Pharmaceutical compositions and derivatives of triazine

 

(57) Abstract:

The invention relates to pharmaceutical compositions containing as active ingredient a derivative of triazine following General formula I or its MES, or its salt and a derivative of triazine. In the above formula, R1and R2may be the same or different and each represents hydrogen, unsubstituted or substituted alkyl, aralkyl, or alkenyl, or together, in combination with the adjacent nitrogen atom, represent a cyclic amino group NR1R2. The cyclic amino group may contain as atom rings, in addition to the neighboring N atom, a nitrogen, oxygen or sulfur, and may also be substituted. Excluded the case when NR1R2represents NH2. Compounds of the invention are suitable as drugs against hepatitis, expand the Arsenal of drugs against hepatitis and has a low toxicity to warm-blooded animals. 2 s and 5 C.p. f-crystals, 1 Il., table 2.

The technical field to which the invention relates

The invention relates to triazine derivative, useful as pharmaceuticals.

Prerequisites create Isabey hepatitis and so on), toxic hepatitis (e.g., caused by drugs) and autoimmune hepatitis.

Among these types of hepatitis are hepatitis, which often corresponds to a sub-chronic-chronic (acute hepatitis C), and refractory hepatitis, characterized by recurrent episodes of acute exacerbation and development, to cirrhosis (chronic hepatitis B). There is also hepatitis, which occurs rapidly, i.e., fulminant hepatitis.

Hepatitis treatment includes, in addition to General therapy to stimulate mechanism of treatment based on rest and diet, antiviral treatment, which is carried out to inhibit the growth of pathogenic virus in cases of viral hepatitis, and immunotherapy to enhance compromised cellular immunity of the host. Affordable medicines to treat liver, among others, are liver hydrolysate, glycyrrhizin (qlycyrrhizin) restored glutathione, tiopronin and patientclinician. As antiviral medicines are interferons, arabinogalactan (Ara-A), arabinosylcytosine (Ara-AMP), acyclovir, etc., as immunoregulators used glucocorticoids, interleukin-2, p is the logical action. It is known that prostaglandin E has cytotoxity action, and it is expected that it will be suitable for protection of liver cells. It is known that in addition to the aforementioned drugs, human epidermal growth factor (hEGF) and human hepatocytes growth factor (hHGF) have activity, reinforcing cytogenes, and believe that their clinical use as factors that enhance the recovery of the liver, is a promising, but they are still at the stage of pre-clinical studies.

Recently, for the treatment and prevention of hepatitis B vaccine is recommended therapy.

However, there is still no satisfactory available drugs for the treatment of hepatitis, as there is a continuous need in the creation of medicines, is effective for preventing the spread of necrosis and enhanced recovery of hepatocytes.

It is known that irsogladine (maleate 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine), which is a derivative of benzoguanamine, on structure similar to the compounds of the present invention, and such a connection, in which position 2 and 5 of the phenyl component of benzoguanamine esteem and is suitable for the treatment of hepatitis (see WO 91/01733, Japanese Kokai Tokkyo Koho S58-55423). Similarly, derivatives, containing 2,5-dichloraniline group, but having piperidino or morpholinopropan instead of one of the above amino groups, namely 2-amino-4-(2,5-dichlorophenyl)-6-piperidino-1,3,5-triazine and 2-amino-4-(2,5-dichlorophenyl)-6-morpholino-1,3,5-triazine, also known as intermediate compounds for obtaining anti-allergic derivatives of nicotinereplacement (Japanese Kokai Tokkyo Koho S57-203083 and S59-104320). Meanwhile, there are a host of known compounds corresponding to benzoguanamine, phenyl group which is either unsubstituted or halogenated, and one amino group which is substituted. As an example, compounds containing acyclic group, substitute one of the above amino groups, may be mentioned 2-amino-4-(2-hydroxyethylamino)-6-phenyl-1,3,5-triazine. As reported, this compound is suitable as the starting material for obtaining the resin (CA 106:34062). It is known that as the compound containing cyclic amino group, 2-amino-4-(4-methyl-piperazine-1-yl)-6-phenyl-1,3,5-triazine has analgesic action (CA 84:135722). However, the connection corresponding to benzoguanamine, in which both 2-and 5-position of the phenyl group substituted by chlorine is in which one of the amino groups substituted or piperidino-, or morpholinopropan.

Description of the invention

The present invention aims triazine derivative having a new structure and low toxicity, demonstrating efficacy in hepatitis, and suitable pharmaceutical composition comprising the aforementioned derivative as an active ingredient.

To achieve the above purpose, the authors present invention synthesized and explored various new by building connections and found that when compared with irsogladine, namely maleate 2,4-diamino-[6-(2,5-dichlorophenyl)-1,3,5-triazine] , which is described in Japanese Kokai Tokio Koho S58-55423 and in WO 91/01733 mentioned above, the compounds of the following General formula [I] find significantly superior protivogerpetical and inhibitory hepatic oncogenesis activity in mammals with low toxicity and, therefore, suitable as therapeutic agents against hepatitis. The present invention is made on the basis of the above findings.

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The present invention relates, in its first aspect, pharmaceutical compositions containing the compound of the above General formula [I] or its MES, or its salt, in the quality of salt.

In the above General formula, R1and R2may be the same or different and each represents hydrogen, unsubstituted or substituted alkyl, aralkyl, aralkyl or aryl, or R1and R2in conjunction and together with the adjacent N atom represent a 4-to 8-membered cyclic amino group such as a group of the formula NR1R2. The cyclic amino group may contain as atom rings, in addition to the above-mentioned N atom, a nitrogen, oxygen or sulfur, and may also be substituted.

The structural feature of this connection is that both 2-and 5-position of the phenyl group of benzoguanamine substituted by chlorine, and one of the amino groups of guanabana is free, and the other amino group is substituted.

The compound of the above General formula [I] is a new connection, never previously described, with the exception of compounds in which R1and R2are hydrogen, and compounds in which NR1R2are piperidino or metroliner. Such compounds are known compounds, and therefore they are not included in claims of the present invention to connect. However zamechatelnaya in the scope of claims of the present invention the composition.

Further, the present invention is described in detail.

Alkyl for R1and R2may be linear or branched and contain from 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, isononyl, n-decyl and Isodecyl. Preferred are alkyl (C1-4-group. The alkyl may be substituted by 1-3 substituents, either identical or different, such as groups that are selected from the group consisting of hydroxy-group, alkoxygroup, amino, monoalkylamines, dialkylamines, killingray, cyclic amino group, carboxypropyl, carbamoyl, alloctype and Kolocep. Especially preferred is a hydroxyl group. When the Deputy has the aryl group, the latter can be substituted C1-4the alkyl or alkoxygroup.

Substituted alkyl includes, but is not limited to, the following groups.

Examples of hydroxyalkyl are 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyphenyl, 6-hydroxyhexyl, 7-hydro is xalkida may be linear or branched and contain from 1-4 carbon atoms, as, for example, a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, etc. Specifically, alkoxyalkyl is a 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 4-methoxybutyl, 3-methoxybutyl, 5-methoxyphenyl, 6-atoxigenic, 7-ethoxyethyl, 8-ethoxyethyl, 9-propoxyphenyl and 10-propoxymethyl.

Aminoalkyl includes 2-amino-ethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 3-aminobutyl, 5-aminopentyl, 6-aminohexyl, 7-aminoethyl, 8-aminoacetyl, 9-aminanani and 10-aminocell.

Monoalkylamines includes 2-methylaminomethyl, 3-methylaminopropyl, 4-methylaminomethyl, 3-ethylaminomethyl, 3-ethylaminomethyl, 5-ethylaminomethyl, 6-acylaminoacyl, 7-propylaminoethyl, 8-propylaminoethyl, 9-butylaminoethyl and 10-butylaminoethyl.

Dialkylaminoalkyl includes 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 4-(N,N-dimethylamino)butyl, 3-(N,N-diethylamino)propyl, 3-(N,N-diethylamino)butyl, 5-(N, N-diethylamino)pentyl, 6-(N,N-diethylamino)hexyl, 7-(N, N-dipropylamino)hekel, 8-(N,N-dipropylamino)octyl, 9-(N,N-dibutylamino)nonyl and 10-(N,N-dibutylamino)decyl.

Arylamine group alluminare includes, among others, the an is certain cyclic group, mentioned above for NR1R2. Especially preferred are piperidinium, piperazinil and morpholinopropan. The cyclic amino group may be substituted C7-13aralkyl.

Carboxylic includes 1-carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxypropyl, 4-carboxybutyl, 3-carboxybutyl, 5-carboxypentyl, 6-carboxyethyl, 7-carboxyethyl, 8-carboxyethyl, 9-carboxyvinyl and 10-carboxymethyl.

Carbamoylethyl includes 1-carbamoylmethyl, 2-carbamoylethyl, 3-carbamoylmethyl, 2-carbamoylethyl, 4-carbamoylethyl, 3-carbamoylmethyl, 5-carbamoylmethyl, 6-carbamoylethyl, 7-carbamoylethyl, 8-carbamoylethyl, 9-carbamoylethyl and 10-carbamoylmethyl.

Aryl group aryloxyalkyl include C6-13-aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and biphenyl. Particularly preferred phenyl.

Arolina group urologically includes C7-10groups, such as, among others, benzoyl and nicotinoyl. Especially preferred is benzoyl.

Aralkyl includes C7-14groups such as benzyl, phenethyl, phenylpropyl, phenylbutyl and diphenylmethyl.

Aralkyl includes C7-10groups, such as, among others, cinami is but preferred is phenyl.

As for the above-mentioned substituents, aryl group, the aryl group may be substituted by 1-3-alkilani or alkoxygroup, either the same or different, and each contains 1-4 carbon atoms.

NR1R24-8-membered cyclic amino group includes, among others, azetidin-1-yl, pyrrolidin-1-yl, 3-pyrrolidin-1-yl, piperidino, hexamethyleneimino, octahydrate-1-yl, piperazine-1-yl, homopiperazin-1-yl, morpholinopropan and thiomorpholine. Preferred are 5 - or 6-membered cyclic amino group. Especially preferred are pyrrolidin-1-yl, piperidino or morpholinopropan. The cyclic amino group may be substituted by 1-4 substituents selected from the group consisting of hydroxyl, carbonyl group, carboxypropyl, alkyl, hydroxyalkyl, aryloxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonamides, alkylsulfonyl, alkylsulfanyl, aryl, aralkyl, 2-pyrimidinyl and cyclic amino groups. Alkyl such Deputy may be any of the above-mentioned linear or branched alkyl groups containing 1-4 carbon atoms. Aryl such Deputy may imagine what alkoxygroup. Especially preferred substituents for the cyclic amino group NR1R2are hydroxyl groups, hydroxyalkyl, oxoprop, the amino and alkyl.

The salt of compound [I], which is covered by the scope of the invention includes salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and Hydrobromic acid, and salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, toluensulfonate acid, naphthalenesulfonate acid and camphorsulfonic acid.

The compound [I] of the present invention can be obtained, for example, in the following way.

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Thus, the compound [I] can be obtained by reacting halogenating derivative [II] (where X represents chlorine or fluorine) with the amine [III] in the presence of a base, in an inert reaction solvent, at a temperature of 0-200oC, preferably 25-100oC. the Solvent which can be used for telharmonic (DMF), ethers, such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, grimy, such as methylcellosolve and dimethyl ether of ethylene glycol, halogenated hydrocarbons such as methylene chloride and chloroform, hydrocarbons, such as benzene, toluene and xylene, and mixtures of such solvents. The base, which can be used is an inorganic bases, such as carbonates of alkali metals (e.g. potassium carbonate, sodium carbonate), bicarbonates of alkali metals (e.g. potassium bicarbonate, sodium bicarbonate), and hydroxides of alkali metals (e.g. potassium hydroxide, sodium hydroxide), and organic bases such as triethylamine and pyridine. Instead of Foundation can be used an excess of amine (HNR1R2).

The reaction time depends on the type of the parent compounds, base and solvent used, but generally may vary from several minutes to 24 hours.

The number of amine [III] is at least equimolar, preferably is 1-1,2 molar equivalent per mole [II] . The amount of base is at least equimolar, preferably 1-2 Japanese Kokai Tokkyo Koho S51-70781). The compound [III] may be available commercially or can be synthesized in the usual way, as mentioned here in reference examples.

In addition, some of the compounds [I] contain one or more asymmetric carbon atoms and can therefore exist in optically active forms, and related isomers and their derivatives mixture also included in the scope of the present invention.

The above-mentioned optically active compounds can be optically separated from the mixtures by known methods, for example using chiral column or by using a chiral acid (e.g. tartaric acid, dibenzoyltartaric, almond acid, 10-camphorsulfonic acid), taking advantage of their basicity. On the other hand, optically active compounds can be obtained by using as starting compound previously obtained optically active compound [III].

The compound [I] of the present invention can be processed directly in a known manner with the formation of any of the aforementioned salts. For example, the hydrochloride of compound [I] can be obtained by dissolving compound [I] in ethanol solution of hydrogen chloride.

Easino in salt in a known manner. Salt, about which we are concerned include the salts of alkali metals such as sodium and potassium salts, and salts of alkaline earth metals such as calcium salt. Alkali metal salts of the compounds [I] can be obtained by adding one equivalent of sodium hydroxide, potassium hydroxide or hydroxide such to contain the carboxyl group of the compound [I] of the invention, preferably in an alcohol solution. Salt of alkaline earth metal compounds [I] of the invention can be obtained by dissolving the above-mentioned alkali metal salt in water, methanol, ethanol or their mixtures, for example with the subsequent addition of one equivalent, such as calcium chloride.

MES (including, Gerad) compounds [I] or its salt of the present invention, also included in the scope of the present invention. MES, in General, can be obtained by recrystallization of the compound from a suitable solvent or a suitable mixed solvent containing the appropriate solvent. For example, a hydrate of the compound [I] of the present invention can be obtained by recrystallization of compound [I] from aqueous alcohol.

The compound [I] of the invention can exhibit Chris is thus Obtained the desired compound [I] can be isolated and purified, in fact, well-known methods, such as concentration, bringing pH, phase transfer, solvent extraction, crystallization, fractional distillation and chromatography.

The compound of the present invention is suitable as a therapeutic drug against hepatitis.

For use as a drug compound of the present invention is administered in the form in which it exists, or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% pure, preferably 0.5 to 90%, of compounds in pharmaceutically acceptable non-toxic inert carrier.

As the carrier may use one or more solid, semi-solid or liquid diluents, fillers and other auxiliary components of the compositions. The pharmaceutical composition is administered, preferably in the form of standard dosage forms. The pharmaceutical composition of the present invention may be administered orally, parenterally, topically (e.g., transdermal or rectal. Of course, should be selected dosage forms suitable for the appropriate route of administration. Especially preferred is oral administration.

The dosage of the other features of the patient, the method of administration, nature and severity of the disease, and so on, As a rule, however, the daily oral dosage for adults can be, in General, from 100 μg to 100 mg per patient, preferably from 500 μg to 30 mg per patient. In some cases, satisfactory can be lower doses, while other cases may require a higher dose. The above dosage may be administered, if necessary, in the form of 2-3 separate doses.

Oral administration can be carried out using solid or liquid dosage forms, such as mass powders, powders, tablets, coated tablets, capsules, granules, suspensions, solutions, syrups, drops and tablets under the tongue.

Mass powders can be produced by grinding the active powder to finely divided form. Powders can be produced by grinding the active substance to a finely divided state with the following mix it with shredded to such a state pharmaceutical carrier such as an edible carbohydrate, such as starch or mannitol. If necessary, also added corrigent, preservative, dispersant, colorant, flavoring, etc.

Capsulae, described for the case of tablets, capsule shells, such as a gelatin capsule shell. Before the operation of filling with powders can be mixed lubrication or pseudoviruses additives, such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol. Enhancing efficacy of a drug after administration can be achieved by adding a disintegrator or a solubilizer, such as carboxymethylcellulose, calcixerollic, hydroxypropylcellulose with a low degree of substitution, nitrocresols (croscarmellose sodium), nitrocarburization, calcium carbonate or sodium carbonate.

Soft capsules can be produced by suspension mentioned finely ground powders in vegetable oil, polyethylene glycol, glycerin or a surface-active substance and wraps suspension layers of gelatin. Tablets can be manufactured by adding excipient in the above-mentioned powders, granulation or clumping of the mixture, add disintegrator or lubricating agent and pressing the whole composition. A powder mixture may be prepared by mixing the aforementioned finely ground is carboxymethylcellulose, methylcellulose, hypromellose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.,), the moderator of dissolution (e.g., paraffin), reabsorbed (for example, Quaternary salts) and the adsorbent (for example, bentonite, kaolin, dicalcium phosphate and so on ). Powdery mixture can be processed into granules by wetting her binder such as syrup, starch paste, Arabian gum, a solution of cellulose or a solution of high-molecular substances, mixing, drying and spraying. Instead of granulation such powders can be pressed powders on teletrauma machine and granulating the resulting piece of raw form. The resulting granules can be protected from adhesion by adding a lubricant, such as stearic acid, a salt of stearic acid, mineral oil, or similar substances. Greased so the mixture is then pressed. On the resulting tablets without coating can be applied a coating of film-forming compositions or compositions containing sugar.

The drug can be mixed freely with the current inert carrier, and the mixture can presenti transparent or translucent protective coating, consisting, for example, from a pressurized film of shellac, sugar or film of the polymer, or a smooth coating of wax. Other oral composition such as a solution, syrup, elixir, can also be obtained in a standard dosage forms, each of which contains a preset amount of medicinal substance. Syrups can be obtained by dissolving the compound in a suitable corrected aqueous solution, while elixirs can be made using non-toxic alcoholic media. Suspensions can be prepared by dispersing the compound in a non-toxic carriers. If necessary, can also be added soljubilizatory and emulsifying agents (e.g. ethoxylated isostearoyl alcohol, ester of polyoxyethylenesorbitan and etc.), preservatives and corrigentov (e.g. mint oil, saccharin, etc).

When necessary, the standard dosage form for oral administration may be microencapsulated. Such a composition can be coated or encased in a polymer, wax or other matrix to get the dosage form with prolonged action or dosage forms with delayed release.

Prekonej, intramuscular or intravenous injection, for example, solutions and suspensions. Such a standard dosage forms can be manufactured by suspension or dissolution of a predetermined number of connections suitable for injection of non-toxic liquid carrier, for example in aqueous medium or in an oil medium, and sterilizing the resulting suspension or solution. To give isotonicity you can add a non-toxic salt or salt solution. In addition, can also be added stabilizers, preservatives, emulsifiers, etc.

Rectal administration can be accomplished with the use of suppositories made by dissolution or suspension of the compounds in low-melting water-soluble or water-insoluble solid carrier, such as polietilenglikol, cocoa butter, semi-synthetic oil (e.g., Witpsol), higher esters (for example, ministervalletta), or their mixtures.

The best way of carrying out the invention

The following examples and test examples relating to some representatives of the compounds of the invention are intended for a more detailed description of the present invention and not on the Sabbath.-hydroxy-L-prolinol

In 30 ml of dry THF suspended of 1.57 g of lithium aluminum hydride, and cooling the solution to -10oC. To this solution dropwise at a temperature in the range -10oC to -5oC, add a solution of methyl ester of TRANS-4-hydroxy-L-Proline (3.00 g) in THF (10 ml). The mixture is stirred at room temperature for 2 hours and then refluxed for 30 minutes. To this reaction mixture are added ethyl acetate and aqueous THF, and the mixture is filtered. Insoluble matter was washed with THF, and the filtrate concentrated under reduced pressure, and obtain 2.0 g of a yellow oil.

Reference example 2

Synthesis of 3-hydroxymethylation

In the reducing medium pressure apparatus with a capacity of 300 ml of a suspension of 1-diphenylmethyl-3-hydroxymethylation (8.00 g) and 5% Pd/C (2.50 g) in methanol (80 ml) is treated with gaseous hydrogen at a pressure of 5.1 kg/cm2and 50oC for 15 hours. This reaction mixture is filtered, and the separated Pd/C, thoroughly washed with methanol. The filtrate and the wash methanol are combined and concentrated under reduced pressure. The residue is diluted with 30 ml n-hexane and thoroughly stirred, decanted the supernatant and obtain 2.85 g of crude 3-hydroxymethylation.

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Reference example 3

Synthesis of 3-methanesulfonylaminoethyl

(Stage 1)

To a suspension of 3-amino-1-benzylpyrrolidine (7,00 g) and potassium carbonate (6,04 g) in THF (100 ml) under stirring at room temperature gradually, drop by drop, add a solution of methanesulfonamide (of 5.00 g) in THF (40 ml), and the mixture is stirred at room temperature for 20 hours. This reaction mixture was concentrated under reduced pressure, and the residue suspended in ethyl acetate. This suspension was washed with water and saturated aqueous NaCl solution, dehydrated over anhydrous magnesium sulfate (MgSO4) and concentrate. The remaining crude product is purified column chromatography (C-200/trademark; CHCl3---> CHCl3:MeOH = 30:1), and receive 10,10 g of 1-benzyl-(3-methanesulfonamido)pyrrolidine in the form of a light brown oil.

(Phase 2)

300 ml of the reducing apparatus of the average pressure of preparing a suspension comprising of 10.00 g of the above-mentioned compounds of 2.00 g of 5% Pd/C, 50 ml of methanol and 10 ml of acetic acid, and treated her with gaseous hydrogen at 5,1 kg/cm3and the 40oC for 15 hours. This reaction mixture is further treated as in reference example 2, and get 9,20 g 3-methanesulfonylaminoethyl a mixture of diethanolamine (9.2 grams), N,N-dimethylformamide (200 ml) and anhydrous potassium carbonate (15 g) under stirring at room temperature, add 20 g of 2-amino-4-chloro-6-(2,5-dichlorophenyl)-1,3,5-triazine, and the mixture is stirred at room temperature for 7 hours. This reaction mixture is diluted with 2 l (liters) of water and stirred for 1 hour. The resulting crystals are collected by filtration, washed with water and dried, to obtain 24 g of a white crystalline substance. This portion of the crystals are recrystallized from methanol, collecting the crystals by filtration and dried, and get 21 grams named the title compound as a white crystalline substance.

So pl. 199 - 200oC.

Elemental analysis for C13H15Cl2N5O2< / BR>
Calculated (percent): C - 45,36; H - 4,39; N - 20,35

Found (Percent): C - 45,58; H - 4,33; N - 20,46.

Example 2

2-Amino-4-(2,5-dichlorophenyl)-6-methylamino-1,3,5-triazine

Using methylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 205 - 206oC.

Elemental analysis for C10H9Cl2N5< / BR>
Calculated (Percent): C - 44,47; H - 3,36; N - 25,93.

Found (Percent): C - Of 44.24; H - 3,30; N - 25,70.

So pl. 178 - 179oC.

Elemental analysis for C11H11Cl2N5< / BR>
Calculated (Percent): C - 46,50; H - 3,90; N - 24,65.

Found (Percent): C - 46,45; H - To 3.73; N - 24,39.

Example 4

2-Amino-4-(2,5-dichlorophenyl)-6-(hydroxyethylamino)- 1,3,5-triazine

Using ethanolamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 198 - 199oC.

Elemental analysis for C11H11Cl2N5O

Calculated (Percent): C - 44,02; H At 3.69; N - 23,33.

Found (Percent): C - 43,82; H - Of 3.46; N - 23,01.

Example 5

2-Amino-4-(2,5-dichlorophenyl)-6-[N-methyl-N-(2-hydroxyethyl)-amino - 1,3,5-triazine

Using N-methyl-N-(2-hydroxyethyl)amine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 153 - 155oC.

Elemental analysis for C12H13Cl2N5O

Calculated (Percent): C - 45,88; H - 4,17; N - 22,29.

Found (Percent): C - 45,60; H - 4,06; N - 22,25.

Example 6

2-Amino-4-(2,5-dichlorophenyl)-6-(2-methoxyethylamine)- 1,3,5-triazine

Using 2-the head connection.

So pl. 195 - 197oC.

Elemental analysis for C12H13Cl2N5O

Calculated (Percent): C - 45,88; H - 4,17; N - 22,29.

Found (Percent): C - 45,72; H - 3,90; N - 22,12.

Example 7

2-Amino-4-(2,5-dichlorophenyl)-6-(8-diethylamino-1 octylamine)- 1,3,5-triazine

Using 8-diethylamino-1 octylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 101 - 102oC.

Elemental analysis for C21H32Cl2N6< / BR>
Calculated (Percent): C - 57,40; H - 7,34; N - 19,12.

Found (Percent): C - 57,16; H - Of 7.48; N - 18,92.

Example 8

2-Amino-4-benzylamino-6-(2,5-dichlorophenyl)-1,3,5-triazine

Using benzylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 200 - 201oC.

Elemental analysis for C16H13Cl2N5< / BR>
Calculated (Percent): C - 55,51; H - Of 3.78; N - On 20, 23.

Found (Percent): C - 55,78; H - 3,66; N - 20,07.

Example 9

2-Amino-4-(2,5-dichlorophenyl)-6-[4-(2-pyrimidyl)-piperazine-1-yl] - 1,3,5-triazine

Using 4-(2-pyrimidyl)piperazine instead of diethanolamine, carry out the same procedure as in example 1, and get NASCl2N8< / BR>
Calculated (Percent): C - 50,63; H - 4,00; N - 27,79.

Found (Percent): C - 50,48; H - 3,91; N - 27,92.

Example 10

2-Amino-4-(N-benzyl-N-methylamino)-6-(2,5-dichlorophenyl)- 1,3,5-triazine

Using N-methylbenzylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 163 - 164oC.

Elemental analysis for C17H15Cl2N5< / BR>
Calculated (Percent): C - 56,68; H - 4,20; N - 19,44.

Found (Percent): C - 56,81; H - 4,20; N - 19,47.

Example 11

2-Amino-4-(2,5-dichlorophenyl)-6-[2-(diethylamino)ethylamino]- 1,3,5-triazine

Using N, N-diethylethylenediamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 141 - 142oC.

Elemental analysis for C15H20Cl2N6< / BR>
Calculated (Percent): C - 50,71; H - 5,67; N - 23,65.

Found (Percent): C - 50,63; H - 5,64; N - 23,50.

Example 12

2-Amino-4-(2,5-dichlorophenyl)-6-phenethylamine-1,3,5-triazine

Using phenethylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 217 - 218oC.

Elemental Ana - 4,16; N - 19,58.

Example 13

2-Amino-4-(2,5-dichlorophenyl)-6-(2-phenoxyethylamine)- 1,3,5-triazine

Using 2-phenoxyethylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 172 - 173oC.

Elemental analysis for C17H15Cl2N5O

Calculated (Percent): C - 54,27; H - Was 4.02; N - 18,61.

Found (Percent): C - 54,45; H - 3,80; N - 18,68.

Example 14

2-Amino-4-aniline-6-(2,5-dichlorophenyl)-1,3,5-triazine

Using aniline instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 180 - 181oC.

Elemental analysis for C15H11Cl2N5< / BR>
Calculated (Percent): C - 54,24; H - 3,34; N - 21,08.

Found (Percent): C - 54,36; H - 3,41; N - To 21.15.

Example 15

2-Amino-4-[(carboxymethyl)amino]-6-(2,5-dichlorophenyl)-1,3,5 - triazine

Using glycine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 271 - 272oC (decomp.).

Elemental analysis for C11H9Cl2N5O2< / BR>
Calculated (Percent): C - 42,06; H - 2,89; N - 22,29.

Found (percent): C - 42 is enamelin instead of diethanolamine, perform the same procedure as in example 1, and get named in the header of the connection.

So pl. 198 - 199oC.

Elemental analysis for C18H15Cl2N5< / BR>
Calculated (Percent): C - 58,08; H - 4,06; N - 18,81.

Found (Percent): C - 58,21; H - 4,10; N - 18,90.

Example 17

2-Amino-4-(2-aminoethylamino)-6-(2,5-dichlorophenyl)-1,3,5-triazine

Using Ethylenediamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 152 - 153oC.

Elemental analysis for C11H12Cl2N6< / BR>
Calculated (Percent): C - 44,16; H - 4,04; N - 28,09.

Found (Percent): C - 44,11; H - 3,93; N - 28,06.

Example 18

Hydrochloride of 2-amino-4-(2-aminoethylamino)-6-(2,5-dichlorophenyl)-1,3,5-triazine

Using the compound synthesized in example 17, named the title compound was produced using the same procedure, which is described below in example 32 (stage 2).

So pl. 267 - 268oC (decomp.).

Elemental analysis for C11H12Cl2N6HCl

Calculated (Percent): C - 39,36; H - 3,90; N - 25,04.

Found (Percent): C - 39,04; H - 4,15; N - 24,96.

Example 19

2-Amino-4-(2,5-dichlorophenyl)-6-[8-(3,4,5-trimethoxybenzoate the same procedure in example 1, and get named in the header of the connection.

So pl. 72 - 73oC.

Elemental analysis for C27H33Cl2N5O5< / BR>
Calculated (Percent): C - 56,06; H - 5,75; N - 12,11.

Found (Percent): C - 56,09; H - 6,01; N - 12,01.

Example 20

2-Amino-4-(2,5-dichlorophenyl)-6-(2-piperidinoethyl)- 1,3,5-triazine

Using 2-piperidinoethyl instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 179 - 181oC.

Elemental analysis for C16H20Cl2N6< / BR>
Calculated (Percent): C - 52,32; H - 5,49; N - 22,88.

Found (Percent): C - 52,12; H - 5,32; N - 22,79.

Example 21

2-Amino-4-(2,5-dichlorophenyl)-6-[4-[2-(4-methylphenoxy)ethyl] - piperazine-1-yl]-1,3,5-triazine

Using N-[2-(4-methylphenoxy)] ethylpiperazine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 140 - 141oC.

Elemental analysis for C22H24Cl2N6O

Calculated (Percent): C - 57,52; H At 5.27; N - 18,29.

Found (Percent): C - 57,59; H At 5.27; N - 18,42.

Example 22

2-Amino-4-(2,5-dichlorophenyl)-6-[2-(N-phenylamino)ethylamino]- 1,3,5-triazine

named in the header of the connection.

So pl. 139 - 141oC.

Elemental analysis for C17H16Cl2N6< / BR>
Calculated (Percent): C - 54,41; H - 4,30; N - 22,40.

Found (Percent): C - 54,43; H - 4,27; N - 22,55.

Example 23

2-Amino-4-(2,5-dichlorophenyl)-6-[4-[2-(2-hydroxyethyl)piperazine - 1-yl] -1,3,5-triazine

Using N-(2-hydroxyethyl)piperazine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 185 - 187oC.

Elemental analysis for C15H18Cl2N6O

Calculated (Percent): C - 48,79; H - 4,91; N - 22,76.

Found (Percent): C - 48,63; H - 4,85; N - 22,74.

Example 24

2-Amino-4-(2,5-dichlorophenyl)-6-(2-morpholinoethyl)- 1,3,5-triazine

Using 2-(morpholino)ethylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 159 - 161oC.

Elemental analysis for C15H18Cl2N6O

Calculated (Percent): C - 48,79; H - 4,91; N - 22,76.

Found (Percent): C - 48,56; H - 4,87; N - 22,86.

Example 25

2-Amino-4-(2,5-dichlorophenyl)-6-[4-(diphenylmethyl)piperazine - 1-yl]-1,3,5-triazine

Using 1-diphenylbutylpiperidine instead of diethanolamine, carry out the same procedimenti analysis for C26H24Cl2N6< / BR>
Calculated (Percent): C - 63,55; H To 4.92; N - 17,10.

Found (Percent): C - 63,68; H - 4,95; N - 17,24.

Example 26

2-Amino-4-[2-(4-diphenylbutylpiperidine-1-yl)ethylamino] -6- (2,5-dichlorophenyl)-1,3,5-triazine

Using 2-(4-diphenylbutylpiperidine-1-yl)ethylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 192 - 193oC.

Elemental analysis for C28H29Cl2N71/2 H2O

Calculated (Percent): C - 61,88; H - 5,56; N - 18,03.

Found (Percent): C - 61,87; H - Of 5.68; N - 18,07.

Example 27

2-Amino-4-(2,5-dichlorophenyl)-6-diethylamino-1,3,5-triazine

Using hydrochloride diethylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 137 - 138oC.

Elemental analysis for C13H15Cl2N5< / BR>
Calculated (Percent): C - Repossessed A 50.01; H - 4,84; N - 22,43.

Found (Percent): C - 50,25; H - 4,75; N - 22,22.

Example 28

2-Amino-4-(2,5-dichlorophenyl)-6-diisopropylamino-1,3,5-triazine

Using Diisopropylamine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the title of the who/BR> Calculated (Percent): C - 52,95; H - 5,63; N - 20,58.

Found (Percent): C - 53,04; H - Of 5.53; N - 20,71.

Example 29

2-Amino-4-[(4-carbamoylmethyl)amino]-6-(2,5-dichlorophenyl)- 1,3,5-triazine

Using hydrochloride glycinamide instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 260 - 261oC.

Elemental analysis for C11H10Cl2N6O 1/4 H2O

Calculated (Percent): C - 41,59; H - To 3.33; N - 26,46.

Found (Percent): C - 41,98; H Is 3.40; N - 25,74.

Example 30

2-Amino-4-(2,5-dichlorophenyl)-6-pyrrolidino-1,3,5-triazine

Using pyrrolidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 191 - 193oC.

Elemental analysis for C13H13Cl2N5< / BR>
Calculated (Percent): C - 50,34; H - 4,22; N - 22,58.

Found (Percent): C - 50,35; H - 4,11; N - 22,53.

Example 31

Maleate 2-amino-4-(2,5-dichlorophenyl)-6-(3-hydroxy-1 - pyrrolidinyl)-1,3,5-triazine

(Stage 1). Using 3-hydroxypyrrolidine instead of diethylamine, carry out the same procedure as in example 1, and get to 7.3 g of free base named in the connection header.

(Stage will contentresult to about 1/5 of its original volume, and collect by filtration the resulting crystals. Get 6.4g named the title compound as light yellow crystals.

So pl. 192 - 194oC.

Elemental analysis for C13H13Cl2N5O C4H4O4< / BR>
Calculated (Percent): C - 47,17; H - A 3.87; N - 15,84.

Found (Percent): C - 46,05; H - 3,84; N - Of 15.75.

Example 32

Hydrochloride (S)-2-amino-4-(2,5-dichlorophenyl)-6-(2-hydroxy-1 - methyl-1-pyrrolidinyl)-1,3,5-triazine

(Stage 1). Using (S)-2-hydroxyethylpyrrolidine instead of diethylamine, carry out the same procedure as in example 1, and obtain 6.2 g of the free base named in the connection header.

(Stage 2). In 50 ml of methanol is dissolved to 5.1 g of compound obtained in stage 1, then, under cooling with ice, add 6 ml of 20% HCl-methanol. The mixture is concentrated to about 1/10 of its original volume, and is collected by filtration of the formed crystals. Obtain 2.6 g named the title compound as white crystals.

So pl. 143 - 145oC.

Elemental analysis for C14H15Cl2N5O HCl H2O

Calculated (Percent): C - 42,60; H - 4,60; N - 17,74.

Found (Percent): C - 42,34; H - Br4.61; N - 17,79.

Example 33

Hydrochlo irreligion instead of (S)-2-hydroxyethylpyrrolidine, perform the same procedure as in example 32, and get named in the header of the connection.

So pl. 140 - 143oC.

Elemental analysis for C14H15Cl2N5O HCl H2O

Calculated (Percent): C - 42,60; H - 4,60; N - 17,74.

Found (Percent): C - 42,63; H - 4,59; N - 17,86.

Example 34

2-Amino-4-(2,5-dichlorophenyl)-6-piperazine derivatives-1,3,5-triazine

Using piperazine instead of diethylamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 163 - 165oC.

Elemental analysis for C13H14Cl2N6< / BR>
Calculated (Percent): C - 48,01; H - 4,34; N - 25,84.

Found (Percent): C - 47,89; H - 4,21; N - 25,81.

Example 35

2-Amino-4-(2,5-dichlorophenyl)-6-(4-phenyl-1-piperazine-1-yl)- 1,3,5-triazine

Using N-phenylpiperazin instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 203 - 206oC.

Elemental analysis for C19H18Cl2N6< / BR>
Calculated (Percent): C - 56,87; H - To 4.52; N - 20,94.

Found (Percent): C - 56,77; H - 4,43; N - 20,85.

Example 36

2-Amino-4-(2,5-dichlorophenyl)-6-(4-hydroxy-1-piperidinyl)- 1,3,5-triazine

Using 4-hydroxypiperidine.

So pl. 222 - 224oC.

Elemental analysis for C14H15Cl2N5O

Calculated (Percent): C - 49,43; H - Of 4.44; N - 20,59.

Found (Percent): C - At 49.30; H - 4,53; N - 20,44.

Example 37

2-Amino-4-(2,5-dichlorophenyl)-6-(3-hydroxy-1-piperidinyl)- 1,3,5-triazine

Using 3-hydroxypiperidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 178 - 180oC.

Elemental analysis for C14H15Cl2N5O

Calculated (Percent): C - 49,43; H - Of 4.44; N - 20,59.

Found (Percent): C - 49,37; H Was 4.42; N - 20,57.

Example 38

2-Amino-4-(2,5-dichlorophenyl)-6-dimorpholino-1,3,5-triazine

Using thiomorpholine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 239 - 241oC.

Elemental analysis for C13H13Cl2N5S

Calculated (Percent): C - 45,62; H - 3,83; N - 20,46.

Found (Percent): C - 45,45; H - 3,66; N - 20,49.

Example 39

2-Amino-4-(2,5-dichlorophenyl)-6-(2,6-dimethyl-4-morpholinyl)- 1,3,5-triazine

Using 2,6-dimethylmorpholine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the title N5O

Calculated (Percent): C - 50,86; H - 4,84; N - 19,77.

Found (Percent): C - 50,62; H - 4,73; N - 19,99.

Example 40

2-Amino-4-(2,5-dichlorophenyl)-6-[4-[3-(4-methylphenoxy)propyl] - 1-piperazinil]-1,3,5-triazine

Using N-[3-(4-methylphenoxy)propyl] piperazine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 148 - 150oC.

Elemental analysis for C23H26Cl2N6O

Calculated (Percent): C - 58,36; H Is 5.54; N - 17,75.

Found (Percent): C - 58,14; H - 5,43; N - 17,82.

Example 41

2-Amino-4-(2,5-dichlorophenyl)-6-(3-pyrrolin-1-yl)-1,3,5-triazine

Using 3-pyrrolin instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 205 - 206oC.

Elemental analysis for C13H11Cl2N5< / BR>
Calculated (Percent): C - 50,67; H - 3,60; N - 22,73.

Found (Percent): C - 50,61; H Is 3.57; N - 22,69.

Example 42

2-Amino-4-(2,5-dichlorophenyl)-6-(3-oxo-1-piperazinil)- 1,3,5-triazine

Using 2-oxopiperidin instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. > 275oC.

E is (%): C - 45,86; H - TO 3.73; N - 24,60.

H-NMR (DMSO-d6) : 3,23 (2H, CL), with 3.89 (2H, CL), 4,20 (2H, s), 7,20 (2H, CL), 7,56 (2H, s), 7,73 (1H, s), 8,11 (1H, s).

Example 43

2-Amino-4-(4-benzyl-1-piperidinyl)-6-(2,5-dichlorophenyl)-1,3,5-triazine

Using 4-benzylpiperidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 159 - 161oC.

Elemental analysis for C21H21Cl2N5< / BR>
Calculated (Percent): C - 60,88; H - 5,11; N - 16,90.

Found (Percent): C - 60,74; H - 5,09; N - 16,97.

Example 44

2-Amino-4-(2,5-dichlorophenyl)-6-(hexamethyleneimino-1-yl)- 1,3,5-triazine

Using hexamethylenimine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 155 - 156oC.

Elemental analysis for C15H17Cl2N5< / BR>
Calculated (Percent): C - 53,27; H Is 5.07; N - 20,71.

Found (Percent): C - 53,17; H - 4,99; N - 20,66.

Example 45

2-Amino-4-(2,5-dichlorophenyl)-6-(2-methyl-1-piperidinyl)- 1,3,5-triazine

Using 2-methylpiperidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 136 - 137oC.

Example 46

2-Amino-4-(2-carboxy-4-hydroxy-1-pyrrolidinyl)-6- (2,5-dichlorophenyl)-1,3,5-triazine

Using 4-hydroxyproline instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So square 138 - 145oC.

Elemental analysis for C14H13Cl2N5O3H2O

Calculated (Percent): C - 43,32; H - To 3.89; N - 18,04.

Found (Percent): C - 43,63; H - 3,65; N - 18,17.

Example 47

2-Amino-4-(2,5-dichlorophenyl)-6-(2-hydroxymethyl-4-hikkoshi - 1-pyrrolidinyl)-1,3,5-triazine

Using 2-hydroxymethyl-4-hydroxypyrrolidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the title compound as a white powder.

Elemental analysis for C14H15Cl2N5O21/2 EtOH 1/2H2O

Calculated (Percent): C - 46,40; H - Is 4.93; N - 18,04.

Found (Percent): C - 46,36; H - 4,80; N - 18,24.

H-NMR (CDCl3) : 1,7 - 2,0 (1H, m), from 2.1 to 2.25 (1H, m) to 2.67 (1H, CL), 3,4 - of 3.85 (3H, m), 3.95 to of 4.25 (1H, m), 4,35 - 4,55 (2H, m), of 5.53 (2H, d, J = 11 Hz), 7,25 to 7.4 (2H, m), the 7.65 (1H, d, J = 19 Hz).

Example 48

Hydrochloride of 2-amino-4-(2,5-dichlorophenyl)-6- (3-hydroxymethyl-1-pyrrolidinyl)-1,3,5-triazine

Using 3-gsena in the connection, perform the same procedure as in example 32 (stage 2), and get named in the header of the connection.

So pl. 241 - 243oC.

Elemental analysis for C14H15Cl2N5O HCl

Calculated (Percent): C - 44,64; H - 4,28; N - 18,59.

Found (Percent): C - 44,47; H - 4,34; N - 18,68.

Example 49

2-Amino-4-(2,5-dichlorophenyl)-6-(4-methanesulfonyl-1-piperazinil)- 1,3,5-triazine

Using 1-methanesulfonylaminoethyl instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 184 - 186oC.

Elemental analysis for C14H16Cl2N6O2S

Calculated (Percent): C - 41,70; H - 4,00; N - 20,84.

Found (Percent): C - 41,59; H - 3,85; N - To 20.91.

Example 50

(S)-2-Amino-4-(2-carboxy-1-pyrrolidino)-6- (2,5-dichlorophenyl)-1,3,5-triazine

Using (S)-Proline instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 144 - 147oC.

Elemental analysis for C14H13Cl2N5O2< / BR>
Calculated (Percent): C - 47,47; H - 3,70; N - 19,77.

Found (Percent): C - 47,59; H - 3,88; N - 19,77.

Example 51

2-Amino-4-(2,5-dichlorophenyl)-6-(3-methanol is, syshestvyut the same procedure as in example 1, and get named in the header of the connection.

So pl. 102 - 107oC.

Elemental analysis for C14H16Cl2N6O2S 1/2CH3OH 1/2CHCl3< / BR>
Calculated (Percent): C - 39,44; H - 3,98; N - 18,71.

Found (Percent): C - 39,77; H - 3,90; N - 18,77.

Example 52

2-Amino-4-(2,5-dichlorophenyl)-6-(3-hydroxy-1-azetidine)- 1,3,5-triazine

Using 3-hydroxyazetidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 256 - 257oC.

Elemental analysis for C12H11Cl2N5O

Calculated (Percent): C - 46,17; H - 3,55; N Of 22.44.

Found (Percent): C - 45,93; H - 3,48; N - 22,03.

Example 53

2-Amino-4-(2,5-dichlorophenyl)-6-(3-hydroxymethyl-1-azetidine)- 1,3,5-triazine

Using 3-hydroxymethylation instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 224 - 226oC.

Elemental analysis for C13H13Cl2N5O

Calculated (Percent): C - 47,87; H - Was 4.02; N - 21,47.

Found (Percent): C - 47,67; H - 3,88; N - To 21.15.

Example 54

2-Amino-4-(2-carboxy-1-piperidinyl)-6-procedure, in example 1, and get named in the header of the connection.

So pl. 237 - 240oC.

Elemental analysis for C15H15Cl2N5O2< / BR>
Calculated (Percent): C - 48,93; H - 4,11; N - 19,02.

Found (Percent): C - 48,58; H - 4,19; N - 18,79.

Example 55

2-Amino-4-(2,5-dichlorophenyl)-6-(4-hydroxy-4-phenyl-1 - piperidinyl)-1,3,5-triazine

Using 4-hydroxy-4-phenylpiperidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 176 - 178oC.

Elemental analysis for C20H19Cl2N5O

Calculated (Percent): C - 57,70; H - 4,60; N - 16,82.

Found (Percent): C - 57,54; H - 4,58; N - 16,76.

Example 56

2-Amino-4-(2,5-dichlorophenyl)-6-(4-oxo-1-piperidinyl)- 1,3,5-triazine

Using 4-oxopiperidin instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 223 - 225oC.

Example 57

2-Amino-4-(2,5-dichlorophenyl)-6-(4-hydroxymethyl-1 - piperidinyl)-1,3,5-triazine

Using 4-hydroxyethylpiperazine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So 0,86; H - 4,84; N - 19,77.

Found (Percent): C - 50,79; H - 4,80; N - To 19.74.

Example 58

2-Amino-4-(2,5-dichlorophenyl)-6-(1-Osotimehin-4-yl)- 1,3,5-triazine

In 150 ml of acetic acid was dissolved 2.0 g of the compound synthesized in example 38. To this solution is added dropwise, while cooling with ice, add 1.3 ml of 30% aqueous hydrogen peroxide solution, and the mixture is stirred at the same temperature for 3 hours. Excess peroxide is decomposed with an aqueous solution of sodium sulfite, and the mixture concentrated. The precipitated crystals are collected by filtration, washed with water and dried, to obtain 1.86 g named the title compound as white crystals.

So pl. 267 - 269oC.

Elemental analysis for C13H13Cl2N5OS

Calculated (Percent): C - 43,58; H - 3,66; N - 19,55.

Found (Percent): C - 43,21; H - To 3.58; N - 19,24.

Example 59

2-Amino-4-(2,5-dichlorophenyl)-6-(1,1-diocletianopolis-4-yl)- 1,3,5-triazine

In 150 ml of acetic acid was dissolved 2.0 g of the compound synthesized in example 38. To this solution is added dropwise, while cooling with ice, add 2.5 ml of 30% aqueous hydrogen peroxide solution, and the mixture was stirred at 50oC for 6 hours. The precipitated crystals are collected by filtration, washed with SUP>C.

Elemental analysis for C13H13Cl2N5O2S

Calculated (Percent): C - 41,72; H - 3,50; N - 18,71.

Found (Percent): C - 41,80; H - 3,50; N - 18,67.

H-NMR (DMSO-d6) : 3,1 - of 3.25 (2H, m), 4,1 - of 4.25 (2H, m), a 7.2 to 7.35 (2H, CL), 7,56 (2H, s), 7,73 to 7.75 (1H, m).

Example 60

1.5-Dideoxy-1,5- [[2-amino-4-(2,5-dichlorophenyl)-1,3,5-triazine-6-yl] imino-D-glucit

Using 1.5-dideoxy-1,5-imino-D-glucit instead of diethanolamine, carry out the same procedure as in example 1, and get named in the title compound as a white powder.

Elemental analysis for C15H17Cl2N5O41/2C2H5OH 3/10H2O

Calculated (Percent): C - 44,62; H - 4,82; N - 16,26.

Found (Percent): C - 44,65; H - 4,99; N - 16,32.

H-NMR (DMSO-d6) : 3,29 - to 3.38 (1H, m), 3,49 - of 3.54 (1H, m), to 3.58 - 3,66 (2H, m), 3,74 - 3,82 (2H, m), 4,45 - of 4.57 (2H, m), of 4.67 (1H, t, J = 5 Hz), 4,89 - 4,96 (2H, m), 5,19 - to 5.21 (1H, m), 6,85 - 7,05 (2H, CL), 7,53 - 7,58 (2H, m), 7,69 - of 7.70 (1H, m).

Example 61

2-Amino-4-(2,5-dichlorophenyl)-6-(1-azetidine)-1,3,5-triazine

Using azetidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 207 - 208oC.

Elemental analysis for C12H11Cl2N5< / BR>
the ID 2-amino-4-(2,5-dichlorophenyl)-6-(3-aminomethyl-1-pyrrolidinyl)- 1,3,5-triazine

Using 3-(tert-butoxycarbonylamino)pyrrolidin instead of diethylamine, carry out the same procedure as in example 1. The resulting compound (6.3 g) was dissolved in 60 ml of methanol, with stirring and ice cooling, add 20 ml of 30% HCl in CH3OH, and then stirred the mixture for 2 hours. The resulting crystals are collected by filtration, and get 4,18 g named in the connection header.

So pl. > 275.

Elemental analysis for C14H16Cl2N62HCl 2H2O

Calculated (Percent): C - 37,52; H - 4,95; N - 18,75.

Found (Percent): C - 37,60; H - 4,96; N - 18,93.

H-NMR (DMSO-d6) : 1,7 - of 1.95 (1H, m), 2,05 - 2,3 (1H, m), 2,5 - 2,8 (1H, m), of 2.92 (2H, CL), of 3.25 to 3.45 (1H, m), 3.45 points - of 3.65 (1H, m), 3,65 to 4.0 (2H, m), 7,68 (2H, s), 7,83 (1H, s), 8,31 (3H, CL).

Example 63

Hydrochloride of 2-amino-4-(2,5-dichlorophenyl)-6-(3-methanesulfonyl - aminomethyl-1-pyrrolidin)-1,3,5-triazine

In 40 ml of THF was dissolved 2.1 g of the free base, obtained by neutralizing the compound of example 62, then add to 0.94 g of potassium carbonate and 0.78 g of methanesulfonamide. The mixture reacts at room temperature for 20 hours. THF is removed by concentration and the residue diluted with water and extracted with chloroform. Extract polanie CHCl3: MeOH = 19:1), the resulting oil is treated in the same manner as in example 32 (stage 2). Get named in the header of the connection.

So pl. 220 - 230oC.

Elemental analysis for C15H18Cl2N6O2S HCl 1/2H2O

Calculated (Percent): C - 38,93; H Is 4.36; N - 18,16.

Found (Percent): C - 38,64; H - 4,13; N - 17,92.

Reference example 4

2-Amino-4-(2,5-dichlorophenyl)-6-piperidino-1,3,5-triazine

Using piperidine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 192 - 194oC.

Elemental analysis for C14H15Cl2N5< / BR>
Calculated (Percent): C - 51,87; H - 4,66; N - 21,60.

Found (Percent): C - 51,86; H With 4.65; N - 21,64.

Reference example 5

2-Amino-4-(2,5-dichlorophenyl)-6-morpholino-1,3,5-triazine

Using morpholine instead of diethanolamine, carry out the same procedure as in example 1, and get named in the header of the connection.

So pl. 189 - 191oC.

Elemental analysis for C13H13Cl2N5O

Calculated (Percent): C - 47,87; H - Was 4.02; N - 21,47.

Found (Percent): C - 47,85; H - To 3.92; N - 21,52.

Example test 1

Protivogerpetical the eating is the most common test on animals assessment protivogerpetical of drug action. It is known that the evaluation protivogerpetical actions with this test method correlates well with the clinical results in humans (Kondo, Y., et al., Chem. Pharm. Bull., 38, 2887-2889, 1990).

Way. Male BALB/C mice aged 6 weeks give intravenous dose of 1 mg VCI, and after 2 weeks administered orally 50 mg/kg of the test drug. Then, 1 hour later, make intravenous injection of 2.5 μg of lipopolysaccharide (LPS) to induce hepatitis. To determine the lethality associated with LPS, after 48 hours to determine the percentage of deaths. Mortality in the control group is 80-100%. It is known that the content of transaminase [aspartate aminotransferase GOT), aluminiumindustrie (GPT)] in the plasma begins to increase after about 8 hours after administration of LPS, and 4 hours is not enough for evaluation. However, for comparison, take away the blood from the orbital vein after 4 hours, and determine the concentration of transaminases (GOT, DTP) in plasma. As a compound for comparison using 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine. The results are given in table. 1.

Compounds of the present invention show essentially the same paragraph the nya transaminase in serum, which is an indicator of disturbances in the liver.

Thus, the compounds of the present invention have protivogerpetical activity and are therefore suitable for the treatment and prevention of hepatitis.

Example of test 2.

Inhibitory effect on hepatic homonculous

Way. Male F344 rats (Slc) at 5 weeks of age create a model of precancer using given at the end of the text of the scheme, in accordance with the method Solt and Faber (Nature, 263, 702 - 703, 1976).

Thus, during the experiment, which is installed in 4 weeks, first injected intraperitoneally with 200 mg/kg diethylnitrosamine (hereinafter referred to cragnotti called DEN). Since 2 weeks, give, unlimited drinking water containing 0.02% of 2-acetylaminofluorene (next to the multiplicity called AAF). At the beginning of 3 weeks perform 70% hepatectomy. Check the drug is mixed with food animals (F-2, Funabashi Farm) at a concentration of 0.01%, and give 2 weeks until the last day of the experiment. As a verifiable connection use connection example 1, and connection (standard) use of 2,4-diamino-6-(2,5-dichlorophenyl)-1,3,5-triazine.

On the last day of the experiment secene, quickly frozen in acetone with ice and stored until use. Dissect from the liver frozen sections with a thickness of 8 μm, and using a set of vectastain ABC (Funakoshi Yakuhin), paint the immune method ABC (method with enzyme labeled antibody), using the antibody antiglycation-S-transferase placental form (next to the multiplicity called DST-P) as primary antibodies. So, the slices in the absence of water return to the conditions of room temperature and immersed in 10 mm phosphate buffered saline (hereinafter for brevity referred to SFR), pH of 7.2, for 15 minutes. Then slice put the serum of healthy goats and primary antibody (dilution 500, 20 μl), and allow to react overnight. After the reaction slice washed SFR. Then apply anti-rabbit secondary antibody, and carry out the reaction for 30 minutes. After washing SFR enter avidin-biotherapy complex, and allow to react for 30 minutes. Slice washed SFR and treated with 0.1% diaminobenzidine (DAB) containing 0.02% hydrogen peroxide, for signs of staining, dehydrating and close.

Under an optical microscope to count the number of positive for GST-P damage cm2slice PETERKA average values when teaching students, and the result is evaluated at 5% level of confidence. The results are given in table. 2.

Compounds of the present invention, at a concentration of 0.01%, reduces the number and area of GST-P-positive lesions. The degree of inhibition is 28,9% and 48.6%, respectively. On the other hand, 0,01% standard connection does not show inhibitory effect on the number of GST-P-positive lesions or on the area of damage (degree of inhibition of 7.7%).

Test example 3

Acute toxicity

Using rats of either sex (line SD, 280 - 360 mg) in groups of 5 individuals. On the eve of the test (for 16 - 18 hours) the animals are deprived of food, and administered orally by gastric probe, 1 g/kg of the compound of example 1. Then record the deaths during the next one week. The result has not been any death.

Thus, the toxicity of the compounds of the invention is very low.

Test example 4

Effect on weight gain

The compound of example 1 daily administered to rats in order to investigate its influence on weight gain. Even with the reintroduction of the 1000 mg/kg of the compound of the present invention does not affect weight gain.

An example of bauleni 25 ml of a 16% solution of hydroxypropylcellulose the mixture is stirred and granularit. Thus obtained granules are dried, sieved, and mixed with 2 g of magnesium stearate and 2 g of talc, and the whole composition is pressed at the rotary teletrauma car. Get pills.

Composition: 110 mg per pill

Connection example 1 2 mg

Lactose 70 mg

Corn starch 30 mg

Hydroxypropylcellulose 4 mg

Magnesium stearate 2 mg

Talc 2 mg

Example composition 2

To 4 mg of the compound of example 1 add 996 mg of lactose, and the mixture is uniformly mixed to obtain a powder.

Industrial application

Compounds of the present invention possess strong protivogerpetical activity, as the activity of inhibition of hepatic carcinogenesis, which is not detected in standard drug irsogladine, and are safe compounds with low toxicity. Therefore, the compounds are suitable as pharmaceuticals for the treatment and prevention of hepatitis in mammals, including humans.

1. Medicinal composition for the treatment of hepatitis in mammals, including humans, contains the active ingredient and pharmaceutically acceptable carrier or diluent, Otley is new or different, and each represents hydrogen, unsubstituted or substituted alkyl, aralkyl, aralkyl or aryl, or R1and R2together with the adjacent N atom represent a 4 - to 8-membered cyclic amino group of the formula NR1R2cyclic amino group may contain as atom rings, in addition to the above-mentioned N atom, nitrogen, oxygen, or sulfur and may be substituted, provided that exclude the case when R1and R2represent hydrogen, its salt or its MES as an active ingredient in an effective amount.

2. Medicinal composition for p. 1, wherein R1and R2may be the same or different, and each represents (1) hydrogen, (2) alkyl, which is either unsubstituted or substituted Deputy selected from the group consisting of hydroxyl group, alkoxygroup, amino, monoalkylamines, dialkylamines, killingray, 4 - to 8-membered cyclic amino group, carboxypropyl, carbamoyl, alloctype and Kolocep, (3) aralkyl, (4) aralkyl or (5) aryl.

3. Medicinal composition for p. 1, characterized in that NR1R2is a 4 - 8 from the group consisting of hydroxyl group, carbonyl group, carboxypropyl, alkyl, hydroxyalkyl, aryloxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonamides, alkylsulfonyl, alkylsulfanyl, aryl, aralkyl, 2-pyrimidyl and cyclic amino groups.

4. Medicinal composition for p. 1, wherein R1and R2may be the same or different and each represents hydroxyalkyl, or NR1R2is pyrrolidinone, piperidine or morpholinopropan, which may be substituted.

5. Medicinal composition for p. 1, wherein R1and R2may be the same or different and each represents hydroxyalkyl, or NR1R2is pyrrolidinone, piperidine or morpholinopropan, which may be either unsubstituted or substituted hydroxyl group, hydroxyalkyl, exography, alkyl, amino group or aminoalkyl.

6. Medicinal composition for PP.1 to 5, characterized in that it is a therapeutic drug against hepatitis.

7. The compound of General formula I

< / BR>
where R11and R2together with the adjacent N atom represent a 4 - to 8-membered cyclic amino group of the formula NR1R2cyclic amino group may contain as atom rings, in addition to the above-mentioned N atom, nitrogen, oxygen, or sulfur and may be substituted, provided that exclude the case when R1and R2represent hydrogen, and the case when NR1R2are unsubstituted piperidino or morpholino group, its salt or MES.

 

Same patents:

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

The invention relates to a new group of imidazole compounds, method of their production and use for the treatment of diseases, mediasound cytokines, as well as to pharmaceutical compositions used for such therapy

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The invention relates to physiologically active agents that produce nitric oxide, process for their preparation, containing compositions, and methods of use thereof

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

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and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

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FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

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