Hiv-inhibiting 2-(4-cyanophenyl)-6-hydroxylamino-pyrimidines

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) and their pharmaceutically acceptable addition salts having HIV replication inhibiting properties. In formula (I), R1 is halogen; R2 and R3 each independently denotes C1-6-alkyl. The invention also relates to a method for synthesis of said compounds and a pharmaceutical composition.

EFFECT: increased effectiveness of derivatives.

7 cl, 6 ex

 

The present invention relates to 2-(4-cyanophenyl)-6-hydroxylaminopurine with any abscopal the replication of HIV (human immunodeficiency virus) properties. This invention further relates to methods of producing these pyrimidines and pharmaceutical compositions containing these compounds, and their use to prevent or treat HIV infection.

The resistance of the HIV virus to the currently available drugs against HIV infection remains a major cause of adverse outcome of therapy. This has led to the introduction of combination therapy of two or more anti-HIV agents generally have different activity profile. Significant progress has been made through the introduction of HAART therapy (highly active antiretroviral therapy), which leads to significant morbidity and mortality if exposed to it through treatment of HIV patients. HAART therapy includes various combinations of inhibitors nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside inhibitors of reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). Modern directives in relation to antiretroviral therapy recommend this triple combination therapy even for initial treatment. However, these multiplikatsionnye therapy is not always effective and Niko is Yes not completely destroy HIV. Described that half of the patients subjected to combination anti-HIV therapy, it is not treatable, mainly due to resistance to one or more used medicines. The transition to alternative combinations, as a rule, leads to temporary relief, but any form of long-term treatment at the end not be successful due to the development of resistance to many drugs. In addition, it is shown that the resistant virus is transferred to newly infected individuals, leading to variants strictly limited therapy for these, beyond the effects of drugs in patients.

The enzyme targets in the case of the HIV virus is able to mutate in such a direction that the known medicines become less effective or even ineffective against these mutant HIV viruses. Or, in other words, the HIV virus causes even increasing the resistance against the available medicines. More and more strains of HIV that are resistant to NNRTIS detected in patients not amenable to anti-HIV therapy are double or even multiply mutated strains. Such strains are mutants of HIV have two or more mutations in the gene for reverse transcriptase and, therefore, have a strong resistance on the RH is increased based on NNRTIS therapy.

Due to their ability to rapid mutation and provoking resistance in relation to existing drug therapies there is a continuous need for new combinations of active ingredients which are effective against HIV. In particular, there is a continuing need for new types of effective anti-HIV active ingredients, differing in chemical structure and activity profile, for use in new types of combined therapy. There is a particular need for new types of effective anti-HIV active ingredients that are active against double or multiple mutant strains of HIV. Detection of such active ingredients, therefore, it is highly desirable to achieve the purpose.

The present invention relates to certain new series binarization pyrimidine derivatives that may find use in HIV therapy, especially as a new component of drug combinations. Binarization pyrimidines with any abscopal HIV replication properties known from WO 00/27825.

A new series of pyrimidine derivatives according to the present invention exhibits excellent in relation to inhibition of HIV replication properties, particularly against strains of HIV that have dual or multiple mutations in the gene britneyfanssite.

The present invention relates to the compound of formula (I):

its pharmaceutically acceptable additive salts or its stereochemical isomeric form, where

R1means halogen;

R2and R3each independently means1-6-alkyl.

As used in this context, the term "C1-4-alkyl" means a saturated hydrocarbon radical with a linear or branched chain having 1-4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl and the like; the term "C1-6-alkyl" includes1-4-alkyl radicals and the higher homologues having 5 or 6 carbon atoms, such as 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl etc. of interest among1-6-alkyl radicals are1-4-alkyl radicals.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

For therapeutic use of salts of compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are pharmaceutically unacceptable, may also find use, for example, receiving or purification of pharmaceutically acceptable compounds. All salts, whether they are pharmaceutically acceptable or not, includes the scope of the present invention.

The term "pharmaceutically acceptable salt additive"as used in this context, includes therapeutically active non-toxic acid additive salt form, which are capable of forming compounds of formula (I). Last suitable way can be obtained by processing the basic form of such appropriate acids as inorganic acids, such as halogen acids, for example hydrochloric acid, Hydrobromic acid and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic acid, propanoic acid, hydroxyestra acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylate acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like acids. On the contrary, the salt form can be converted into the free base by treatment with alkali. The compounds of formula (I)containing acidic protons may be converted into their therapeutically active non-toxic additive is Olevia form with metal or amine by treatment with appropriate organic or inorganic bases.

The term "additive salt" also includes hydrates and additive forms with solvents, which are capable of forming compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, etc.

Some of the compounds of formula (I) and their additive salts can have one or more chiral centers and can exist in the form of stereochemical isomeric forms. Stereoisomers can exist when R2and R3mean4-6-alkyl. The term "stereochemical isomeric forms"as used in this context, includes all the possible stereoisomeric forms which can have the compounds of formula (I) and their additive salt. Assume that the stereochemical isomeric forms of the compounds of formula (I) are included in the scope of this invention.

A preferred subgroup of these compounds are those compounds of formula (I)as described above, or any subgroup of compounds of formula (I)described in this context, where R1means chlorine or bromine, more preferably where R1means bromine.

Other preferred subgroup of compounds are those compounds of formula (I)as described above, or any subgroup of compounds of formula (I)described in this context, where R2and R3mean1-4-alkyl, more preferably where R2and R3Osnach who are methyl. Of particular interest are those compounds where R1means bromine, and R2and R3means methyl; or R1means chlorine, and R2and R3means methyl.

In General, the compounds of formula (I) can be obtained by reacting a derivative of a pyrimidine of formula (III) with a protected hydroxylamine of the formula NH2OP, thereby obtaining the intermediate product (II), which subsequently removing the protective group. The group W in the pyrimidine derivatives of the formula (III) represents a suitable removable group, such as halogen, for example chlorine or bromine, preferably, it represents chlorine.

In an alternative embodiment of the intermediate product (III) can be entered into interaction with hydroxylamine with the direct formation of compounds of formula (I)as indicated in the following reaction scheme:

Suitable protective groups (denoted as P in the above diagram) include any of hydroxylamine groups used in the prior art, including those that can be removed by acidic cleavage, such as methoxyethoxymethyl (MEM), tetrahydropyranyl (TNR), tert-butyl (t-Bu) and the like, or by hydrogenation, such as benzyl (Bz), etc., trialkylsilyl groups, such as the trim is ililil (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl, etc. that can be split in acidic or alkaline conditions. It is preferable TNR-group.

The interaction of the original substance (III) with a protected hydroxylamine NH2OP can be performed in a suitable solvent, preferably in the presence of a base, which can be added to catch the acid which is liberated during the reaction, such as a carbonate or bicarbonate of an alkali metal such as potassium carbonate, or organic bases, such as trialkylamine, such as triethylamine. Suitable solvents include, for example, acetonitrile, alcohols, such as ethanol, 2-propanol; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, acetonitrile; ethers such as 1,4-dioxane, onomatology ether of propylene glycol, tetrahydrofuran. The preferred ethers are ethers, in particular tetrahydrofuran.

The group P in the thus obtained intermediate product (II) can then be removed using known prior art methods. In the case where the group R represents the TPR, it can easily be removed under acidic conditions, such as when using halogen acids such as hydrochloric acid, etc the use of sulfonic acids, however, when using a resin with acid groups, such as ion-exchange resin containing alphagroup.

The compounds of formula (I) can also be obtained directly from the compound (III)using hydroxylamine. This reaction can be performed using similar conditions as such, in the case of compound (III) using protected hydroxylamine.

In the above synthesis methods for producing compounds of formula (I) and also in the following ways to obtain intermediate products R1means halogen, but also can be a precursor of a halogen group such as a hydroxyl group or a protected hydroxyl group (e.g. benzyloxy), which can be converted into a halogen group using a halogenation agent such as POCl3or POBr3. This can help to avoid undesirable side reactions.

Intermediates of formula (II) can also be obtained by reacting the intermediate product of formula (IV) or formula (VI) with an intermediate product of the formula (V) or formula (VII), as shown in the following reaction scheme, where R1, R2and R3have the meanings as defined for compounds of formula (I) or any subgroup, and W represents a suitable removable group, such as, for example, halogen, for example chlorine, br the m etc. Intermediates of formula (II) can be converted into the end products of the formula (I) by removing the protection. Alternatively, you can use the intermediates (IV) or (VI), in which gidroksilaminopurina is unprotected, so directly obtain the compounds of formula (I).

The reaction of the pyrimidine derivative (IV), (VI), with cyanoaniline (V), respectively, with cyanophenyl derivative (VII)is preferably carried out in a suitable solvent, such as, for example, acetonitrile, an alcohol, such as ethanol, 2-propanol, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone; simple ether such as 1,4-dioxane, onomatology ether of propylene glycol. The interaction can be performed in acidic conditions, which can be obtained by adding quantities of a suitable acid, such as camphorsulfonate, and a suitable solvent, such as tetrahydrofuran or an alcohol, for example ethanol, 1 - or 2-propanol, or when using acidified solvents, as, for example, hydrochloric acid, dissolved in alkanol, such as ethanol, 1 - or 2-propanol.

In an alternative embodiment unprotected derivatives of pyrimidine (IV), i.e. the intermediates (IV), where R denotes hydrogen, can be introduced into vzaimode the op perate with compound (V), thus directly receiving end products of the formula (I). To avoid side reactions, it is preferable to use the protected intermediates (IV) and then delete the group R.

Intermediates of formula (II) can also be obtained by reacting cyanophenyl derivative (VIII) c pyrimidine derivative (IX) or by interaction cyanophenyl derivative (X) with a pyrimidine derivative (XI), as shown in the following diagrams.

In these reaction schemes, R1, R2and R3have the meanings as defined for compounds of formula (I) or any sub-groups, R represents a protective group, as described above, and W represents a suitable removable group, as described above. These reactions are preferably carried out in a suitable solvent, in particular any of the solvents mentioned above in connection with the reaction of the compound (IV) with compound (V).

In an alternative embodiment unprotected derivatives of pyrimidine (IX) or (XI), i.e. intermediate products (IX) or (XI), where R denotes hydrogen, can be introduced into interaction with the compound (VIII) or (X), thus directly obtaining the final products of the formula (I). To avoid side reactions, it is preferable to use the of protected intermediates (IX) or (XI) and then delete the group R.

The compounds of formula (I), in addition, can be obtained by transformation of compounds of formula (I) into each other according to known prior art reactions of transformation groups. For example, chlorine analogs can be converted into the corresponding bromo-analogues or, on the contrary, by exchange reactions of halogen.

Some of the compounds of formula (I) and some intermediate products precursor may contain an asymmetric atom. Stereochemical pure isomeric forms of the above compounds and the above-mentioned intermediate products can be obtained by using known from the prior art methods.

Synthesis of some intermediate products used according to the previous reaction schemes described later, where the reaction schemes, R1, R2and R3have the meanings as defined for compounds of formula (I) or any subgroup, and W represents a suitable removable group, in particular chlorine or bromine.

Educt of the formula (III) can be obtained as described in WO-00/27825. In particular, they can be obtained, as shown in the following diagram:

Protected 4-cyanoprop (VIII) enter into interaction with the pyrimidine derivative (XII), where each W independently represents a removable group, such as the above.

The intermediate product of the formula (IV) can be obtained as shown in the following reaction scheme:

In this way it is possible to obtain intermediate products (VI), based on pyrimidine (XIV), as shown in the following diagram:

In the case of the above-mentioned interaction between the amino group can be protected or not protected by a suitable protective group. In an alternative embodiment it is possible to interact unprotected pyrimidine derivatives (XIII) or (XIV), i.e. intermediates (XIII) or (XIV), where R means hydrogen, with a compound (VIII) or (X). To avoid side reactions, it is preferable to use the protected intermediates (XIII) or (XIV) and then delete the group R.

Intermediates (IX) can be obtained by condensation of a derivative of pyrimidine (XIII) with cyanoaniline (V), as shown in the following diagram. If it is desirable to avoid side reactions, W-band, which is nariakira, and/or R1can be a precursor of halogen as stated above.

Intermediates (XI) can be obtained by condensation of a derivative of pyrimidine (XV) with cyanoaniline (V), as shown in the following diagram. If it is desirable to avoid side reactions, the hydroxy-group in the compound (XV) can be protected and/or R1may be what Resistencia halogen, as specified above.

In a further aspect this invention relates to a chemical compound of the formula (II):

or its acid salt additive or stereochemical isomeric form, where R1, R2and R3have the meanings as defined in the present description and the claims, and R means hydroxyamino group. The preferred acid additive salts are pharmaceutically acceptable acid additive salts, in particular those as described above. The protective group R can be represented as such, as described above.

In another further aspect, this invention relates to a chemical compound of the formula (III), where W denotes chlorine, R1means bromine, and R2and R3means methyl, the compound which can be represented by formula (III-a):

or its acid salt additive. The preferred acid additive salts are pharmaceutically acceptable acid additive salts, in particular those listed above.

The compounds of formula (I) show antiretroviral properties (inhibiting reverse transcriptase properties, in particular against human immunodeficiency virus (HIV), which is the etiologic agent of syndrome preobretena what about immunodeficiency syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or change their normal function, in particular the coordination of the immune system. In the infected patient is always decreasing the number of T-4 cells, which, in addition, behave abnormally. Therefore, immunological protective system is unable to fight infections and tumors, and HIV-infected subject usually die from infections caused by opportunistic microorganisms, such as pneumonia, or cancer. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system characterized by progressive demyelination, which leads, as a result of dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. HIV infection, further, is also associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).

Compounds according to the present invention also show activity against resistant (many) of drug-resistant HIV strains, in particular resistant (many) of drug-resistant HIV-1, moreover, in particular, the compounds according to the present invention exhibit AK is Yunosti against strains of HIV, mainly strains of HIV-1 that have acquired resistance to one or more known from the prior art inhibitors non-nucleoside reverse transcriptase inhibitor. Known in the prior art inhibitors non-nucleoside reverse transcriptase inhibitors are inhibitors non-nucleoside reverse transcriptase inhibitors, other than the compounds according to the present invention, and known to a qualified specialist in this field, in particular, as commercially available inhibitors non-nucleoside reverse transcriptase inhibitor. Compounds according to the present invention also have little or no binder" affinity to human α-1-acid glycoprotein; human α-1-acid glycoprotein is not exposed or only weakly exposed to anti-HIV activity of the compounds according to the present invention.

Due to their antiretroviral properties, particularly their anti-HIV properties, mainly their anti-HIV-1 activity, the compounds of formula (I), their pharmaceutically acceptable additive salts and their stereochemical isomeric form suitable for the treatment of individuals infected with HIV and for the prophylaxis of these infections. In General, compounds according to the present invention may be suitable for the treatment of warm-blooded animals infected with viruses of existence which are mediated by or dependent on the enzyme reverse transcriptase. Conditions that can be prevented or treated with the compounds according to the present invention, mainly, are the States associated with HIV and other pathogenic retroviruses, including AIDS, AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic diseases of the Central nervous system caused by retroviruses, such as, for example, mediated HIV dementia and multiple sclerosis.

Compounds according to the present invention or any subgroup, therefore, can be used as drugs against the above-mentioned conditions. The above use as a medicine or method of treatment includes the introduction of HIV-infected subjects an effective amount of the compounds to combat conditions associated with HIV and other pathogenic retroviruses, primarily HIV-1. In particular, the compounds of formula (I) can be used to obtain medications in order to treat or prevent HIV infections.

In a further aspect the present invention provides a method of treating warm-blooded animals, including humans, suffering from viral infections, or to the way of protection of warm-blooded animals, including humans, suffering from viral infections, mainly the zoom, from HIV infections. The above method includes the introduction, preferably oral administration, of an effective amount of the compounds of formula (I), its pharmaceutically acceptable salt additive or a possible stereoisomeric form of warm-blooded animals, including humans.

In another aspect, the compounds of formula (I) or any subgroup suitable in the case of a method of preventing, treating or combating infection or disease associated with infection of a mammal mutant HIV virus, including the introduction of the above to the mammal an effective amount of the compounds of formula (I) or any subgroup.

In another aspect, the compounds of formula (I) or any subgroup suitable in the case of a method of preventing, treating or combating infection or disease associated with infection of a mammal are resistant to many drugs the HIV virus, including the introduction of the above to the mammal an effective amount of the compounds of formula (I) or any subgroup.

In a further another aspect of the compounds of formula (I) or any subgroup suitable in the case of the method of inhibiting the replication of the HIV virus, in particular the HIV virus with reverse transcriptase mutant HIV, even, in particular, reverse transcriptase mutant HIV resistentes the many medicines, includes introduction to the mammal in need, an effective amount of the compounds of formula (I) or any subgroup.

Preferably, a mammal, as described in the methods according to this invention, is the man.

The present invention also relates to compositions for the treatment of viral infections, containing a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds according to the present invention or any subgroup can be used for various pharmaceutical forms for administration. As appropriate compositions can be called all compositions usually applied to systematically injected drugs. To obtain pharmaceutical compositions according to this invention an effective amount of a particular compound, optionally in the form of a salt additive, as an active ingredient, combined with careful mixing with a pharmaceutically acceptable carrier, and the carrier can have a wide variety of forms depending on the finished dosage form desired for administration. These pharmaceutical compositions are desirable in a standard dosage form suitable, in particular, for oral administration, rectal introduction the tion, percutaneous injection or parenteral injection. For example, upon receipt of the compositions in oral dosage form can be any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid finished dosage forms such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets.

Due to ease their introduction of tablets and capsules represent the most advantageous oral standard dosage forms, in which case typically use solid pharmaceutical carriers. In the case of parenteral compositions, the carrier typically includes sterile water, at least for the most part, although there may be other ingredients, for example, to aid solubility. Can be obtained injectable solutions, for example in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can also be obtained injectable suspension, in which case can be used suitable liquid carriers, suspendresume agents etc. Sud is composed of drugs in solid form, designed for turning shortly before use of liquid medicines. In the compositions suitable for percutaneous administration, the carrier optionally includes improving the penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, and the additive does not have a significant detrimental effects on the skin. The above additives can facilitate the introduction into the skin and/or may be useful to obtain the desired compositions. These compositions can be administered in a number of ways, for example in the form of a transdermal patch, in the form of the adjustment, in the form of ointment. Compounds according to the present invention can also be administered by inhalation or insufflation, by methods and with the use of finished dosage forms used in the prior art for introducing this way. Thus, in General, the compounds according to the present invention can enter into the lungs in the form of a solution, suspension or dry powder. Any system developed for the introduction of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation, suitable for administration of the compounds according to the present invention.

To facilitate the solubility of the compounds of formula (I) in the composition of what you can include the appropriate ingredients, for example cyclodextrins. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers, where one or more hydroxyl groups anhydroglucose links cyclodextrin substituted With1-6-alkyl, especially stands, ethyl or isopropyl, as, for example, statistically methylated β-CD; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, particularly carboxymethyl or carboxyethyl; C1-6-alkylcarboxylic, especially acetyl. Especially noteworthy as complexing agents and/or solubilization are β-CD, statistically methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD). Another type of substituted cyclodextrins are sulfosalicylate.

The term "simple mixed ether" means derivative of cyclodextrin, where at least two hydroxyl groups of the cyclodextrin converted into ethers with different groups, such as, for example, hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of the CNS units per mol of anhydroglucose. The average degree of substitution (D.S.) Rel is referring to the average number of substituted hydroxyl groups on the level of anhydroglucose. Values .S. and D.S. can be determined by various analytical methods such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the method used can be obtained slightly different values for one of this cyclodextrin derivative. Preferably, when measured using mass spectrometry, is .S. ranges from 0.125 to 10, and the value D.S. ranging from 0.125 to 3.

Other suitable compositions for oral or rectal injection include particles consisting of a solid dispersion containing the compound of formula (I) and one or more suitable pharmaceutically acceptable, water-soluble polymers.

The term "solid dispersion", as used above, defines a system in a solid state (as opposed to liquid or gaseous state)comprising at least two components, in the case of the compounds of formula (I) and the water-soluble polymer, where one component is more or less evenly dispersed in the other component or components (in the case of the inclusion of additional, pharmaceutically acceptable for the finished dosage forms agents are generally known in the prior art, such as plasticizers, preservatives and the like). When the above dispersion component is in is such, that the system is chemically and physically completely homogeneous or homogeneous or consists of one phase, as defined in thermodynamics, such a solid dispersion can be called a "solid solution". Solid solutions are preferred physical systems, as components in them are usually easily bioavailable to the organisms in which they entered.

The term "solid dispersion" also includes dispersion, which are in all respects less homogeneous than solid solutions. Such dispersions are not chemically and physically completely homogeneous or include more than one phase, for example, systems that have areas or small areas where amorphous, microcrystalline or crystalline compound of formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both, more or less evenly dispersed in the other phase comprising water-soluble polymer or the compound of formula (I), or a solid solution containing the compound of formula (I) and water-soluble polymer. The above areas are areas of solid dispersion, clearly visible due to the physical features: small in size and on the occasion and statistically distributed in the solid dispersion.

There are various ways to obtain a solid dispersion comprising the extrusion of u is ava the spray drying and dissolution-evaporation. After the formation of the solid dispersions obtained products are optional, you can grind and sift. The product in the form of a solid dispersion can be milled or crushed to particles having a size less than 600 microns, preferably less than 400 μm and most preferably less than 125 microns. Particles obtained as described above can then be used to obtain the usual pharmaceutical dosage forms such as tablets and capsules.

Water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20°C in aqueous solution with a concentration of 2% (wt./vol.), component 1-5000 MPa·s, more preferably 1-700 MPa·s and most preferably 1-100 MPa·S. for Example, suitable water-soluble polymers include alkylaryl, hydroxyethylcellulose, hydroxyethylmethylcellulose, karboksimetsiltsellyulozy, alkali metal salts of carboxymethylcellulose, carboxylmethylcellulose, esters of karboksimetsiltsellyulozy, starches, pectines, chitin derivatives, di-, oligo - and polysaccharides such as trehalose, alginic acid or their alkali metal salts or ammonium salts, carragenan, galactomannan, tragakant, agar-agar, gum Arabic, guar gum and humectants, poly is krylovii acids and their salts, polymethacrylic acid and their salts, copolymers based on methacrylates, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, a combination of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene and copolymers of ethylene oxide and propylene oxide. Preferred water soluble polymers are hydroxypropylmethylcellulose.

One or more cyclodextrins can be used as the water-soluble polymer upon receipt of the above particles, as described in WO 97/18839. These cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in the prior art, more preferably, α-, β - or γ-cyclodextrins or their pharmaceutically acceptable derivatives.

Substituted cyclodextrins that can be used to obtain the above-described particles include polyethers described in U.S. patent 3459731. Next, substituted cyclodextrins are described above as agents to promote the solubility of the compounds of formula (I).

The ratio of the compounds of formula (I) to a water-soluble polymer can be widely varied. For example, you can use the ratio of from 1/100 to 100/1. Interest ratio of compounds of formula (I) to cyclodextrin is from PR is approximately 1/10 to 10/1. Of great interest ratio is from about 1/5 to 5/1.

Further, it may be suitable to the use of compounds of formula (I) to obtain a finished dosage form in the form of nanoparticles which have a surface modifier adsorbed on their surface, in a quantity sufficient to maintain an effective average particle size of less than 1000 nm. Assume that suitable surface modifiers include those that are physically linked to a surface of the compounds of formula (I), but not at the expense of the chemical bond with the above connection, and which can be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, oligomers, low molecular weight, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting way of using compounds of formula (I) to obtain a finished dosage forms includes a pharmaceutical composition where the compounds of formula (I) is introduced into the hydrophilic polymer, and this mixture is applied as a coating film on a set of small granules, thereby obtaining a composition which can suitable the way to process and which is suitable for the production of pharmaceutical dosage forms for oral administration. These granules include a Central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I), and, optionally, a sealant coating layer. Substances suitable for use as cores in granules, varied, provided that the above compounds are pharmaceutically acceptable and are of suitable size and density. Examples of such substances are polymers, inorganic substances, organic substances and sugars and their derivatives.

Particularly advantageous is the preparation of the above pharmaceutical compositions in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, as used in this context, refers to physically discrete units suitable as standard doses, with each standard dose contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated), capsules, pills, packaged powders, pills, suppositories, injectable solutions or suspensions and the like, and their segrega the data set.

A qualified specialist in the treatment of HIV infection may determine the effective daily amount from the test results presented in this context. In General, assume that the effective daily amount is from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg of body weight. It may be appropriate to introduce the required dose in the form of two, three, four or more subds appropriate intervals during the day. The above subdata can be obtained in a standard dosage forms, for example, containing 1 to 1,000 mg, and particularly 5-200 mg of the active ingredient at a standard dosage form.

The exact dosage and frequency of injection depends on the specific compounds of formula (I), specific treatable condition, severity treatable condition, age, weight and General physical condition of the particular patient, and the use of other drug therapy for the individual, as is well known to a qualified specialist in this field. In addition, it is obvious that the above effective daily amount may be reduced or increased, depending on the reaction being treated subject and/or depending on the evaluation of the physician prescribing the reception of the compounds according to the present is the invention. The above ranges effective daily amounts, therefore, are only recommended and not intended to limit the scope of the present invention or the use of this invention in any amount.

The compounds of formula (I) according to the present invention can be used individually or in combination with other therapeutic agents such as antiviral agents, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They can also be used separately or in combination with other prophylactic agents to prevent viral infections. Compounds according to the present invention can be used in the vaccines and methods of protecting individuals against viral infections for a long period of time. Connection you can use in such vaccines or individually or together with other compounds according to the invention or in conjunction with other antiviral agents, to a certain extent compatible with the standard use of reverse transcriptase inhibitors in vaccines. Thus, the compounds according to the present invention can be combined with pharmaceutically acceptable auxiliary means, commonly used in vaccines, and to enter in prophylactically effective amounts to for the of ITA individuals for a long period of time against HIV infections.

A combination of one or more antiretroviral compounds and the compounds of formula (I) can be used as a drug. Thus, the present invention also relates to a product containing (a) compound of formula (I) and (b) one or more additional antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. Various drugs can be combined in one preparation together with pharmaceutically acceptable carriers. The above other antiretroviral compounds may be known antiretroviral compounds, such as suramin, pentamidine, thymopentin, castanospermine, dextran (textresult), foscarnet-sodium (trinatriumfosfaat); inhibitors nucleoside reverse transcriptase inhibitors (NRTIs)such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ASN-126443) and the like; inhibitors non-nucleoside reverse transcriptase inhibitors (NNRTIS), such as delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine (V), calanoid And TMS 120, etravirine (TMC 125), DMS, BMS-561390, DPC-083, and the like; inhibitors nucleotide reverse transcriptase inhibitor (NtRTI), e.g. the measures tenofovir (TDF) and tenofovirdisproxil etc.; connection type TIBO (tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-he and-tion), such as (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-tion; connection type α-APA (α-anilinoquinazoline), for example α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic etc.; inhibitors transactivity proteins, such as TAT-inhibitors, e.g. RO-5-3335; REV-inhibitors; protease inhibitors, such as ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), APV (VX-478), TMC-126, S-232632, VX-175, DMP-323, DMP-450 (mozenavir), nelfinavir (AG-1343), atazanavir (BMS 232632), palinavir, TMC-114, RO033-4649, fosamprenavir (GW433908 or VX-175), P-1946, BMS 186318, SC-55389a, L-756423, tipranavir (PNU-140690), BILA 1096 BS, U-140690, and the like; inhibitors of infiltration, which include inhibitors of hybridization (e.g., T-20, T-1249); attachment inhibitors and inhibitors of the receptor; the latter include antagonists R5 and CXR4 antagonists (e.g., AMD-3100); examples of inhibitors of infiltration are enfuvirtide (ENF), GSK-873140, PRO-542, SCH-417690, TNX-355, maraviroc (UK-427857); inhibitor of maturely, such as PA-457 (Panacos Pharmaceuticals); inhibitors of viral integrase; inhibitors ribonucleotides (cell inhibitors, such as hydroxyurea, etc.

With the introduction of the compounds according to the present invention with other antiviral agents that target various ways in which the Oia in the viral life cycle, can be enhanced therapeutic effect of these compounds. Combined therapy, as described above, have a synergistic effect on the inhibition of HIV replication, because each component of the combination acts on another site of HIV replication. The use of such combinations may reduce the dosage used standard antiretroviral agent, which is required for the desired therapeutic or prophylactic effect, compared with that when the agent is administered as monotherapy. These combinations can reduce or eliminate the side effects of one standard antiretroviral therapy, when there is no mutual influence of antiviral agents. These combinations reduce potential resistance to therapy with a single agent, while going minimizing any associated toxicity. These combinations can also improve the efficiency of standard agent without increasing the associated toxicity.

Compounds according to the present invention can also be entered in combination with immunomodulatory agents such as, for example, levamisole, bropirimine, the antibody against human alpha-interferon, alpha-interferon, interleukin-2, Medininkai, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, t is Kimi as, for example, pentanedinitrile etc.; cholinergic agents such as, for example, taken, rivastigmine, donepezil, galantamine and the like; blockers of the NMDA channel, such as, for example, memantine; to prevent or combat infection and diseases or symptoms of diseases associated with HIV infections, such as AIDS and ARC, for example dementia. The compound of formula (I) can be combined with another compound of the formula (I).

Although the present invention is directed primarily to the use of compounds according to the present invention for the prevention or treatment of HIV infections, the compounds according to the present invention can also be used as inhibitory agents for other viruses that depend on such reverse transcriptase inhibitors against obligatory events in their life cycle.

Derivatives of pyrimidine according to this invention not only have a positive effect in regard to their ability to inhibition of replication of human immunodeficiency virus (HIV), but also exhibit improved ability to inhibit the replication of mutant strains, including strains that have dual or multiple mutations in the viral genome, encoding a reverse transcriptase. Compounds according to this invention, therefore, can find note the persistence in the treatment of patients infected with HIV that has become resistant to one or more known drugs NNRTIS (drugs as inhibitors non-nucleoside reverse transcriptase inhibitor (NNRTI), and strains are strains of HIV that are resistant to the drug or to many medicines.

The following examples are intended to illustrate the present invention and do not limit its scope.

EXAMPLES

Example 1

To 2,11 g of 4-[(4,6-dichloro-2-pyrimidinyl)amino]benzonitrile (0,00796 mol) is added 500 ml l3and the mixture is stirred for 30 minutes to dissolve almost all of the original connection. In one portion was added 1-bromo-2,5-pyrrolidinedione (0,0397 mol) and the reaction mixture was stirred at room temperature. After about 30 minutes, the mixture solution becomes light orange color, and with time the reaction mixture becomes more and more reddish. After 40 hours, TLC (thin layer chromatography) and HPLC/MS shows that the reaction is complete. The reaction mixture was purified using flash column-chromatography on silica gel using CH2CL2as eluent. The fractions containing the desired product is separated, and the solvent is evaporated. The residue is recrystallized from acetonitrile, getting 1.51 g of 4-[(5-bromo-4,6-dichloro-2-pyrimidinyl)amino]b is isonitrile (yield 55%) (intermediate 1).

Example 2

A mixture of 0.47 g of 4-hydroxy-3,5-dimethylbenzonitrile (0,00320 mol) and 1,4-dioxane (3 ml) is introduced into the tube under pressure, in an argon atmosphere. Type of 0.13 g of 60%NaH (0,00320 mol) and the mixture stirred for 2 minutes. Add 1-methyl-2-pyrrolidinone (3 ml) and the mixture is stirred for 10 minutes. Add intermediate product 1 (0,00291 mol) and the mixture is heated in a sealed tube at a temperature of 155°C for 16 hours. The mixture was poured into water (15 ml). The tube is washed with water, 1,4-dioxane (11 ml) and again with water, and the washing liquid combined with the aqueous phase, into which was poured the reaction mixture. Thus, the resulting solution is stirred for 15 minutes and placed in the fridge. The resulting material is filtered off, receiving of 1.43 g of 4-[[5-bromo-6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy] - for 3,5-dimethylbenzonitrile (yield 45%) (intermediate 2).

Example 3

Synthesis of 4-[[6-tetrahydropyranyloxy-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy] - for 3,5-dimethylbenzonitrile

The mixture hydrobromide intermediate 2 (1.55 g, 2.89 mmol), obtained as described in example 2, triethylamine (1,43 ml, 1.04 g, 10.2 mmol, 3.5 EQ.) and O-(tetrahydro-2H-Piran-2-yl)hydroxylamine (2.00 g, 17,1 mmol, 5.9 EQ.) refluxed in THF (30 ml) over night. Analysis LCMS (liquid is astna chromatography/mass spectrometry) shows 50%conversion. Add another portion of O-(tetrahydro-2H-Piran-2-yl)hydroxylamine (1,00 g, 8,54 mmol, 3 equiv.) and the reaction mixture is refluxed for two days. The LCMS analysis shows complete conversion. The reaction mixture is cooled, add silica gel and evaporated THF. Using column chromatography, using a mixture of heptane/EtOAc = 2/1 containing 0.3% triethylamine, to obtain 2.7 g of a yellow oil, which was treated with EtOAc, washed twice with saturated solution of NH4Cl, water, and brine. After drying over Na2SO4gain of 1.43 g (yield 92%) of yellow foam-white (intermediate 3).

The LCMS analysis (4 ml/min, linear gradient, t0100% 10 mm aqueous HCOOH/acetonitrile to t10100% 10 mm aqueous HCOOH/acetonitrile, UV-DAD): purity 98%, t=7,2 min, mass spectrum, m/z=533, 535 [M-N]-.

Example 4

Synthesis of 4-[[6-hydroxylamino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy] - for 3,5-dimethylbenzonitrile

A mixture of intermediate 3 (1.40 g, 2,61 mmol) and Amberlyst-15 (1.10 g, 80 wt.%) in methanol is stirred over night at room temperature in argon atmosphere. Amberlyst-15 is filtered off and the filtrate is concentrated and treated with THF and "connect" with silica gel. Using column chromatography, using a mixture of heptane/EtOAc = 1/1 reach only partial separation. Net is racchi is evaporated and the remaining solid was stirred in dichloromethane and filtered, receiving 250 mg (yield 21%) of compound 1 in the form of a solid white color. Mixed fractions also contain the desired product, but they are not clear and do not analyze; melting point - 211aboutC (decomposition).

1H-NMR (300 MHz, DMSO): δ 2,14 (C, 6N), 7,41 (d, 2H), 7,55 (d, 2H), of 7.75 (s, 2H), remaining 9.08 (s, 1H), 9,88 (s, 1H), 9,94 (s, 1H).

The LCMS analysis (1 ml/min, linear gradient, t095% 10 mm aqueous HCOOH/acetonitrile to t155% 10 mm aqueous HCOOH/acetonitrile, UV-DAD): purity 98%, t=9,90 min, mass spectrum, m/z=449, 451 [M-N]-.

Example 5

Finished dosage forms

Capsules

Connection 1, which is the compound described in example 4, is dissolved in an organic solvent, such as ethanol, methanol or methylene chloride, preferably in a mixture of ethanol and methylene chloride. Polymers such as a copolymer of polyvinylpyrrolidone and vinyl acetate (PVP-VA) or hypromellose (receiver array), usually with an apparent viscosity of 5 MPa·s, dissolve in organic solvents, such as ethanol, methanol and methylene chloride. Mostly the polymer is dissolved in ethanol. The polymer solutions and compounds are mixed and then subjected to spray drying. The ratio of compound/polymer chosen from 1/1 to 1/6. Intermediate ranges can be 1/1,5 and 1/3. A suitable ratio can be 1/6. Obtained by spray Inoi drying powder, solid dispersion, then fill capsule for introduction. The amount of drug loaded in one capsule ranges from 50 mg to 100 mg, depending on the size of the capsule.

Tablets film coated

Obtain core tablets

A mixture of 100 g of compound 1, 570 g lactose and 200 g starch are thoroughly mixed and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The entire mixture is thoroughly mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Coating

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the previous solution and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and the entire mixture is homogenized. The core tablets are coated with such education is resulting mixture in the enrobing machine.

Example 6

Antivirus spectrum

Because of the increasing emergence of drug-resistant strains of HIV compounds according to the present invention were tested for their efficacy against clinically isolated strains of HIV with some hidden mutations. These mutations are associated with resistance to reverse transcriptase inhibitors and lead to viruses that exhibit different degrees of phenotypic cross-resistance to commercial currently available drugs, such as AZT and delavirdine.

Antiviral activity of the compounds according to the present invention was evaluated in the presence of HIV wild-type and mutant HIV caused by mutations in the gene for reverse transcriptase. The activity of compounds was evaluated using the cell analysis, and the residual activity was expressed in values RES50. In the following table, in columns IIIB and A-G lists the values RES50against different strains IIIB, A-G.

Strain IIIB is a strain of HIV-LAI wild-type;

the strain contains a mutation AS in the reverse transcriptase of HIV;

the strain contains a mutation 103N in the reverse transcriptase of HIV;

the strain contains the L100I mutation in the reverse transcriptase of HIV;

strain D contains Y188L mutation and S162K in reverse t is inscriptus HIV;

strain F contains mutations L100I and 103N in the reverse transcriptase of HIV;

strain F contains a mutation CE and 103N in the reverse transcriptase of HIV.

Strain G contains mutations L100I, 103N, E138G, V179I, US, L214F, V276V/I and A327A/V in the reverse transcriptase of HIV.

Connection # IIIBABCDEFG
18,40a 7.928,638,92charged 8.528,738,446,32
A8,558,008,758,548,618,09to 8.345,24

The compound a is a compound, which is described in WO00/27825 and has the following structure:

Compared with the reference compound And the Association 1 shows improved activity against double mutant strains, such as strains of E. and F. Connection 1, in particular, shows superior activity against repeatedly mutated strain of G.

1. The compound of formula (I)

or its pharmaceutically acceptable additive salt, where
R1means halogen;
R2and R3each independently mean C1-6-alkyl.

2. The compound according to claim 1, where R1means chlorine or bromine.

3. The compound according to claim 1, where R1means bromine.

4. The compound according to any one of claims 1 to 3, where R2and R3means methyl.

5. The pharmaceutical composition inhibiting HIV replication, containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 4.

6. A method of obtaining a compound according to any one of claims 1 to 4, characterized in that interoperate intermediate product (III) with a protected hydroxylamine to obtain the intermediate product (II) and subsequent removal of the protection in the intermediate product (II) to obtain the final products (I):

where R1, R2and R3have the meanings as described in any one of claims 1 to 4, R represents hydroxyamino group selected from methoxyethoxymethyl (MEM), tetrahydropyranyl (TNR), tert-butyl (t-Bu), benzyl (Bz), trimethylsilyl (MS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl; and
W represents a leaving group;
and, if necessary, obtaining pharmaceutically acceptable acid additive salt forms of the compounds of formula (I) by processing pharmaceutically acceptable acid.

7. The method according to claim 6, where P means hydroxyamino group, in particular R means tetrahydro-2H-Piran-2-yl.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) , where Z means where R means hydrogen, C4-C6cycloalkyl group attached either through one of ring carbon atoms, or through a lower alkylene group attached to the ring, or a linearly chained or branched lower alkyl group or a lower hydroxyalkyl group, or a lower aminoalkyl group, or a phenyl(lower alkyl) group optionally substituted with 1-2 substitutes chosen from lower alkyl, lower alkoxy, halogen and hydroxy, or heteroaryl(lower alkyl)group where heteroaryl is chosen from the group consisting from thienyl, substituted with lower alkyl group, imidazolyl, and thiazolyl substituted with the lower alkyl group; n means 0 or 1; or Z means a group where R means the lower alkyl group; X1 means methylene or NH group; and X2 means methylene; or X1 means methylene and X2 means methylene or a bond; or X1 means methylene, and X2 means O, S or a bond; Y1 means methylene, and Y2 means methylene, vinylene, ethylene, or a bond; Ar1 means unsubstituted or substituted phenyl; Ar2 means unsubstituted or substituted phenyl, unsubstituted or substituted thienyl, unsubstituted or substituted furyl, unsubstituted or substituted pyridyl; and when Ar1 and Ar2 are substituted, each Ar1 and Ar2 are independently substituted with one or more substituted chosen from lower alkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, halogen, di- and trihaloalkyl, di- and trihaloalkoxy, mono- and dialkylamino, alkilthio, alkyl ester and nitro; provided that Ar1 and Ar2 do not simultaneously mean unsubstituted phenyl; W means oxygen or sulphur; or to their pharmaceutically acceptable salts; provided those specified in cl. 1 of the patent claim. Besides the invention concerns the compounds chosen from the group, to compounds of formula (I), to pharmaceutical compositions, to a method of inhibition of monoamine receptor activity, to a method of inhibition of monoamine receptor activation, to a method of treating a diseased state associated with serotonin receptor, to a method of treating schizophrenia, to a method of treating migraine, and also to a method of treating psychosis.

EFFECT: preparation of the new biologically active compounds capable to inhibit monoamine receptor activity.

65 cl, 140 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, and specifically to compounds of general formula I , where A is an oxygen atom, an alkylene, alkenyl or hetero alkylene group, in which the CH2 group is substituted with a NH group, where the said groups can be optionally substituted with OH, =O or CH2OH groups, X1, X2, X3, X4 and X5 independently represent nitrogen atoms or groups of formula CH or CR4, Cy is cycloalkylene or heterocycloalkylene group containing at least one nitrogen atom, R1 is a hydrogen atom, an alkyl or alkyloxy group, R2 is a halogen atom, a hydroxy group, an alkyl or heteroalkyl residue, where the said groups can be optionally substituted with OH, NH2 groups and/or a =O group, R3 is a group of formula -B-Y, in which B denotes an alkylene, alkenyl or heteroalkylene group, where the said groups can be optionally substituted with OH, NH2, COOH groups or a =O group, and Y is an optionally substituted phenyl, optionally substituted heteroaryl group containing 5 or 6 ring atoms, or an optionally substituted bicyclic heterocycle in which one ring is phenyl or pyridyl, and the other is a 5-, 6- or 7-member heteroaryl or heterocycloalkyl group which contains up to 3 heteroatoms selected from nitrogen, oxygen and sulphur atoms, R4 is a halogen atom, n equals 0, 1 or 2 and m equals 0 or 1, or their pharmaceutically acceptable salts, solvates and hydrates. The invention also relates to a pharmaceutical composition based on the formula I compound and use of the compound or the pharmaceutical composition to treat bacterial infections.

EFFECT: obtaining novel compounds possessing useful biological properties.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide and/or one of its physiologically acceptable salts, characterised by that a compound of formula (I),

, in which L is CI, Br, I, SO2F, SO2CF3, SO2C2F5, is reacted with 3-(4-piperazin-1-ylbutyl)indole-5-carbonitrile through transition metal catalysed combination through complex compounds of Pd and/or that the formed 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid, and to a second method which is characterised by that a formula (II) compound, as a base or salt HX (where X=Cl, Br), is reacted with 3-(4-oxobutyl)-1H-indole-5-carbonitrile through reductive amination, and or that 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide is converted to one of its acid addition salt through treatment with an acid.

EFFECT: obtaining a compound which is a 5-HT1A receptor agonist.

4 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chroman derivatives of formula I: , or to their pharmaceutically acceptable salts where m has a value of 0; p has a value of 2; q has a value of 2; Ar represents phenyl optionally substituted with halogen atom; R2 represents ; X represents -NR9-; n has a value of 2 or 3; each R3, R4, R5 and R6 independently represents hydrogen or C1-12alkyl; each R7 and R8 independently represents either hydrogen, or C1-12-alkyl, or R7 and R8 together with nitrogen whereto attached, can form 4-6-members ring, or one of R7 and R8 and one of R5 and R6 together with atoms whereto attached can form 4-6-members ring; and R9 represents hydrogen or C1-12-alkyl, or when R7 represents hydrogen or methyl, R9 together with R8 and atoms whereto attached can form 6-members ring.

EFFECT: preparation of chroman new derivatives and the pharmaceutical composition containing compounds of formula (I).

22 cl, 1 tbl, 5 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel triazole-substituted aminobenzophenone compounds of formula (Ia) or (Ib), (values of radicals are given in the formula of invention) and a pharmaceutical composition containing the said compounds.

EFFECT: obtaining novel compounds which can be used in treating inflammatory, ophthalmological diseases or cancerous growths.

20 cl, 67 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I) and pharmaceutically acceptable salts, where R1-R7 mean the same as provided in the invention description and claim. Compounds of the formula (I) are specific inhibitors of 11b-HSD1. They can be applied in treatment and/or prevention of diseases caused by dysfunctions related to 11b-HSD1 enzyme, particularly in treatment and/or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, especially diabetes type "П". Additionally subject matter includes pharmaceutical composition for treatment and/or prevention of the said diseases.

EFFECT: improved efficiency of derivatives.

21 cl, 1 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-(4-cyanophenylamino)-pyrimidine-oxide derivatives exhibiting activity with respect to HIV of formula (I): , where R1 represents bromine atom; each R2 and R3 independently from each other represents C1-6-alkyl, and also to their pharmaceutically acceptable additive salts. The invention also concerns a pharmaceutical composition and a method of preparing a pharmaceutical composition.

EFFECT: preparation of new 2-(4-cyanophenylamino)-pyrimidine-oxide derivatives exhibiting activity with respect to HIV.

4 cl, 7 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds having inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK) of formula (I)

, where R0 denotes hydrogen; R1 is a saturated 6-member monocyclic or 10-member bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, which can be substituted with piperidinyl, (C1-C7)alkylpiperidinyl, hydroxy, (C1-C7)alkyl, piperazinyl, (C1-C7)alkylpiperazinyl; R2 and R3 together with the carbon or nitrogen atom to which they are bonded form a 5- or 6-member heterocycle containing one heteroatom selected from a nitrogen atom which is substituted with (C1-C7)alkyl and/or oxo- group, R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; halide, (C1-C7)alkoxy; carbamoyl which is unsubstituted or substituted with (C1-C7)alkyl; (C1-C7)alkoxy(C1-C7)alkoxy; 5- or 6-member heterocycle containing one or two heteroatoms independently selected from nitrogen or oxygen, and is unsubstituted or substituted with a substitute independently selected from hydroxy, (C1-C7)alkyl, mono- or di(C1-C7)alkylamino, 6-member heterocycle containing one or two nitrogen ring atoms which are unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle(C1-C7)alkoxy containing one nitrogen ring atom which is unsubstituted or substituted with (C1-C7)alkyl; R9 is hydrogen; R10 is hydrogen, halide or (C1-C7)alkoxy; or their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and use of formula (I) compounds.

EFFECT: obtaining novel compounds with inhibitory effect on focal adhesion kinase (FAK) and/or anaplastic lymphoma kinase (ALK), having formula (I) .

7 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: medicine.

SUBSTANCE: invention relates to 2,4-pyrimidindiamins, such as N4-(4-Chlorine-3-methoxyphenyl)-5-fluorine-N2-[3-(N-ethylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-(3-Chlorine-4-methjopxycarbonylmethylenoxyphenyl)-5-fluorine- N2-[3-(N-methylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-[3-Chlorine-4-(N-methylamino)carbonylmethylenoxyphenyl]-5-fluorine-N2-[3-(]N methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin, N4-[3-Chlorine-4-(2-hydroxyethylenoxy)phenyl]-5-fluorine-N2-[3-(N- methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin and other compounds given in item 1 of claimed invention as Syk-kinase inhibitors, as well as to based on them pharmaceutical composition and their application.

EFFECT: claimed compounds can be applied for treatment of autoimmune diseases, systemic http://lingvo.yandex.ru/?text=lupus%20erythematosus, rheumatoid arthritis, etc.

12 cl, 27 dwg, 11 tbl, 1797 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 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: pharmaceutical composition for treating syphilis and viral diseases specified from influenza, human immunodeficiency virus, cytomegalovirus infections, viral hepatitis type A, D, C and herpes infections, containing an amount of polyphenol compounds of sea buckthorn leaves, including at least 60 % of halloellagotannines, flacoside, a pharmacologically acceptable carrier and a substance of licorice extract, or glycyrrhizic acid, or its pharmaceutically acceptable salt, acridonoacetic acid or its pharmaceutically acceptable salt, birch bark extract or betulin taken in therapeutically effective amounts. A method of treating syphilis and viral diseases, including the introduction of the declared pharmaceutical composition by 2-3 doses 3 times a day.

EFFECT: composition exhibits an evident antiviral action with respect to the infections stated above.

22 cl, 1 dwg, 12 tbl, 7 ex

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