Chloropyrimidine intermediate compounds

 

(57) Abstract:

Describes the new chlorpheniramine intermediate compounds of General formula

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where R1and R2- may be the same or different and selected from C1-8-alkyl, and their salts, processes for their preparation and methods for their conversion into substituted at the 9-th position 2-aminopurine, which are suitable for therapy. New connections can be used for the treatment and prevention of viral infections. 11 C. and 4 h.p. f-crystals.

The invention concerns of some new pyrimidine intermediates, processes for their preparation and conversion into substituted at the 9-th position 2-aminopurine type carbocyclic, heterocyclic and acyclic analogues of purine nucleosides, their salts, esters and pharmaceutically acceptable derivatives.

It is known that a number of analogs of 2-aminopurine nucleosides can be used for treatment and prophylaxis of viral infections, such as is described that the compound of formula (A)

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possesses strong activity against human immunodeficiency virus (HIV) and hepatitis b virus (HBV) [EP 0434450].

The methods proposed for obtaining substituted at the 9-th position 2-aminopurine, usually n is gasolinera rings and the introduction of any suitable substituent in the 6-th position.

Pyrimidine compounds suitable for the production of substituted 9-th position 2-aminopurine include 2,5-diamino-4,6-dichloropyrimidine, N,N'-(4,6-dichloro-2,5 - pyrimidinyl)bisformamide, and N-2-acylated derivatives of pyrimidines, such as 2-acetamide and 2-isobutyramide derivatives [U.S. Patent 5087697].

Methods of synthesis of these intermediate compounds usually consist of several stages, some of which are difficult to perform and give a low output product, which limits any large-scale their embodiment in quantities of more than a few grams, and makes them uneconomical.

Methods of synthesis of intermediate 2,5-diamino-4,6-dichloropyrimidine include direct chlorination easily accessible 2,5-diamino-4,6-dihydroxypyrimidine using phosphorus oxychloride. The first study of this reaction was conducted Temple and other [J. Org.Chem., 1975, 40:3141-3142]. These researchers concluded that the reaction was unsuccessful probably due to the decomposition of the pyrimidine cycle. Subsequently Hanson described the method of direct chlorination of 2,5-diamino-4,6-dihydroxypyrimidine by boiling under reflux with phosphorus oxychloride in the presence of a large molar excess of the fourth way and found a duplicate of a much lower yield (<10%) of the crude 2,5-diamino-4,6-dichloropyrimidine shown in [WO 91/01310; U.S. patent 5216161]. Extensive decomposition of 2,5-diamino-4,6-dihydroxypyrimidine with the formation of the resin covering the surface of the equipment, combined with the availability of abundant insoluble precipitate caused by the use of insoluble salts of amines, are significant obstacles and make large-scale application of this method is disadvantageous. Modification Legraverend, etc. [Synthesis 1990: 587-589] , consisting in the use of acetonitrile as a solvent and adding pentachloride phosphorus to phosphorus oxychloride and Quaternary ammonium chloride, lead, according to the results of our experiments, the selection with approximately 30% yield after chromatographic purification) of 2,5-diamino-4,6-dichloropyrimidine in amounts from 2 to 5 grams. The scale more than a few grams again is disadvantageous due to the formation of pitched precipitation.

In a recent publication [Lonza AG, EP 0552758] States that higher outputs (35-65%) can be achieved using phosphorus oxychloride in the case when the 5-amino group of 2,5-diamino-4,6-dihydroxypyrimidine protected alkoxycarbonyl-protecting group. It is alleged that as a result of this modification simplifies stage chlorination, to ojasuu in need of removal alkoxycarbonyl-protective group for the conversion of pyrimidine intermediates in purine. Essentially, this publication shows that such is protected by the 5th position of 2,5-diamino-4,6-dichloropyrimidine can be favorably transformed into purines.

The method of synthesis of N,N'-(4,6-dichloro-2,5-pyrimidinyl)bisformamide represents the reaction of 2,5-diamino-4,6-dichloropyrimidine with formic acid and acetic anhydride [Harnden et al. J. Med.Chem. 1990, 33:187-196] and [U.S. patent 5159076].

Platitudinal synthesis of N-2-acylated derivatives, as well as 2,5 - diamino-4,6-dichloropyrimidine required for the synthesis of N,N'-(4,6-dichloro-2,5-pyrimidinyl)bisformamide [Temple et al. J. Org.Chem. 1975, 40:3141-3142], starts with 2-amino-6-chloropyrimidine-4-it contains the introduction phase 5 - nitro subsequent retrieval and recovery very reactionsand 5-nitro-4,6-dichloropyrimidine intermediates, which makes the scaling process is disadvantageous. The output of a number of intermediate compounds during synthesis is low [Legraverend et al. Synthesis 1990:587-589].

We open some new pyrimidine intermediate compounds that may be useful in new ways of synthesis of the above-mentioned substituted at the 9-th position 2-aminopurine and, in addition, can be applied to the synthesis described known R is nd the following new intermediate compounds, which can be applied in the syntheses of 2-aminopurine, namely compounds of formula (I), (II) and (III):

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where R1and R2that may be the same or different selected from C1-8the alkyl. In the preferred embodiment of this invention R1and R2both represent a methyl group.

These new intermediate compounds can easily be obtained with a good yield and is suitable for a wide range of different types of 2-aminopurine, including analogue of the nucleoside of the formula (A), famciclovir [EP 0182024] , penciclovir [EP 0141927] , H2G [0343133], (1'S,3'S,4'S)-2-amino-1,9-dihydro-9-[3,4-dihydroxy-3 - hydroxymethyl-1-cyclopentyl] -6H-purine-6-[EP 0420518] and other substituted at the 9-th position 2-aminopurine, provided that the substituent in the 9-th position is not connected through glycosidic bonds.

As a further aspect of the present invention we provide methods for the synthesis of novel intermediate compounds of formula (I), (II) and (III) are known and the intermediate 2,5-diamino-4,6-dichloropyrimidine (IV). These methods are illustrated in the following simplified diagram, which is intended only to demonstrate possible ways of synthesis of these intermediate comprising chlorination of 2,5-diamino-4,6-dihydroxypyrimidine halomethyltoluenes salt (reagent Vilsmaier) of the formula (V)

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where R1and R1defined as before.

The compounds of formula (V) can be obtained from a number of formamido secondary amines in the reaction with halides, such as phosphorus oxychloride, pentachloride phosphorus, thionyl chloride, phosgene and oxalicacid that is described in detail in the review [Marson, S. M. Tetrahedron 1992, 48:3660-3720] and therein references.

The advantage of the protection diaminopirimidina from extensive decomposition during chlorination is achieved by protection in situ amino groups with two molar equivalent of the reagent Vilsmaier (V) obtaining bisformamide intermediate compounds (fixed by means of thin-layer chromatography), which is subsequently chlorinated to the compounds of formula (I) by passing the reaction with additional equivalents of reagent Vilsmaier. Improved solubility such bisformamide derivative is an additional advantage of the described process, facilitating the subsequent chlorination to compounds of formula (I), their separation and simplifies cleanup.

The inconvenience of applying the 5-alkoxycarbonyl-protective groups [Lonza AG, EP 0552758], which in this case is eliminated, because formamidine the filling compounds (II) and (III); or, alternatively, the compound of formula (I) can be hydrolyzed to compounds of formula (III).

2,5-Diamino-4,6-dichloropyrimidine (IV) can be obtained:

A) hydrolysis of compounds of formula (I);

B) hydrolysis of compounds of formula (II) or

C) hydrolysis of compounds of formula (III).

Hydrolysis of (I), (II) or (III) to 2,5 - diamino-4,6-dichloropyrimidine conveniently carried out at pH values of 3.0+/-0,5 by adding a miscible with water co-solvent type of ethanol. Hydrolysis is more effective when the pH of 1-2, in which it takes less time compared to higher pH values. However, at pH 1-2, it is advisable to protect 2,5-diamino-4,6-dichloropyrimidine from hydrolysis to hydroxypyrimidine by extraction, as education, in the organic layer, is not miscible with the aqueous acid layer. When the pH of the aqueous layer is below 1, extraction of the product into the organic layer inefficient (pKathe compounds of formula (IV) is about 0.5, and a pyrimidine ring, therefore, is at a pH below 1 mainly in the protonated form). Preferably used for carrying out the hydrolysis, the acid would not have asistencial should be those resistant to aqueous acid solution and therefore, which would be soluble compound of the formula (IV). Solvents that meet these requirements are toluene and halopedia solvent type, methylene chloride, chloroform and 1,2-dichloroethane. At the end of the process the organic layer just washed, for example with saturated aqueous bicarbonate, dried and concentrated to obtain the compounds of formula (IV), does not require additional purification.

The compounds of formula (III) can be obtained:

A) selective hydrolysis of compounds of formula (I) or

B) selective hydrolysis of compounds of formula (II).

The hydrolysis of compounds of formula (I) or (II) to (III) is most effective in a dilute aqueous solution of acid, preferably mineral, such as sulfuric, hydrochloric or phosphoric. Prolonged incubation at pH below 1 should be avoided because chloropyrimidine ring is at a pH below 1 mainly in the protonated form and can therefore be attacked by water molecules with the formation of undesirable hydroxypyrimidinone by-products. For the effective education of the compounds of formula (III) is preferable to maintain the pH above 2 and preferably of 3.0+/- 0,5. In this about the Oia (III) with the release of approximately 70%. As hydrolysis formamidine groups of compounds (I) and (II) is liberated secondary amine (HNR1R2), from which was formed the reagent Vilsmaier (V), and causes an increase in the pH value of the solution, thus slowing the hydrolysis. In addition, for some reactive aliphatic amines HNR1R2such as N,N'-dimethylamine, you need to maintain a sufficiently low pH values, protecting the remains of chlorine pyrimidine ring from the substitution of a secondary amine. We found that maintaining the pH of the reaction mixture below 4 avoids significant residual chlorine substitution of secondary amines even in the event of such reactive amine as N,N'-dimethylamine. Thus, it was found to be optimal tebufelone mixture, in which the hydrolysis of the compounds (I) and (II) to compound (III), at pH values of 3.0 +/- 0.5 or adding portions acid during hydrolysis for maintaining the pH value at this level.

The optimal is to conduct hydrolysis of compounds of formula (I) and (II) to compound (III) in the minimum amount of water with the pH value is controlled as described above. Under these conditions, the compound (III) precipitates as education and just ottilie 4 hours or at lower temperatures for a longer period of time.

The compounds of formula (II) can be obtained by selective hydrolysis of compounds of formula (I). Preferred is a selective hydrolysis in the presence of a little more than dvuhpolyarnyy equivalent of mineral acid in water or ethanol and heated for 15 to 30 minutes.

The compounds of formula (I) can be obtained in the reaction of 2,5-diamino-4,6-dihydroxypyrimidine with reagent Vilsmeier formula (V).

2,5-Diamino-4,6-dihydroxypyrimidine is a commercially available compound (Sigma, Maybridge BTB, Pfaltz and Bauer, Polyorganix).

New bisformamide formula (I) are formed and conveniently with high output are allocated in case of 2,5-diamino - 4,6-dihydroxypyrimidine (or its salt such as hydrochloride or hemisulfate) process at least 4 molar equivalents of the reagent Vilsmaier (V). Similar reactions of chlorination are in very mild conditions, without the formation of abundant resin rainfall, characteristic, as noted above, for direct chlorination with phosphorus oxychloride or phosphorus oxychloride with Quaternary ammonium halides. Chlorination on Vilsmeier 2,5-diamino-4,6-dihydroxypyrimidine can be carried out in an inert rastvorityelye solvents are 1,2-dichloroethane, chloroform or methylene chloride. The chlorination can be carried out in the temperature range from 0 to 110oC, preferably from 40 to 100oC, usually at the boiling point of the used solvent. Typical the reaction time from 12 to 48 hours. The emission of compounds of formula (I) is simple, can be easily implemented on a large scale and is simply washing the reaction solution with an aqueous solution containing a suitable base, like sodium bicarbonate, to neutralize all of the formed hydrogen chloride, followed by concentration and drying of the organic layer, resulting in new chlorinated pyrimidines of the formula (I). The compounds of formula (I) in General stable and can be presideny from a variety of solvents such as ethyl acetate, store or use without further purification.

Particularly preferred examples of compounds of formula (I), (II) and (III) are:

a) 4,6-dichloro-2,5-bis-[(dimethylamino)methylamino]pyrimidine,

b) 2-amino-4,6-dichloro-5-[(dimethylamino)methylamino]pyrimidine,

C) N-(2-amino-4,6-dichloro-5-pyrimidinyl)formamide.

In accordance with the following aspect of the present invention, n is, is soedineniya formula (I) or (II) can also be applied in the synthesis of 2-amino-6-glucuronoside, due to the fact that the amine HNR1R2(where R1and R2defined earlier), released in the process of turning pyrimidine derivative in purine, is significantly directionspanel in relation to the substitution of chlorine residue in the formed 2-amino-6-chloropurine.

The compounds of formula (III) are as described previously, N-2-acylated derivatives, high reactivity, compared with 2,5-diamino-4,6-dichloropyrimidine, in relation to the substitution of chlorine residue on suitable primary amine or a protected hydroxylamine. However, such condensation with the compound of the formula (III) (described in more detail below) can be carried out under milder conditions, at lower temperatures and for a shorter period of reaction time in comparison with the compound of the formula (IV), resulting in less degradation of amines. The products of the condensation of (VI) are highlighted with a higher yield and purity than the corresponding products of formula (VIII), formed by condensation of 2,5-diamino-4,6-dichloropyrimidine (IV). Another advantage of using the intermediate is then, that purines formed from (III), does not require removal of protection, i.e., the hydrolysis of N-2-acyl group (this is a longer method described in [U.S. patent 5087697] and [U.S. patent 5159076]).

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where R3hereinafter defined.

The compound of formula (III) can be applied to obtain a new intermediate compounds of formula (VI), which is an additional feature of the invention:

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where R3represents H or C3-7carbocyclic group which may be substituted by hydroxyl, provided that such a group is not joined by glycosidic bonds.

Preferred R3the groups are:

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b H;

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The most preferred R3the group is:

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Suitable groups R3choose from a, b and C, which are defined above.

As an additional feature of the present invention we provide a method of producing compounds of the formula (VI), which lies in the interaction of the compounds of formula (III) with an amine of formula R3NH2where R3defined above. This condensation is preferably carried out at a temperature of reflux distilled the solvent type ethanol, butanone or potassium carbonate or sodium.

Subsequent references to the compounds of formula VIa, b, or C) denote the compound of formula (VI) in which R3is the group a, b or C, as defined previously.

Especially preferred compound of formula (VI) is (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino] -2-cyclopenten-1-methanol (VIa).

New intermediate compounds of formula (VI) can be converted by reaction cyclization to the corresponding compounds of formula VII

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where R3previously defined.

Cyclization of the compounds of formula (VI) with the formation of the compounds of formula (VII) is conveniently carried out in trialkylaluminium (e.g triethylorthoformate or triethylorthoformate) with concentrated aqueous acid (e.g. 2-4 molar equivalents of hydrochloric, sulfuric or methanesulfonic acids). For example, hydrochloride, a compound of formula (VIIa), i.e. a compound in which the residue R3presents the group and begins to precipitate from such orthoformiate solutions of the compounds of formula (VIa) in minutes and the product yield of over 90% can be achieved by separating the precipitate by filtration, in the optimal case, after several hours at ambient temperature.


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The previously described way of synthesis of intermediate compounds of type (VIII) is longer and, more importantly, contains a larger number of stages required to obtain purine after joining the group R3. In addition, triaminopyrimidine intermediate compounds of type (VIII) sensitive to the action of air and light, and extremely difficult to clean due to their polarity and ability to helatirovat metals (selection after recovering zinc diazopropane is particularly problematic). New 5-formamide intermediate compounds of formula (VI) are easily and directly obtained from compounds of formula (III) in one stage and are usually solids that are stable and can easily be purified by precipitation from a suitable solvent.

(1'S, 3'S,4'S)-2-Amino-1,9-dihydro-9-[3,4-dihydroxy-3-hydroxymethyl-1-cyclopentyl]-6H-purine-6-he (Hz) [EP 0420518] can be obtained by condensation of compounds of formula (III) with 4-amino-3-cyclopenten-1-methanol [U.S. patent 5049671] with the way the / establishment, which can be gidrauxilirovanne using osmium tetroxide/N-methylmorpholin-N-oxide with obtaining the compounds of formula (VII). This connection is hydrolized with the formation of the compounds of formula (Hz).

2-Amino-6-globulin (VII) can be obtained by cyclization of new 2,4-diamino-6-chloro-5-formamidopyrimidine (VI), conveniently synthesized by condensation of compounds of formula (III) with ammonia. The compound of formula (VII) represents an intermediate connection, suitable for the synthesis of acyclic antiviral nucleosides, such as famciclovir, where 2-amino-6-chloropurine intermediate connection (VII) comfortable with the hydrogenolysis is translated in 2-aminopurine nuke.

Nucleosides containing hydrocarbon cycle, can also be synthesized from the compounds of formula (VII), for example using Pd catalyzed reactions combination with a suitable intermediate compound containing a hydrocarbon cycle, as described in [MacKeith et al. J. Chem.Soc. Perkin Trans. 1. 1993:313-314] and cited in the literature.

The compounds of formula (VIIa) and (VIIa) are conveniently hydrolyzed to the corresponding gurinovka compounds by boiling under reflux with a water base or acid.

An additional feature of the present invention is we have discovered an alternative method of synthesis of 2,6-di is slishnimi and selected from H and C3-6cycloalkyl (in particular, R4represents H, and R5is cyclopropyl), directly from the compounds of formula (VI), which advantageously eliminates one of the stages. Such 2-aminopurine compounds may be synthesized from intermediates of formula (VI) by boiling under reflux the compounds of formula (VI) with an excess of amine (HNR4R5in the solvent-type ethanol, isopropanol, n-propanol, t-butanol or n-butanol.

In special cases it may be more useful use of 2,5-diamino-4,6-dichloropyrimidine (IV) to obtain compounds of the formula (VIII), suitable for synthesis of the modified 8-th position of analogues of 2-aminopurine nucleosides, such as 8-Aza-2-aminopurine (which have a broad spectrum anti-herpes activity, as described in [Storer et al. Spec.Publ. Roy. Soc. Chem. (Rec. Adv.Chem. Anti-Infect. Agents) 1993, 119:251-265]); in these cases, to obtain the compounds of formula (IV) can be applied to intermediate compounds of formula (I), (II) and (III).

Pharmaceutically acceptable esters of the compounds provided by the invention, can be obtained by esterification using traditional, well-known specialists of ways. This act is retenu, including their esters, can be a traditional way converted into pharmaceutically acceptable salts in the treatment with acid or base. Ester or salt of the compounds according to the invention can be returned to the original connection, for example, through hydrolysis.

The following examples are intended for illustration only and in no way limit the scope of the invention.

Example 1

4,6-Dichloro-2,5-bis-{[(dimethylamino)methylene]amino}pyrimidine

2,5-Diamino-4,6-dihydroxypyrimidine hemisulfate (Sigma, 25,0 g, 0,131 mol) was stirred in chloroform (Mallinckrodt AR, 400 ml) in a three-neck round-bottom flask with a capacity of 2 l, equipped with a reflux condenser with nitrogen source, connected to the output of the fridge) and the outlet for gaseous HCl connecting another throat bulb with NaOH trap. Into the flask in an additional amount of chloroform (400 ml) was poured chloride (chlormethine)dimethylammonio (reagent Vilsmaier, Aldrich, 88.0 g, 0,651 mol (95%)). The reaction mixture is cautiously brought to reflux distilled, replacing with nitrogen gas evolved HCl into the trap. When the selection HCl was slowed after approximately 1 hour of boiling under reflux, the eviction was stopped and the reaction mixture was stirred in t is whether the reagent Vilsmaier (50.0 g, 0,370 mol), after which boiling under reflux was continued for another 20 hours. The reaction mixture (solution a yellow color with a dark yellow precipitate) with stirring, cooled (ice bath) and diluted with water (enough to dissolve the solid residue, approximately 300 ml). The pH of the aqueous layer was brought to 7 with sodium hydroxide or solid sodium carbonate. The chloroform layer was separated, washed with water (3 x 400 ml), dried (sodium sulfate) and concentrated in vacuo to a solid (36 g) dark yellow color. The resulting substance was dissolved in ethyl acetate (300 ml), stirred with charcoal (1 g) and filtered through a silica gel gasket (3 x 3 inches, in ethyl acetate). The gasket was washed with additional ethyl acetate and the eluent was concentrated in vacuo, getting named in the title compound in the form of solid light reddish-brown color (30,75 g, 81%); T. p. 116-119oC; Range1H-NMR identical to the spectrum of the recrystallized samples.

Analysis. The calculation for C10H14N6Cl20,10 EtOAc: C, 41,92; H, Free 5.01; N, 28,02; Cl, 23,80. Found: C, 42,23; H, Of 4.95; N, 28,46; Cl, 24,11.

Recrystallization of such a sample from ethyl acetate gave named is UP>H-NMR (DMSO-d6) : 8,49 and 8,69 (both s, 1 each, 2CH), and 3.16 (s, 3, CH3), 3,03 (s, 6, 2CH3), of 2.97 (s, 3, CH3); UV (pH 7, phosphate buffer solution)max296 nm ( 33300),min/248 (5200).

Analysis. The calculation for C10H14N6Cl2: C, 41,54; H, 4,88; N, Depreciation Is 29.06; Cl, 24,52. Found: C, 41,59; H, 4,91; N, 29,01; Cl, 24,47.

Example 2

2-Amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine

4,6-Dichloro-2,5-bis-{ [(dimethylamino)methylene] amino)pyrimidine (Example 1, by 5.87 g, 20.3 mmol) was dissolved in 95% ethanol (200 ml) and to the solution was added 6 n aqueous hydrochloric acid (13.5 ml). The solution was heated in an oil bath at a temperature of 55oC for 30 minutes in a nitrogen atmosphere, resulting according to TLC (silica gel, 5% methanol-chloroform) of the original material is completely transformed into a product with a lower Rf value. the pH of the cooled (ice bath) solution was brought to approximately 8 with concentrated ammonium hydroxide solution and the resulting mixture was formed white precipitate) was concentrated on a rotary evaporator to a volume of approximately 5 ml, removing the ethanol. After this was added 20 ml of water and cooled mixture was filtered. The precipitate is white washed with additional portions of water (2x20 ml), and dried, obtaining the POI is Cl/CH4): 236, 234 (M+1);1H-NMR (DMSO-d6) : to 7.59 (s, 1, CH), 6.90 to (s, 2, NH2), 3.00 and 2,94 (both s, 3 each, 2CH3); UV (pH 7, phosphate buffer solution)max328 nm( 4500), 255 (15800).

Analysis. The calculation for C7H9N5Cl2: C, 35,92; H, 3,88; N, 29,92; Cl, 30,29. Found: C, 35,66; H, 3,86; N, 29,74; Cl, 30,54.

In another experiment, also as in Example 1, the reaction of 2,5-diamino-4,6-dihydroxypyrimidine of hemisulfate (Sigma, 48,0 g of 0.250 mol) with a smaller amount of reagent Vilsmaier (7,2 molar equivalent) and educated 4,6-dichloro-2,5-bis-{[(dimethylamino)methylene]amino}pyrimidine (92%) without recrystallization hydrolyzed in 95% ethanol (1 l) and 6 n aqueous hydrochloric acid (110 ml), getting named in the header of the connection of the same purity (elemental analysis and1H-NMR) as for the sample described above (44,2 g, total yield, starting from 2,5-diamino-4,6-dihydroxypyrimidine of hemisulfate - 76%).

Example 3

N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (III)

A suspension of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]- amino}pyrimidine (Example 2, 1.50 g, 6,41 mmol) and 1.5 M potassium phosphate buffer solution (35 ml, prepared by summing the pH of a 1.5 M solution of KH2PO4to 3.2 by addition of 85% phosphoric cistaceae 4 hours the pH of the mixture was brought to a value of 3-4 by adding 4 drops of 85% phosphoric acid. After 6 hours after the start of boiling according to TLC (silikagelevye plates, eluruume system 5% methanol-chloroform), most of the source material turned into a product with a lower Rf value. The solid was filtered, washed with water (5 ml), methanol (5 ml), and dried, obtaining named in the title compound in the form of a solid white color (to 0.900 g, 68%), etc. >250oC (with decomp.); mass spectrum (Cl/CH4): 209, 207 (M+1);1H-NMR (DMSO-d6) : 9.81 and 9,46 (s and d, J= 11 Hz, total 1, NH), 8,25 and 8.00 (s and d, J=11 Hz, total 1, CHO), 7,69 and 7,63 (both s, total 2, NH2).

Analysis. The calculation for C5H4N4OCl2: C, 29,01; H, 1,95; N, 27,07; Cl, 34,25. Found: C, 29,12; H, 1,96; N, 27,13; Cl, 34,34.

Example 4

2,5-Diamino-4,6-dichloropyrimidine (IV)

4,6-Dichloro-2,5-bis-{ [(dimethylamino)methylene] amino} pyrimidine (Example 1, and 1.00 g, to 3.36 mmol) in ethanol (25 ml) and aqueous potassium phosphate buffer solution pH of 3.2 (1.5 M, 10 ml, prepared as described in Example 3) was boiled under reflux for 24 hours. In the process of boiling the pH value is maintained for about 3 by adding as needed 85% phosphoric acid. The solution was extracted with chloroform (3 x 25 ml). The combined chloroform layers were dried (sodium sulfate) and x is in the ratio 4:1 gave named in the header of the compound of formula (IV) in the form of needles whitish color (0,324 g, 52%); darkens and shrinks to a solid black color at a temperature above 185oC, not turn into a liquid at temperatures up to 300oC; [data from the Literature - 198oC [5] and 188-191oC [3] ; mass spectrum (Cl/CH4); 181, 179 (M+1);1H-NMR (DMSO-d6) : 6,50 (br s, 2, NH2), to 4.73 (br s, 2, NH2).

Analysis. The calculation for C4H4N4Cl20,12 EtOH: C, 27,60; H, 2,58; N, 30,36; Cl, 38,42. Found: C, 27,99; H, 2,39; N, 30,42; Cl, 38,74.

Example 5

2,5-Diamino-4,6-dichloropyrimidine (IV)

A mixture of 2-amino-4,6-dichloro-2,5-bis-{[(dimethylamino) methylene]amino}pyrimidine (Example 2, 500 mg, 2.14 mmol), aqueous potassium phosphate buffer solution pH of 3.2 (1.5 M, 6 ml, prepared as described in Example 3), water (1 ml) and ethanol (5 ml) was subjected to mild boiling under reflux for 28 hours. In the process of boiling the pH value is maintained for about 3 by adding 85% phosphoric acid. Volatile compounds were evaporated under vacuum and the remaining solid substance was distributed between water (30 ml, pH summarized using ammonium hydroxide to 8) and chloroform (75 ml). The chloroform layer was dried (sodium sulfate) and the chloroform was evaporated, getting a solid whitish color (0,30 g). Crystallization of the resulting product from a mixture of EDI (332 mg, 61%); darkens and shrinks to a solid black color at a temperature above 185oC, not turn into a liquid at temperatures up to 300oC;1H-NMR (DMSO-d6) and mass spectrum identical to that described in Example 4.

Analysis. The calculation for C4H4N4Cl2: C, 26,83; H, 2,25; N, 31,30; Cl, 39,61. Found: C, 26,93; H, 2,25; N, 31,24; Cl, 39,52.

Example 6

2,5-Diamino-4,6-dichloropyrimidine (IV)

N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg, 2,42 mmol) was dissolved at the temperature of reflux distilled in 0.1 n hydrochloric acid (5 ml, 2.5 mEq) and ethanol (7 ml). The solution was boiled under reflux for 5 hours. Volatile compounds were removed under vacuum. The residue was distributed between water (30 ml) with a pH up to 8 with dilute ammonium hydroxide, and ethyl acetate (75 ml). An ethyl acetate layer was dried (sodium sulfate). After evaporation of solvent received solid pink color (0.40 g). Recrystallization of the resulting product from 95% ethanol gave named in the header of the compound of formula (IV) in the form of needles of a light pink color (280 mg, 65%); darkens and shrinks to a solid black color at a temperature above 185oC, not turns into a liquid when the temperature is odd for C4H4N4Cl2: C, 26,83; H, 2,25; N, 31,30; Cl, 39,61. Found: C, 26,95; H, 2,24; N, 31,19; Cl, 39,53.

Example 7

(1S, 4R)-4-[(2-Amino-6-chloro-5-formamido-4-pyrimidinyl) amino] -2-cyclopenten-1-methanol (VIa)

N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2,07 g, 10.0 mmol) was stirred in absolute ethanol (40 ml) at the temperature of reflux distilled in a nitrogen atmosphere to achieve a state of partial dissolution. To this stirred solution was added a solution of freshly prepared (1S,4R)-4-amino-2-cyclopentene-1 - methanol (PCT Application 9204015.3, of 1.57 g, 12.5 mmol (90%) in ethanol (15 ml) followed by the addition of triethylamine (3.5 ml, 25 mmol, freshly over calcium hydride). After boiling under reflux for 14 hours received the dark solution was cooled and to it was added 1 n sodium hydroxide (10 ml). Volatile compounds were evaporated under vacuum. The remaining solid foam reddish-brown color was dissolved in a mixture of 5% methanol-ethyl acetate and the solution was passed through the gasket with silica gel, getting after evaporation of the solvents named in the title compound in the form of solids whitish color (2.50 g, 88%). Recrystallization of the product from a mixture of ethyl acetate-methanol (20: 1) gave named in reception is 4 (M+1), 190, 188 (B+H);1H-NMR (DMSO-d6) 8,99 and 8,58 (s and d, J= 11,1 Hz, total 1, amide NH), 8,11 and 7,80 (s and d, J=11,1 Hz, total 1, amide CH), 6,77 and 6.61 (two d, J= 8.0 Hz) overlapping 6,60 and 6,48 (two br s, total 3, NH and NH2), 5,85 and 5,70 (two m, 1 each, CH=CH), 5,15-5,00 (m, 1, NCH), 4,71 (t, J=5,1, 1, OH), 3,45-3,30 (m overlapping H2O, OCH2), 2,80-to 2.65 (m, 1, CH), 2,45-of 2.25 and a 1.45-1,30 (both m, 1 each, CH2); []20589+21,2o, []20578+22,2o, []20546+25,2o, []20436+41,4o, []20365+48,3o(1,50, methanol).

Analysis. The calculation for C11H14N5O2Cl: C, 46,57; H, Equal To 4.97; N, 24,69; Cl, 12,50. Found: C, 46,63; H, 4,99; N, 24,58; Cl, 12,59.

Example 8

(1S, 4R)-4-(2-Amino-6-chloro-9-H-purine-9-yl)-2-cyclopenten-1-methanol hydrochloride (VIIa)

To a mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl) amino]-2-cyclopenten-1-methanol (Example 7, and 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 ml) under stirring was added one portion of concentrated hydrochloric acid (37%, 1.25 ml). The resulting clear colorless solution was stirred in nitrogen atmosphere. After 15 minutes, began the formation of a white precipitate. After 4 hours, TLC drops of the reaction mixture, dissolved in methanol and neitralizovav light) showed the compound of formula (VIa) is almost completely turned into a product with higher Rf value. The precipitate was filtered off, washed with t - butylmethylamine ether (15 ml), and dried at a pressure of 0.2 mm Hg, a temperature of 25oC for 18 hours, getting named in the title compound as white powder (975 mg, 92%), etc. > 300oC decomp.; mass spectrum (Cl/CH4): 266 (M+1);1H-NMR (DMSO-d6) : 8,18 (s, 1, purine CH), to 7.2 and 6.7 (br s, NH2HE covered by water), 6,20 and 5,90 (both m, 1 each, CH= CH), of 5.48 (m, 1, NCH), 3,47 (d, J=5.7 Hz, 2 CH2O) 2,90 (m, 1, CH), of 2,75 2,55 and 1.75-1,60 (both m, 1 each, CH2);

Analysis. The calculation for C11H12N5OCIHCl: C, 43,73; H, 4,34; N, 23,18; Cl, 23,48. Found: C, 43,62; H, 4,34; N, 23,07; Cl, 23,53.

Example 9

(1S, 4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purine-9-yl)-2-cyclopenten-1-methanol (Ha)

A solution of (1S, 4R)-4-chloro-5-formamido-6-{ [4-hydroxymethyl)- 2-cyclopenten-1-yl] amino}pyrimidine (Example 8, 250 mg, 0,883 mmol) was subjected to mild boiling under reflux (oil bath temperature 130oC) in n-butanol (dried over 4A molecular sieve, 5 ml) with cyclopropylamine (Aldrich, of 0.30 ml, 4.4 mmol) for 16 hours under nitrogen atmosphere. Then added the second portion of cyclopropylamine (0.15 ml) and the boiling continued more who Asa 1 n sodium hydroxide (0.5 ml). After repeated removal of volatile compounds, the residue was chromatographically on the column for flash chromatography (110") filled with silica gel. (1S, 4R)-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino] -2-cyclopenten-1-methanol (VIIIa, 35 mg, 16%) was elyuirovaniya a mixture of 5% methanol-ethyl acetate. Continued elution with a mixture of 10% methanol-ethyl acetate allowed to obtain (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9-H-purine-9-yl)-2-cyclopenten-1-methanol (Ha) in the form of a solid foam light reddish-brown color (160 mg, 60%);1H-NMR (DMSO-d6) : 7,58 (s, 1, purine CH), 7,25 (d, J=4.5 Hz, 1, NH), 6,10 (m, 1, = CH), 5,80-of 5.75 (m, 3, =CH and NH2), of 5.40 (m, 1, NCH), 4,72 (m, 1, OH), of 3.45 (m, 2, OCH2), and 3.0 (br m, 1, CH cyclopropyl), 2,80 (br m, 1, CH), 2,70-2,50 (m overlapping solvent, CH), 1,50-of 1.05 (m, 1, CH), 0,70 -0,50 (m, 4, 2 CH2cyclopropyl).

Analysis. The calculation for C14H18N6O0,20H2O0,40CH3HE: C, 57,32; H, 6.35MM; N, 27,85. Found: C, 57,59; H, 6,48; N, 27,70.

Example 10

(1S, 4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purine-9-yl)] -2 - cyclopenten-1-methanol (Ha)

(1S,4R)-4-(2-Amino-6-chloro-9-H-purine-9-yl)-2-cyclopenten-1 - methanol [18] or its hydrochloride (Example 8) was boiled under reflux in ethanol with 10 molar equivalents of cyclopropylamine within 2 hours. After cooling the resulting solution to those who, what was taken as starting material the compound of formula (VIIa) or its hydrochloride). Volatile compounds were removed under vacuum. (1S,4R)-4-[2-Amino-6-(cyclopropylamino)-9-H-purine-9-yl)-2-cyclopenten-1-methanol (IXa) was passed through the gasket with silica gel, elwira a mixture of 5% methanol-chloroform and 10% methanol - ethyl acetate and separating in the form of a solid white foam (80%); the spectra are identical spectra of the product from Example 9.

Example 11 (1'S,3'S,4'S)-2-Amino-1,9-dihydro-9(3,4-dihydroxy-3-hydroxymethyl-1-cyclopentyl)-6H-purine-6-he

a) (4R)-4-[2-Amino-6-chloro-5-formamido-4-pyridinyl)amino] - 1-cyclopenten-1-methanol

Using the method described in Example 7, were the interaction of N-(2-amino-4,6-dichloro-5-pyrimidinyl)of formamide (Example 3, of 2.56 g, a 52.4 mmol) of (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, a 52.4 mmol), which can be obtained from (-)- 2-amabella[2.2.1] hept-5-ene-3-one (Chiroscience) by the method described in Examples 1-4 and 42 [15]. Crystallization from a mixture of ethyl acetate-methanol gave named in the title compound as white crystals, etc., 148-150oC; mass spectrum (Cl/CH4): 286, 284 (M+1), 190, 188 (B+H);1H-NMR (DMSO-d6) : 8,97 and 8,55 (s and d with J= 11.3 Hz, total 1, amide NCHO), 8,12 and 7,80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7,78 (both d, J= 7,4 Hz, total 1, NH), 6,60 and 6,40 (both 8, the); []20589-4,4o, []20578-5,2o, []20546-4,8o, []20436-20,0o, []20365-60,4o(C 0.25, methanol).

Analysis. The calculation for C11H14N5O2Cl: C, 46,57; H, Equal To 4.97; N, 24,69; Cl, 12,50. Found: C, 46,64; H, Free 5.01; N, 24,60; Cl, 12,45.

b) (4R)-4-(2-Amino-6-chloro-9H-purine-9-yl)-1-cyclopenten-1-methanol

To stir a mixture of (4R)-4-[(2-amino-6-chloro-5-formamido - 4-pyrimidinyl)amino]-1-cyclopenten-1-methanol (part a, 1,60 g, the 5.65 mmol) and triethylorthoformate (29 ml) was added in one portion concentrated hydrochloric acid (37%, 2.0 ml). The resulting clear colorless solution was stirred in nitrogen atmosphere. After 5 hours the precipitate was separated by filtration, washed with t-butylmethylamine ether (3 x 10 ml), and dried, obtaining a white powder (1.25 g). It was dissolved in water and the pH was brought to 3 by adding 1 n hydrochloric acid. The solution was heated at a temperature of 60oC for 4 hours, cooled, neutralize and evaporated to a solid residue, which was chromatographically on silica gel. Named in the title compound was suirable a mixture of 5% methanol-chloroform and was led from a mixture of e1H-NMR (DMSO-d6) : of 8.09 (s, 1, purine CH), 6,9 (br s, 2, NH2), 5,64 (m, 1, =CH), 5,2 to 5.0 (m, 1, NCH), to 4.87 (t, J=5.5 Hz, 1, OH), of 4.05 (m, 2, CH2O), 3,0-2,5 (m, 4, 2 CH2).

Analysis. The calculation for C11H12N5OCl: C, 49,06; H, With 4.64; N, 26,01; Cl, 13,16. Found: C, 49,18; H, 4,63; N, 26,11; Cl, 13,19.

b) (1S, 2S,4R)-4-(2-Amino-6-chloro-9H-purine-9-yl)-2-(hydroxymethyl)-1,2-cyclopentanediol

(4R)-4-(2-Amino-6-chloro-9H-purine-9-yl)-1-cyclopenten-1-methanol (Part b, 501 mg, 1,89 mmol), N-methylmorpholin-N-oxide (60% aqueous solution, Aldrich, 0.33 ml, 1,89 mmol), osmium tetroxide (2.5% in t-butyl alcohol, Aldrich, of 0.47 ml) and t-butyl alcohol (12 ml) was heated at 60oC for 1.5 hours. Volatile compounds were evaporated and the solid residue was chromatographically on silica gel. Named in the title compound was suirable a mixture of 10% methanol-chloroform and got in a solid reddish-brown color (210 mg), after which it was perioadele of absolute ethanol, obtaining a white powder, etc., 217-219oC; mass spectrum (Cl/CH4): 302, 300 (M+1), 172, 170 (B+H);1H-NMR (DMSO-d6) : 8,29 (s, 1, purine CH), 6,9 (br s, 2, NH2), 5,15-of 4.90 (m, 1, NCH), 4,80 (d, J=3,9 Hz) overlapping 4,78 (t, J= 3.5 Hz, total 2, 2 OH), 4,30 (s) overlapping the 4.3 to 4.2 (m, total 2, HE and OCH), 3,45-to 3.35 (m, overlapped with water, C2HE's in), 2.25-2,05 (m, 4, 2 CH2).

g) (1'S,3'S,4'S)-2-Amino-1,9-dihydro-9(3,4-dihydroxy-3-hydroxymethyl-1-cyclopentyl)-6N-purine-6-he

(1S, 2S, 4R)-4-(2-Amino-6-chloro-N-purine-9-yl)-2-(hydroxy-methyl)-1,2-cyclopentanediol (Part b, 90 mg, 0.27 mmol) was boiled under reflux with 1 n hydrochloric acid (2.7 ml) for 45 minutes. Volatile compounds were evaporated under vacuum. After evaporation of the water balance of pererestorani in the water. the pH of the solution was brought to a value of 5 using hydrochloric acid, and the resulting mixture was cooled and filtered; the precipitate was dried, getting named in the title compound in the form of a whitish powder colouring (51 mg, 68%), etc. >300oC decomp.; mass spectrum (Cl/CH4) : 283 (M+1);1H-NMR (DMSO-d6) identical to that described in [U.S. patent 5233041].

Example 12 N-(2,4-Diamino-6-chloro-5-pyrimidinyl)formamide

N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 500 mg, 2.14 mmol) and ammonia (150 ml) was stirred in a Parr bomb at the 50oC for 18 hours. The ammonia was evaporated and the solid residue triturated with water (10 ml). The solid was dried, getting named in the title compound in the form of powder red (400 mg, 89%), etc. >300oC; mass spectrum (Cl/CH4): 190, 188 (M+1);1H-NMR (DMSO-d6) : 9,05 and at 8.60 (both br s, total 1, NHCO), 8,1 : C, 32,01; H, Up 3.22; N, 37,34; Cl, 18,90. Found: C, 31,97; H, 3,23; N, 37,26; Cl, 19,00.

1. Chloropyrimidine compound of the formula I

< / BR>
where R1and R2that may be the same or different selected from C1-8the alkyl.

2. Chloropyrimidine compound of formula I under item 1, in which R1and R2both represent methyl.

3. Chloropyrimidine compound of formula II

< / BR>
where R1and R2such, as defined in paragraph 1 or 2.

4. Chloropyrimidine compound of formula III

< / BR>
5. The compound of formula IV

< / BR>
where R3represents H or C3-7carbocyclic group which may be substituted by hydroxyl, provided that such a group is not joined by glycosidic bonds.

6. Connection on p. 5, wherein R3represents a group chosen from:

< / BR>
B. H

< / BR>
7. The compound of formula VI under item 5, in which R3represents a group

< / BR>
8. The method of obtaining 2-amino-6-globulinemia the compounds of formula VII

< / BR>
where R3defined as in PP.5 to 7, characterized in that the compound of formula VI

< / BR>
is subjected to cyclization in the presence of acid.

9. With iremedi subjected to interaction with the compound of the formula V

< / BR>
where R1and R2defined as in paragraph 1.

10. The method of obtaining the compounds of formula II

< / BR>
where R1and R2defined as in paragraph 1,

wherein the hydrolyzing a compound of the formula I

< / BR>
11. The method of obtaining chloropyrimidine the compounds of formula III

< / BR>
wherein said hydrolyzing the compounds of formula I or II

< / BR>
12. The method of obtaining chloropyrimidine the compounds of formula VI

< / BR>
where R3defined as in paragraph 5, 6 or 7, wherein the compound of formula III, as defined in paragraph 4, is subjected to the interaction with the amine of formula R3NH2.

13. The method of obtaining 2,5-diamino-4,6-dichloropyrimidine by acid hydrolysis of the compounds of formula I, II or III

< / BR>
< / BR>
< / BR>
14. The method of obtaining 2,6-diaminopurine formula

< / BR>
where R3represents H or C3-7carbocyclic group, possibly substituted by hydroxyl;

R4and R5that may be the same or different, selected from H and C3-6cycloalkyl,

characterized in that the compound of formula VI

< / BR>
where R3represents H or C3-7carbocyclic group, possibly substituted guy who e may be the same or different, selected from H and C3-7cycloalkyl in boiling solvent.

15. The method according to p. 14, characterized in that to obtain (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl] -2-cyclopenten-1-methanol is used as a compound of formula VI, as defined in paragraph 7, and cyclopropylamine.

 

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FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

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FIELD: organic chemistry, herbicides, agriculture.

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EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

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EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

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3 cl, 1 sch, 6 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of synthesis.

15 cl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the pyrimidine derivatives with general formula I and their pharmaceutically acceptable salts, which possess tyrosine kinase ZAP-70, FAK and Syk-inhibiting activity, and to their application. The compounds can be used for treatment or prevention of diseases or conditions, where the activation of tyrosine kinase ZAP-70, FAK and/or Syk is involved, e.g., heart failure, chronic obstructive pulmonary disease, Alzheimer's disease et al. In general formula (I) , X is for CR0; R0, R1, R2, R3 and R4 - each identifies independently hydrogen; C1-C8alkyl; hydroxyC1-C8 alkyl; or R3 and R4 together with the adjoined nitrogen and carbon atoms create the 5-10-term heterocyclic ring and, besides, contain 1, 2 or 3 heteroatoms, chosen from N, O and S; or R1 , R2 and R3 each identifies independently the halogen; C1-C8alcoxy; hydroxyC1-C8 alcoxy; C1-C8 alcoxy -C1-C8 alcoxy; phenyl; 5-6-term heterocyclic ring; containing 1-4 heteroatoms, chosen from N and O; nitro; carboxy; -N(C1-C8alkyl)C(O)-C1-C8 alkyl; -CONR10R11; -SO2N(R10)R11; where R10 and R11 each identifies independently the hydrogen; hydroxy; C1-C8 alkyl; C2-C8alkenyl; C3-C8cycloalkyl; C3-C8 cycloalkyl -C1-C8 alkyl; C2-C8 alcoxy -C1-C8 alkyl; hydroxy C1-C8 alcoxy -C1-C8 alkyl; hydroxyC1-C8 alkyl; or 5-10-term heterocyclic ring, containing up to two heteroatoms, chosen from N and S; or R1 and R2 together with the adjoined carbon atoms create the aryl or 5-10-term heteroaryl radical, containing one or two heteroatoms, chosen from N, O and S; or R5 and R6 identifies independently from each other the hydrogen; halogen; cyano; C1-C8 alkyl; haloC1-C8alkyl; R7, R8 and R9 identifies independently from each other the hydrogen; hydroxy; C1-C8alkyl; haloC1-C8alkyl; C1-C8alcoxy; -Y-R12, where Y means the simple link or O and R12 means C1-C4alkyl, substituted or unsubstituted 5-, 6- or 7-term heterocyclic ring, containing 1, 2 or 3 heteroatoms, chosen from N, O and S; carboxy; -N(C1-C8 alkyl)-CO-NR10R11; - -N(R10)(R11); R7 and R8 or R8 and R9, correspondingly, together with the adjoined carbon atoms create the 5- or 6-term heteroaryl containing 1, 2 or 3 heteroatoms, chosen from N; or 5- or 6- term carbocyclic ring; or R7 means hydrogen, hydroxyl, C1-C4alkyl, unsubstituted or terminally substituted hydroxyl group; C1-C8alcoxy group, unsubstituted or terminally substituted by hydroxyl, C1-C4 alcoxy group or unsubstituted or substituted C1-C4alkyl 5-6-term heterocyclic ring, containing 1-3 heteroatoms, chosen from N and O; Provided, one R1, R2 or R3 means -CON(R10)R11; or -SO2N(R10)R11.

EFFECT: therapeutic efficiency is increased.

7 cl, 14 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: in general formula , R is unsubstituted or substituted with -OH, C1-4alkyl or -O-C1-4alkyl, straight or branched alkyl C1-C4; R1 has formula -(L)x-R3; R3 is a fragment, chosen from a group consisting of substituted or unsubstituted phenyls, where the substitute is chosen from C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl or fluorine; R2 has formula -(L1)y-R4; R4 is a fragment, chosen from a group consisting of i) hydrogen atom; ii) substituted with -OH, -O-C1-4alkyl or phenyl or unsubstituted straight or branched hydrocarbyls C1-C10, where the hydrocarbyl is C1-6alkyl; L and L1 are bridge fragments -NR5-; each of the fragments R5 is a hydrogen atom, straight or branched alkyl C1-C4; indices x and y can independently assume values 0 and 1.

EFFECT: compounds can be used for curing diseases, mediated by activity of phlogistic cytokines, such as arthritis.

10 cl, 4 dwg, 3 tbl, 200 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine.

SUBSTANCE: method of mite controlling in warm-blooded animals includes introduction to the specified mammal of compound of formula I wherein R1 means hydrogen; R2 and R3 independently mean hydrogen or formyl; R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 independently mean hydrogen, halogen, nitrogroup, C1-C2alkyl or halogenC1-C2alkyl; both X1 and X2 mean O.

EFFECT: improvement of the method.

5 cl, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess properties inhibiting HIV replication, of general formula (I) , in form of E-isomer, in which -a1=a2-a3=a4- represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4. Represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n equals 0; m equals 2; each of R1 radicals independently on each other stands for hydrogen atom; C1-6alkyl; R2a stands for cyanogroup; X1 stands for -NR1-; R3 represents C2-6alkenyl, substituted with cyanogroup; R4 stands for C1-6alkyl; R5 represents radical of formula -Y-Alk-L, -Alk'-Y-L or -Alk'-Y-Alk-L; each of radicals Alk or Alk' independently represents bivalent C1-6alkyl or C2-6 alkenyl group; L stands for aryl or Het; Y stands for NR1; -CH=N-O-; Het stands for 5- or 6-member fully saturated ring system, in which one, two or three ring elements represent heteroatoms, each of which is independently selected from group, including nitrogen, oxygen and sulphur, and in which other ring elements represent carbon atoms; and, if possible, any nitrogen ring element can be optionally substituted with C1-6alkyl; and ring system can be optionally bound with benzene ring; and in which any carbon atom of ring, including any carbon atom of optionally bound benzene ring, each independently can be substituted with substituent selected from such groups as halogen atom, C1-6alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, C1-4 alkylcarbonyloxyC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aryloxy, morpholinyl, aryl, Het1; Het1 stands for thienyl, isoxazolyl, thiadiazolyl, each of which can be optionally substituted with one or two C1-4alkyl radicals; Q stands for hydrogen atom; each aryl represents phenyl or phenyl, substituted with one, two substituents, each of which is independently selected from such groups as halogen atom, C1-6alkyl, C2-6alkinyl, cyano, polyhalogen C1-6alkyl or Het1, as well as to its pharmaceutically acceptable additive salts Invention also relates to pharmaceutical composition.

EFFECT: creation of novel compounds, which possess properties inhibiting HIV replication

5 cl, 7 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which have anti HIV-1 activity, of general formula (I) , where X stands for NH, as well as their pharmaceutically acceptable additive salt. Invention also relates to pharmaceutical composition, method of obtaining pharmaceutical composition and method of obtaining compound.

EFFECT: novel compounds possessing anti-HIV-1 activity.

5 cl, 7 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-substituted pyrimidines of general formula (I), their pharmaceutically acceptable additive salts probably in form of their stereochemically isomeric form. In general formula (I), A represents -CH2-CH2-, -CH=CH-; each of R1 independently represents hydrogen; R2 represents cyano; X1 represents -NR1-; R3 represents H, C1-6-alkyl, halogen; R4 represents H, C1-6-alkyl, halogen; R5 represents nitro, amino, mono- and di(C1-4-alkyl)amino, phenyl, probably substituted by halogen, halogen, -CO-H-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 represents C1-4-alkyl, amino, mono- or di(C1-4-alkyl)amino or polyhalogen-C1-6-alkyl; R7represents hydrogen, C1-6-alkyl; R8 represents hydrogen, C1-6-alkyl. Invention also relates to pharmaceutical composition based on novel compounds.

EFFECT: elaborated are compounds which possess antiviral activity with respect to HIV infection.

7 cl, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds described by general formulas specified below, in the free form as pharmaceutically acceptable salts possessing anticancer activity and may be applicable in medical practice as a therapeutic agent for treating cancer. The compounds under the present invention are described by one of structure formulas: or wherein Ar represents Ph or 4-NO2-C6H4.

EFFECT: presented compounds enable reducing or eliminating completely tumour cell growth by disturbing cell division at the level of enzyme inhibition.

1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

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