 mmol) in dimethylformamide (30 ml) were stirred at 88-80 ° C for 5 hours. The reaction mixture was worked up on the cake described in Example 7 and the resulting oil was chromatographed on a silica gel 60 column with dichloromethane: methanol (8: 2). The resulting pure product is 3 equivalents in ethyl alcohol

2.2 g (35.95%) of the ohmic compound are obtained.

Melting point: 175 ° C

Elemental Analysis: Calculated for CbN8O6S6 (612,021). C 41.21%, H 8.75%, Cl (ion) 17.38%, N 13.73%, S 5.24%, C 41.98%, δ 8.72%, Cl (ion) 17, 32%, N 13.78%, S 5.44%,

Example 16

4,8 'diamino-2- (2- (4-acafil-1'plperazinil) -efil fioj-5- (2-mafoxi ~ benzyl) -pyrimidine

2 kfóréfil 2.22 g (Lommel) ~ piperazine dihydrochloride are dissolved in 10 cm ³ of water and cooled to 0 ° C ^fi. A solution of sodium hydroxide (1.80 g, 40 mmol) at -5 ° C was added dropwise over a short period of time to 1.4 ml (1.57 g, 20 mmol) of aoethyl24 φφ XX X φ Φ Φ X Φ χφ Φ x

While maintaining the temperature below δ, the mixture was stirred at this temperature for 6 minutes and then extracted with ethyl acetate and the organic phase was evaporated. The thus obtained 1.64 g (86%, 8.6 mmol) of 4-ethyl-1- (2-chloroethyl) · -piperazine was dissolved in 15 ml of ethanol, 2.46 g (8.2 mmol) of 4,6-diamino. ~ 5- (2-methoxybenzene!) - 2 ~ methyl-apto-pinnidine potassium! and refluxed with 0.57 g (4.1 mmol) of potassium carbonate for 2 hours. Pour into 86 cm ^{3 of} water, filter, wash with water. The crude product obtained is recrystallized from methanol.

1.70 g (50%) of product are obtained.

Melting point; 1t Eiemanaiisis;

calculated (8.5-199.5 ^;

C 20 H 8 N 8 O 2 S (416.55)

57.87% H6 _: 78% N 26.18% $ 7.70% 0 57.57% H6.79% N 20.15% $ 7.84%.

Example 17

4,6-diamino-2- (3- (1-piperazinyl) - propyl ~ thio-5 - '(4-chloro-benzyl) -pírimldln trihydrochloride-trlhidrát

3.05 g (10 mmol) of 4 _s 8-diamino-2-mercapto-5- (4-carbobenzyl) -pyrimidine potassium chef, 2.78 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) of potassium iodide and 2.36 g (10 mmol) of 1- (3-chloropropyl) piperazine dihydrochloride in 30 ml of dimethylformamide were stirred at 6 to 8 ° C for 7 hours. After filtration of the inorganic compounds, the mother liquor was evaporated to give an oil which was treated with water to give a crystalline product which was dichloromethane and methyl alcohol 8; The resulting pure product was isolated as the isolate salt containing 3 equivalents of hydrochloric acid in ethyl alcohol.

2.76 g (49.7%) of the title compound are obtained. Melting point: 187 ° C ν * s Φ *. φ χ φ ** Φ **

(.ίχύ Φ-χ ** ♦ '**

Elemental: Calculated for C ^ HH C CClNNOOsS (555.39):

C 38.86%, H 6.16%, Cl (δ) 25.49%, CR 11) 18.12%. H, 16.10%, δ 5.76%, Found:

39.20%. H 6.24%, Cl (6) 25.77%, Cl (1on) 19.05%. N, 15.22%, δ, 5.95%.

4,6-Diamino-2- [4- (1-piperazinyl) butyl (η 5 -CIAmethoxy-1'-benzylpyrimidine)

3.0 g (10 mmol) of potassium salt of 4,6-diaminG-2-mercapto-5 ~ (2 ”methoxybenzyl) pyrimidine, 4.14 g (30 mmol) of potassium carbonate, 0.33 g of 2 mmol) of potassium iodide and 2.5 g (10 mmol) of 1- (4-chloro-butyl) -piperazin-dihydrochloride are stirred in 50 ml of formamide dimatíl 120-130 ^o C for 22 hours and after filtering the inorganic compounds include The crude product was purified as described in Example 17 and then salt was prepared with 3 equivalents of hydrochloric acid isopropyl alcohol.

2.38 g (46.6%) of the title compound are obtained.

Mp 255 ° C

Elemental Analysis: Calculated for C0 H20 C8 N8 OS (511,949); C 46.92%, H 6.50%, Cl (ion) 20.78%, N 16.42%, S 6.26%, Found: C 46.38%, H 6.58%, Cl (ion) ) 20.31%, N 16.08%, S6.08%.

4,8-Diamino-2- (2- (1-piperazinyl) -ethyl-thio-5- (4-fluorobenzyl) -pinimidine triblock hydrochloride

Potassium salt of 2.68 g (10 mmol) of 4,6-d {amino-2-mercapto-5- (4-fluorobenzyl) pyrimidine, 2.76 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) of potassium iodide and

1- (2-Chloroethyl) -perpiperazine dihydrochloride (2.22 g, 10 mmol) in dimethylformamide (30 mL) was stirred at 60-80 ° C for 8.5 hours. After filtration of the inorganic compounds, the mother liquor was evaporated and then dichloromethane and methanol χ * λ XX * 0 * κ 0 χ «

X * * ·> 0 0 0

0 «W0 X *

X *

X X <χ4 0 ·% · χΧ 0 X χ «X *

It is chromatographed on a silica gel 80 column with egy *: 2 ratio. The pure product is salted with isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol. 1.81 g (36.94%) of dm is obtained. Melting point 168-170 ° C

H, 6.78; Cl, ion 21.71; N, 17.18; S, 8.55. Found: C, 41.72; C, ,HssCCbFNeOS (469.374) requires C, 41.68; H 5.79%, Cl (1on) 21.54%, N 17.26%, 38 8.49 33.

-trihydrochloride hydrate -, 'A

O, 6 g (100 mmol) of potassium hydroxide in 140 ml of aqueous solution 5.78 g (20 mmol)

Potassium salt of 4 _t 8-dodamino-2-mercapto-5- (4-fluorobenzyl) -pyrimidine was added followed by stirring 1- (3-chloropropyl) piperazine dihydrochloride (4.71 g, 20 mmol) in 20 ml. water solution is added dropwise.

After stirring at room temperature for 20 hours, the precipitated crystals are filtered off and washed with water. After drying, it is chromatographed on a silica gel 80 column column using a 6: 2 mixture of dichloromethane and methanol to form a salt with hydrochloric acid isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol. 6.6 g (65.5%) of the title compound are obtained. Mp 269-271 ° C

Elemental Analysis: Calculated for C) HHsoCObBFNgOS (503.901): C 42.91%, H 8.0%, Cl (lon) 21.11%, 14. 18.88%, 3. 8.38%. C 42.74%, H 8.07%, Cl (ion) 20.88%, N 18.38%, S 6.26%.

Example 21

4 _is 6-Diamino-2- {2- [4- (2-amino-dim © ~ tii eW) -1-piperazinyl efii-thio-5- (4-fluoro ~ henzíl) ~ pyrimidine-tetrahidrokterld thhídrái

To a solution of potassium hydroxide (2.8 g, 48 mmol) in water (50 mL) was added the potassium salt of 4 _t 6-diamino-2-mercapto-S- (4-fluorobenzyl) pyrimidine (2.31 g, 8 mmol) and φφ

X

^'>> ΦΦφ φ * «$ £ Φ * with stirring 2.78 g (8 mmol) of 1- (2-chloro ~ EtO) ~ 4- (2-dimethylamino) ~ piperazin-tnhidroklorid hydrate in 30 ml of water The reaction mixture is stirred at room temperature for 8 hours, and the resulting crystals are filtered, washed with water, and the base is salted with hydrochloric acid isopropanol containing 3 equivalents of hydrochloric acid in ethyl alcohol. 2.96 g (58.41%) of the title compound are obtained.

Melting point; 218-229 ^U C

The elemental analysis; date; C 38.82%, found C 39.84%,

H, 8.88; Cl, Ion; 23.38; N, 15.48; S, 5.06; H, 6.50; Cl, Ion; 22.89; 15.69%, S 5.19%.

Example 22

4,6-Diamino "2- [3- (1 'piperazinyl) propyl tloj" 5- (4-methoxybenzyl> pyrimidine

-trihidroklorld-dihydro

3.0 g (10 mmol) of potassium 4,6-diamino-2-mercapto-6- (4-methoxybenzyl) p-methylenediamine, 2.78 g (20 mmol) of potassium carbonate, 0.33 g of mmol) of potassium chloride and

1- (3-Chloropropyl) piperazine dihydrochloride (2.38 g, 10 mmol) in dimethylformamide (30 mL) was reacted at 80-80 ° C for 8 hours. In the following, all the procedures of Example 17 are followed.

2.8 g (48.7%) of the title compound are obtained.

Melting point: 110-113 ° C

Elemental Analysis: Found: C 42.74%, R 8.81%, Cl (cmn) 19.92%, N 18.74%, S 8.01% calculated for C 23 H 8 Cl 2 N 8 O 5 S (833.95).

C, 42.25%; H, 8.72%; Cl (ion) 19.27%; N, 15.38%; S, 5.95%.

Example 23

4,8-Dlamino-2- [2- (1-piperazinyl) ethylphenyl] -5- (4-mephoxybenzyl) pyrimidine hydrate

3.0 g (19 mmol) of 4,8-diamino-2-naphtho-S- (4-methoxy-benzyl) -pinimidine potassium salt, 2.78 g (29 mmol) of potassium carbonate, 9.33 g of mmol) of potassium iodide and

2.22 g (10 mmol) of 1 '- (2 ~ chloro ~ etl1) piperazine in 30 ml of dimethyl formamide dihidrokloddot * χ' .. * s * _t »» was reacted at 80 ° C for ~ 14 hours. After filtering out the inorganic compounds, the mother liquor was replaced and chromatographed on a silica gel 60 column column using an 8: 2 mixture of dichloromethane and methanol.

2.03 g (61.72%) of the title compound are obtained.

135-138 ° C

H, 7.19; H, 21.41; S, 8.17. Found: C, 54.66; H, 7.17. , N 21.11%, S 8.11%.

Example 24

4,8-diamino-2- [3- (1-piperazinyl) - propyl ~ thio-5- (4-Dimethylamino-benzyl) -pyrimidine-tefrahldíökiorid trihydrate

3.13 g (10 mmol) of potassium salt of 4,8-diamino-2-mercapto-5- (4-dimethylaminobenzyl) -pinnimidine, 2.78 g (20 mmol) of potassium carbonate, 0.33 g (2 mmol) of potassium iodide and 2.38 g (10 mmol) of 1- (1-chloropropyl) piperazine dihydrochloride in 50 ml of methyl alcohol are refluxed for 5 hours. After filtering out the inorganic compounds, the mother liquor was evaporated and then dichloromethane and methanol 8; The resulting base is isopropyl alcohol containing 3 equivalents of hydrochloric acid in ethyl alcohol. we even train. 2.85 g (44.08%) of the title compound are obtained. 128-124 ° C

Elemental Analysis: Calculated for C 20 H 41 Cl 4 N 7 O 3 S (801.47): C 38.94%, H 8.87%, - Cl (ion) 23.53%, N 18.30% _; S, 5.33%. Found: C, 40.32%, H, 8.82%, Cl (ion) 23.18%, N, 15.85%, S, 5.45%.

Example 25

4,8-Dlamini "2- (2 '(1-piperazinyl} ethyl-thio] -5- (4-isopropyl-benzyl) -pyrimidine

2.0 g (7 mmol) 4 _; 8-Diamino-2-mercapto-5- (4-iso-propyl-carbonyl) -pyrimidine _< 2.9 g (28 mmol) potassium carbonate, 0.33 g (2 mmol) potassium iodide and 1.1 g (7 mmol) 1- (2-chloroethyl) -piperazine dihydrochloride in 30 mL of dimethylformamide

X φ * φ φ X φφ ΧΧΦ Φ φ φ Φ X

Φ X ΦΦΦΦΦΧ φ φ φ φ φ φφ φφ φφφ

80-80 ^o C, reacted for δ hours. After filtering out the inorganic compounds, the mother liquor is sued and chromatographed on a silica gel 60 column with dichloromethane: methanol (8: 2).

1.56 g (57.66%) of the title compound are obtained.

M.p. 83-84 ° C

ANALYSIS:

date:

because:

H, 7.62; N, 21.74; S, 6.2

61.94%, H 7.75%, N 21.38%, S 8.15%.

%

Example 26

4- ₍ 6-Dlamino-2 '{2- (4- (3-dimethylaminopropyl) -1-piperazinophenyl] ethylthio) -5- (2' -methoxybenzyl-1 H-pyrimidine, tetrahydrochloride)

To a solution of potassium hydroxide (3.37 g, 80 mmol) in water (60 mL) was added potassium salt (4.8 g, 10 mmol) of 4,8-diamino-2-methylcapto-5- (2-methoxybenzyl) pyrimidine, followed by a solution of 3.61 g (10 mmol) of 1- (2-chloroethyl) -4- (3-dimethylaminopropyl) piperazine trihydrochloride hydrate in 30 ml of water was added dropwise with stirring. The reaction mixture was stirred at room temperature for 30 hours. and the resulting crystals are filtered off and washed with water. The base is salted with isopropyl alcohol containing 4 equivalents of hydrochloric acid in ethyl alcohol. 3.31 g (53.1%) of the title compound are obtained.

Mp 282-264 ° C

Elemental: Calculated for C23H43Cl4N7O2S (823.621): C, 44.31%, H, 8.95%, Cl (ion) 22.74%, N, 15.72%, S, 5.14%, Found: C, 44.21%, H 6.90%, Cl (ion) 22.17%, N 15.19%, S 5.05%.

Claims (9)

Claims The piperazinylalkylpiperidine derivatives of formula (I) are. where 'i R ' R * 'is hydrogen, C 1-4 alkyl, C 1-4 alkanoyl, or di (C 1-4 alkyl) amino- (C 1-4 alkyl) alkyl, which is substituted with 1-3 substituents wherein the substituent is independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, di (C 1 -C 4 alkyl) -amino, and / or halogen, being 2, 3 or 4, 5avászaiilao are suitable acid addition salts. 2, n and their pharmaceutically acceptable acid addition salts, 2, The piperazinyl-alkyl-t-piperidinyl derivatives of claim 1, wherein R ¹ is hydrogen, C 1-4 alkyl, C 1-4 alkanoyl or di (C 1-4 alkyl) aminoethyl; R ² is a benzyl group substituted with 1-3 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, di (C 1-4 alkyl) amino and / or halogen, n being 2 or 3, and pharmaceutically acceptable acid addition salts thereof. The piperazinylalkylthiopyrimidine derivatives of claim 1, wherein R? is hydrogen, dimethylamino (C 1-4 alkyl), R ² is benzyl substituted with 1-3 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, di (C 1-4) alkyl) amino, and / or halogen, Φ φ Φ ♦ Φ * Φ Φ Φ * Φ ΦΦ Φ * η is 2 or 3 and their pharmaceutically acceptable acid addition salts. 4. The pyperazinylalkylthiopinnidine derivatives of claim 3, wherein R 'is hydrogen or dimethylamino (C 1-4 alkyl) R' 'is benzyl substituted with C 1-4 alkoxy or fluoro, A process for the preparation of a piperazinylalkylthiopyrimidine derivative of formula (I) wherein R 1, R ² and n are as defined in claim 1 and which are pharmaceutically acceptable acid addition salts thereof. -mercapto-pyrimidine, wherein R ² is as defined above, or an alkali metal salt thereof with a haloalkylpiperazine of formula (III) wherein R 'and n are as defined above. Diluted with a halogen atom, preferably with a chlorine or bromine atom, or with an acid addition salt thereof, the desired compound of formula (I) may be converted or liberated from a pharmaceutically acceptable acid addition salt, if desired. Pharmaceutical composition according to claim 6, characterized in that the active ingredient is a piperazinyl-alkylpyrimidine derivative of the formula (I), wherein R ¹ , R ² and n are as defined in claim 3 or a pharmaceutically acceptable acid addition salt thereof. 8. The pharmaceutical composition of claim 7 wherein the compound is a (!) Wherein piperazinyl Alkirian-pyrimidine derivative with FC, R ^z and n are included in the 4, appended claims, or a pharmaceutically acceptable acid addition salt thereof. 8. A pharmaceutical composition comprising, as active ingredient, a piperazinylalkylthiopyrimidine derivative of formula (I) wherein R ¹ , R ² and n are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, in a conventional carrier (s). ) next to. <·· φφ χ φ Φ Φ Φ Φ φ X X φ. φφ φ φ * φ φ * φφ »X X Φ 9. The piperazinylalkylthio-pinmldine derivatives of formula (I) wherein: R 1, R ² and n are the use of a pharmaceutically acceptable acid addition salt thereof as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.