Hiv inhibiting derivatives of 2-(4-cyanophenylamino) pyrimidine

FIELD: medicine, pharmaceutics.

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

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

5 cl, 7 dwg, 1 tbl, 14 ex

 

The present invention relates to the derivatives of pyrimidine with any abscopal the replication of HIV (human immunodeficiency virus) properties, their reception and pharmaceutical compositions containing these compounds. This invention also relates to the use of these pyrimidine derivatives for the prevention or treatment of 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 by conducting "HAART" (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 HIV inhibitors selected from different classes, such as inhibitors nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside inhibitors of reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). HAART therapy is successfully used despite the remaining challenges. In particular, half of the patients subjected to combination anti-HIV therapy, it is not treatable, g is awnym way due to resistance to one or more used medicines. 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. Therefore, according to the latest directives in relation to antiretroviral therapy is recommended triple-combination therapy for initial treatment. Finally, none of these multirecording therapies does not destroy HIV, and long-term treatment usually leads to resistance to many drugs.

Therefore, there is a continuous need for new combinations of active ingredients which are effective against HIV. New types of effective anti-HIV active ingredients, differing in chemical structure and activity profile required to obtain such new drug combinations. Detection of such active ingredients, therefore, it is highly desirable to achieve the purpose.

The present invention relates to specific new binarization aminopyrimidines. Class binarization pyrimidines as HIV inhibitors described in the international application WO-00/27825. Binarization aminopyrimidine according to the of this invention, however, differ in structure from such aminopyrimidines known in this field, and not only have a positive effect from the point of view of their ability to inhibit the replication of human immunodeficiency virus (HIV), but also their improved ability to inhibit the replication of mutant strains, including strains that have become resistant to one or more known NNRTIS-medicines (medicines that inhibit non-nucleoside reverse transcriptase) and which are resistant to drug or multilocational means strains of HIV.

The present invention relates to compounds of formula (I):

their pharmaceutically acceptable additive salts and stereochemical isomeric forms, where

X is NH, S, SO or SO2.

The present invention also relates to the use of compounds of formula (I)as described herein, to obtain drugs for treatment or prevention of HIV infection.

In this description and the claims sulfoxide and sulfon can be represented by SO and SO2respectively, or S=O and O=S=O, respectively, or S→O or O←S→O, respectively.

For therapeutic use of salts of compounds of formula (I) are salts where protivo which is pharmaceutically acceptable. However, salts of acids and bases, which are not pharmaceutically acceptable may also find use, for example, in the case of obtaining or purification of pharmaceutically acceptable compounds. All salts, whether they are pharmaceutically acceptable or not, are included in the scope of the present invention.

Assumes pharmaceutically acceptable salt additive, as indicated above, include therapeutically active non-toxic salt additive form acids, which are capable of forming compounds of formula (I). The latter can be obtained by processing the basic form of such appropriate acids as inorganic acids, such as halogen acids, such as hydrochloric acid, Hydrobromic acid and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, such as 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, Ziklag consultationa acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids. Conversely, the salt form can be converted into the free base by treatment with alkali.

Of particular interest are the forms of the bases of the compounds of formula (I). As used herein, the term "form the basis" refers to the compound of formula (I), occurring in the form of a free base. The term "additive salt" also includes hydrates and additive forms a solvent which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, etc.

It is implied that the term "compounds of formula (I)or any similar terms, such as "the compounds according to this invention" and the like, and also includes any Quaternary amines of compounds of formula (I). The term "Quaternary amine" refers to Quaternary ammonium salts, which are capable of forming compounds of formula (I) by the interaction between the basic nitrogen of compounds of formula (I) and suitable quaternization agent such as, for example, optionally substituted alkylhalogenide, aryl halides or arylalkylamine, such as methyliodide or benzylated. You can also use other reagents with easily removable groups such as alkylarylsulfonate, alkylarylsulfonate the alkyl-p-toluensulfonate. Quaternary amine contains positively charged nitrogen atom. Pharmaceutically acceptable counterions include anions of chlorine, bromine, iodine, triptoreline and acetate. Selected counterion can be entered using ion-exchange resins.

It is implied that the term "compounds of formula (I)or any similar terms, such as "the compounds according to this invention" and the like, and also includes any N-oxide forms of the compounds of formula (I), which are compounds of formula (I)wherein one or several tertiary nitrogen atoms oxidized to N-oxide form.

The term "stereochemical isomeric form or stereoisomeric form," as used in this description above, includes all the possible stereoisomeric forms which can meet the compounds of formula (I), and assume that they are included in the scope of this invention. Stereoisomers can exist in the case where X is SO.

Preferred subgroups of compounds are a group of compounds of formula (I)as described above, or any subgroup of compounds of formula (I)specified herein, where X is NH or S; or where X is NH; or where X is S.

The compounds of formula (I) can be obtained by reacting the intermediate product of the formula (II) or formula (IV) with an intermediate product of the formula (III) or formula (V as shown in the following reaction scheme, where W is a suitable removable group, such as, for example, halogen, for example chlorine, bromine, etc.

The reaction of the pyrimidine derivative (II), respectively, (IV), with cyanoaniline (III), respectively cyanophenyl derivative (V)is preferably carried out in a suitable solvent, such as, for example, alcohol such as ethanol, 2-propanol; polar aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone and acetonitrile; simple ether, such as tetrahydrofuran (THF), 1,4-dioxane, onomatology ether of propylene glycol. These reactions can be carried out in acidic conditions, which can be achieved by adding a quantity 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 using acidic solvents, such as, for example, hydrochloric acid, dissolved in alkanol, such as ethanol, 1 - or 2-propanol.

The compounds of formula (I-a)are compounds of formula (I), where X is NR4or S, can also be obtained by reacting cyanophenyl derivative (VI) with a pyrimidine derivative (VII) or by interaction cyanoaniline of proizvodi the th (VIII) with a pyrimidine derivative (IX), as shown in the following reaction schemes.

In the above reaction schemes X1mean NR4or S, and W represents a suitable removable group, such as, for example, halogen, such as chlorine and bromine. These interactions are preferably carried out in a suitable solvent, in particular in any of the solvents mentioned above in connection with the interaction of the compound (II) with compound (III).

Still another way of obtaining compounds of formula (I) is the bromination of starting compound (X) with the help of free bromine or compounds, which is the donor of bromine, such as N-bromosuccinimide. This reaction synthesized preferably carried out in a suitable inert under reaction conditions solvent, such as a simple ether, in particular in THF. N-bromosuccinimide can be used in the presence of acetic acid.

The compounds of formula (I) can further be obtained by transformation of compounds of formula (I) into each other, in accordance with well-known in this field by the reactions of transformation of functional groups. The compounds of formula (I), where X is S, can be transformed into the corresponding compounds of formula (I), where X denotes SO or SO2, oxidation reaction, in particular by use of a suitable peroxide. Suitably the peroxides include hydrogen peroxide or its derivatives, nagkalat. By selecting the oxidant and controlling the reaction conditions, this reaction can lead to the formation of sulfoxide or sulfone. If necessary, they can be separated from each other by crystallization or column chromatography. Suitable peroxides for receiving sulfoxidov are nadventure acid, such as m-chlormadinone acid (MSRA).

Sulfoxide or sulfonic group can be introduced at an early stage of the synthesis, i.e. in one of the intermediate products used to produce final products of the formula (I). In particular, intermediates of formula (II), formula (IV) or formula (X), where X is S, can be transformed into the corresponding intermediates of formula (II), formula (IV) or formula (X), where X means SO controlled by the oxidation reaction of the initial intermediates using nagkalat, such as m-chlormadinone acid. Thus obtained intermediate product (II), (IV) or (X), where X is SO, then converted into the corresponding end products (I), where X is SO. By using the hard conditions of oxidation, for example using an excessive amount of a suitable peroxide, such as peroxides described below to obtain the N-oxides, receive intermediate products, where x is the SO2that can be converted to the corresponding the following end products (I), where X means SO2.

The compounds of formula (I) can be converted into the corresponding N-oxide forms, the following well-known in the field of methods of transformation of the tertiary nitrogen atom in its N-oxide form. The above reaction of N-oxidation can usually be made by the interaction of the source compounds of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include nagkalat, such as, for example, benzoylperoxide acid or halogen-substituted benzoylperoxide acid, such as 3-chlorobenzalmalononitrile acid; paracalanidae acid, for example purakayastha acid; alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like; hydrocarbons such as toluene; ketones, such as 2-butanone; halogenated hydrocarbons such as dichloromethane; and mixtures of such solvents.

The compounds of formula (I), where X is SO, and some of the preceding intermediate products may contain asymmetric atom. Stereochemical clean some the forms of the above compounds and the above-mentioned intermediate products can be obtained, using known in the field methods. Enantiomers can be obtained from racemic mixtures by turning first to the above racemic mixtures with suitable disintegrating agents, such as, for example, chiral acids, mixtures of diastereomeric salts or compounds; then by physical separation of the above mixtures of diastereomeric salts or compounds, for example by selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally, by transformation of the above separated diastereomeric salts or compounds into the corresponding enantiomers. Stereochemical pure isomeric forms may also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that we make the stereospecific reactions take place.

Some of the intermediates and starting compounds used for producing compounds of formula (I)are known compounds and may be commercially available or can be obtained in accordance with known in this field means. The synthesis of some of the intermediates described in more detail below, and in the reaction schemes as defined for compounds of formula (I) or any subgroup is, X1mean NR4or S, and W represents a suitable removable group, in particular chlorine or bromine. The group of bromine in these intermediate products can be replaced by a predecessor of bromine, such as hydroxy or protected hydroxy-group (for example, benzyloxy), which can be converted into the group of bromine using a halogenation agent such as POBr3. This can help to avoid undesirable side reactions.

Intermediate products of the formula (II-a), which are intermediates of the formula (I), where X means X1can be obtained, as shown in the following reaction scheme. Other intermediate products of the formula (II) can be obtained from intermediates of formula (II-a), where X1means S, the oxidation reaction to relevant sulfoxidov or sulfones.

Similarly, intermediate products (IV-a), which are intermediates of the formula (IV), where X means X1can be derived from pyrimidine (XIV), as shown in the following diagram:

In the above reaction, the amino group may be protected or there is a suitable protecting group. The latter includes benzyl, benzyloxycarbonyl, tert-butyloxycarbonyl etc.

Intermediates (IX) alocate condensation reaction pyrimidine derivative (XV) with a 4-aminobenzonitrile, as shown in the following diagram. If it is desirable to avoid side reactions, the group-X1N and/or the amino group can be protected, and the group of bromine may be replaced by a predecessor of bromine, as described above, and the resulting intermediates (IX') include intermediate products (IX) or a precursor intermediates (IX).

Intermediates of formula (X) can be obtained, as shown in the following reaction scheme.

First 4-aminobenzonitrile subjected to interaction with cyanamide, receiving 4-cyanophenylacetic (XVI). This reaction can be carried out in water in the presence of a strong acid, such as hydrochloric acid, at elevated temperature, for example at temperatures from about 50°C to 70°C, for example at a temperature of about 60°C. the Latter is subjected to interaction with di-C1-6alkilany ester of malonic acid of the formula (XVII), where each R is independently means1-6alkyl, preferably each R is methyl. This reaction can be carried out in a suitable solvent, for example alcohol, such as methanol, in the presence of a strong base such as an alkali metal alkoxide such as sodium methoxide, at high t is mperature, such as the boiling temperature under reflux.

Thus obtained 4,6-dihydroxypyrimidine (XVIII) make pyrimidine derivative (XIX), where each W means delete the group and, in particular, means halogen, preferably chlorine or bromine. This transformation can be performed using a suitable halogenation agent such as POCl3or POBr3. This reaction can be performed in a suitable solvent, in particular in polar aprotic solvent, such as DMF, DMA, SMRT, N-organic, DMSO and the like, preferably acetonitrile. This reaction can be conducted at elevated temperature, preferably at the boiling point under reflux. Other delete group you can enter the following well-known in this field reactions of conversion of the alcohol group in a group to delete.

Derived pyrimidine (XIX) is subjected to interaction with 4-substituted benzonitrile (XX), where X1has the meaning as described above, receiving the desired intermediates (XXI). The interaction of the compound (XIX) with compound (XX) can be carried out in a suitable solvent, such as a simple ether, for example THF, halogenated hydrocarbon, for example CH2Cl2, CHCl3and, in particular, polar aprotic solvent, such as DMF, DMA, NMRT, acetonic the sludge, DMSO and the like, and preferably N-organic. For trapping of acid released during the reaction, may be added to the basis, for example a carbonate of an alkali metal such as potassium carbonate. The interaction of the compound (XIX) with compound (XX) can be carried out at slightly elevated temperature, for example at temperatures from about 30°to 50°, for example at a temperature of about 40°C.

Intermediates of formula (X) or additive, acid salts can be obtained by reacting the intermediate product (XXI), as described above, introducing the amino group agent. This reaction is preferably carried out in a suitable solvent, such as alcohol, for example methanol or ethanol; a simple ether, such as THF or ether of ethylene glycol or propylene glycol, such as onomatology ether of ethylene glycol, onomatology ether of propylene glycol (PGMME); polar aprotic solvent, such as DMF, DMA, NMRT, acetonitrile, DMSO and the like, and, in particular, N-organic. Suitable agents to introduce the amino group include ammonia in liquid or gaseous form; ammonia dissolved in water or dissolved in an organic solvent such as an alcohol, for example methanol or ethanol, or in a polar aprotic solvent such as DMF, DMA, NMRT, acetonitrile, DMSO, etc. Alternative, introducing the am is nogroup agent may be benzylamine, interactions which are benzylamino. The latter can be converted into the amino group using a suitable reaction dibenzylamine, for example by the reaction of catalytic hydrogenation of benzylaminopurine, for example using hydrogen in the presence of a catalyst based on a noble metal such as Pd.

Preferred to introduce the amino group agent is ammonia. It is added to the mixture of the source materials and the solvent, preferably at elevated temperature, for example at temperatures from 100°C to the boiling temperature of the reaction mixture, in particular at a temperature of 120-160°C., for example at a temperature of from about 140°C to 150°C and at high pressure, for example at elevated pressure, such as pressure from about 2 bar to 10 bar, in particular from about 3 bar to 8 bar, for example at a pressure of 4-5 bar. The reaction mixture is kept at this temperature for several hours, for example for about 5-24 hours, or about 8-10 hours. In some cases where the reactivity of the W group is low, the reaction mixture was kept at this temperature for one or several days, for example 1-10 days, in particular 2-8 days.

The reaction can be completed, pouring the reaction mixture into hot water, for example with a temperature of about 100°C. the Desired product is the give an opportunity to crystallize, for example, adding additional amounts of water and leaving the mixture to cool. If this is acceptable to the mix, you can make a seed crystal in the form of minor amounts of the final product, which can be obtained in the previous test, to facilitate the crystallization process.

Intermediates of formula (X), where X denotes SO or SO2can be obtained from the appropriate intermediates (X), where X is S, using a suitable oxidation reaction, as described above.

Intermediates of formula (XX-a), which are intermediates of formula (XX), where X1N means-SH, can be obtained from the corresponding 4-hydroxybenzonitrile (XXV), as shown in the following reaction scheme.

Intermediates (XXIV) is first subjected to interaction with dimethylthiocarbamate, receiving intermediate products (XXIII), which is transformed into intermediate products (XXII) by means of thermal conversion, heating the intermediate products (XXIII). Intermediate products (XXII) is subjected to interaction with the bottom, in particular NaOH or KOH, getting mercaptopropionate (XX-a).

The compounds of formula (I) show antiretroviral properties (inhibiting reverse transcriptase properties), in particular, against the Rus human immunodeficiency (HIV), which is the etiologic agent of acquired 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 a diminishing 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 is usually dying caused by conditionally pathogenic microorganisms infections 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 results in dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. HIV infection, further, is also associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and the AIDS-related complex (ARC).

Compounds according to the present invention also show activity against resistant (multi)drug-resistant HIV strains, particularly against resistant (multi)drug environments is twam strains of HIV-1; in particular, the compounds according to the present invention are active against strains of HIV, mainly strains of HIV-1 that have acquired resistance to one or more known in this field inhibitors non-nucleoside reverse transcriptase inhibitor. Known in this field 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 the person skilled in the art, in particular, as commercially available inhibitors non-nucleoside reverse transcriptase inhibitor. Compounds according to the present invention also have little or no affinity binding 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) useful for the treatment of individuals infected with HIV, and to prevent HIV infection. In General, the compounds according to the present invention can be useful for the treatment of warm-blooded animals infected with viruses,the existence of which is mediated or dependent enzyme reverse transcriptase. Conditions that can be prevented or treated with the compounds according to the present invention, mainly, the condition associated with HIV and other pathogenic retroviruses, include AIDS related AIDS 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 of these compounds, therefore, can be used as a drug 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 for getting medicines for the treatment or prevention of HIV infections.

Taking into account the usefulness of the compounds of formula (I), provides a method of treating warm-blooded animals, including humans, suffering from viral infections, or a method of preventing warm-blooded animals, including humans, suffering from viral is Pecci, mainly from HIV infections. The above method includes the introduction, preferably oral administration, of an effective amount of the compounds of formula (I), its N-oxide form, pharmaceutically acceptable additive salt, Quaternary amine or a possible stereoisomeric form, warm-blooded animals, including humans.

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 of these compounds 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 by thorough mixing with a pharmaceutically acceptable carrier, which may be represented by a great variety of forms, depending on the finished product desired for administration. These pharmaceutical compositions zhelatelny a suitable unit dosage form, in particular, for oral administration, rectal administration, percutaneous injection or administration by parenteral injection. For example, upon receipt of the compositions in oral dosage forms you can use 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 of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case typically use solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least for the most part, although there may be other ingredients, for example, to facilitate solubility. Can be obtained injectable solutions, in which case the carrier includes a saturated saline solution, glucose solution or a mixture of saturated salt solution and glucose solution. Can also be obtained injectable suspension, in which case can be used on the walking in liquid media suspendresume agents, etc. are Also included solid preparations intended for turning, shortly before use, to liquid form preparations. 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 supplements should 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. Song data can be entered in various ways, for example in the form of a transdermal patch, in the form of a wipe, in the form of ointment. Compounds according to the present invention can also be administered by inhalation or insufflation means in the form of finished products used in this area for the introduction of the specified path. Normally, therefore, the compounds according to the present invention can enter into the lungs in the form of a solution, suspension or dry powder. Any system designed for the delivery 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 is astronote compounds of formula (I), in the composition may include suitable ingredients, such as cyclodextrins. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers, where one or more hydroxy groups in parts of anhydroglucose cyclodextrin substituted With1-6the alkyl, in particular the stands, ethyl or isopropyl, as, for example, randomly methylated β-CD; hydroxy-C1-6the alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6the alkyl, in particular carboxymethyl or carboxyethyl; C1-6alkylcarboxylic, in particular acetyl. Especially noteworthy as complexing agents and/or solubilization are β-CD, randomly 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).

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

The average molar substitution (MS) is used as a measure of the average number of moles of alkoxyamines per mole of anhydroglucose. The average degree of substitution (DS) refers to the average number of substituted hydrox the groups link in anhydroglucose. The values of MS and DS 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, as, for example, when measuring by mass spectrometry, MS ranges from 0.125 to 10, and DS ranges from 0.125 to 3.

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

The term "solid dispersion", as used hereinafter, refers to 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 water-soluble polymer, where one component is more or less evenly dispersed in the other component or components (in the case include additional pharmaceutically acceptable for the finished drug agents generally known in this field, such as plasticizers, preservatives and the like). When the above variance components is what aka, 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 organisms in which they are entered. This advantage can probably be explained by the ease with which the above solid solutions can form liquid solutions when it comes in contact with the liquid medium, such as gastro-intestinal juice. Ease of dissolution can be attributed at least partly to the fact that the energy required for dissolution of the components of the solid solution, is less than the energy required for dissolution of the components of the crystalline or microcrystalline solid phase.

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, the term "solid dispersion" also refers to the system having a area or a small area where amorphous, microcrystalline or crystalline compound of formula (I), or amorphous, microcrystalline or crystal is a water-soluble polymer, or are they both more or less evenly dispersed in the other phase comprising a water-soluble polymer, or a compound of formula (I), or a solid solution containing the compound of formula (I) and water-soluble polymer. The above areas are areas in the solid dispersion, clearly visible due to some physical features: small in size and are evenly and randomly distributed throughout the solid dispersion.

There are various ways to obtain a solid dispersion comprising the extrusion of the melt, spray drying and dissolution-evaporation. After receiving the solid dispersions obtained products can optionally be milled and sifted. 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 microns, and most preferably less than 125 microns.

Particles obtained as described above can then be used to obtain, by conventional means, a pharmaceutical unit 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 at a concentration of 2% (wt./vol.), component 1-5000 MPa·s, more preferably 1-700 MPa·s, and most of predpochtitel is but 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, polyacrylic acids and their salts, polymethacrylic acids and their salts, methacrylate copolymers, polyvinylalcohol, 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 soluble(s) in water of the polymer(s) upon receipt of the above particles, as described in WO-97/18839. These cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in this area, more preferably α-, β - or γ-cyclodextrins or their pharmaceutically acceptable is derived.

Substituted cyclodextrins that can be used to obtain the above-described particles include polyethers described in U.S. patent 3459731. Next, substituted cyclodextrins are ethers, where the hydrogen of one or more hydroxyl groups of the cyclodextrin replaced With1-6by alkyl, hydroxy-C1-6by alkyl, carboxy-C1-6the alkyl or C1-6allyloxycarbonyl-C1-6the alkyl, or mixed ethers. In particular, such substituted cyclodextrins are ethers, where the hydrogen of one or more hydroxyl groups of the cyclodextrin replaced With1-3by alkyl, hydroxy-C2-4the alkyl or carboxy-C1-2the alkyl, in particular the stands, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

Particularly suitable are β-cyclodextrine ethers, for example dimethyl-β-cyclodextrin, and polyethers, such as hydroxypropyl-β-cyclodextrin, and hydroxyethyl-β-cyclodextrin. So simple alkilany ether can be simple methyl ether with a degree of substitution of from about 0.125 to 3, for example from about 0.3 to 2. This hydroxypropylcellulose, for example, can be obtained by the reaction of β-cyclodextrin with propylene oxide and may have a value of MS from about 0.125 to 10, for example from about 0.3 to 3./p>

Another class of substituted cyclodextrins that can be used are sulfosalicylate.

The ratio of the compounds of formula (I) to a water-soluble polymer can vary widely. 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 about 1/10 to 10/1. Of great interest ratio is from about 1/5 to 5/1.

Hereinafter, may be an appropriate use in the ready preparation of compounds of formula (I) 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 the useful surface modifiers include modifiers 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.

Suitable surface modifiers 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 on Ernesto-active substances.

Another interesting way of using compounds of formula (I) to obtain finished products includes the introduction of compounds of formula (I) in hydrophilic polymers and applying this mixture as a film coating on a small granules, which can then be processed to obtain the composition for oral administration. These granules include a Central, rounded or spherical core, a film coating of a hydrophilic polymer and a compound of formula (I) and, optionally, a sealant coating layer. Materials suitable for use as cores in these granules, varied, provided that the above materials are pharmaceutically acceptable and are of suitable size and density. Examples of such materials are polymers, inorganic substances, organic substances and sugars and their derivatives.

Particularly advantageous is the preparation of the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein, refers to physically discrete units suitable as unit dosage forms, with each unit contains a predetermined quantity of active phrases is that, designed to achieve the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored tablets or coated), capsules, pills, packaged powders, pills, suppositories, injectable solutions or suspensions and the like, and segregated set.

A qualified specialist in the treatment of HIV infection may determine the effective daily amount from the test results presented in this description. It is generally assumed 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 at appropriate intervals during the day. The above subdata can be obtained in the form of a unit dosage forms, for example, containing 1 to 1,000 mg, particularly 5 to 200 mg, of active ingredient in a unit dosage form.

The exact dosage and frequency of injection depends on the specific compounds of formula (I), concrete subjected to treatment condition, the severity being treated condition, age, weight and General physical condition of the particular patient, and the other is on the medical treatment of the individual, which can be used, as is well known to the person skilled in the art. In addition, it is obvious that the above effective daily amount may be reduced or increased depending on the response under treatment of the subject and/or depending on the evaluation of the physician prescribing the reception of the compounds according to the present invention. The ranges of effective daily amounts specified above, 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 individually 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 this invention, or in conjunction with other protivo the originate 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 adjuvants commonly used in vaccines, and to enter in prophylactically effective amounts to protect individuals over 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, in the form of 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 a known antiretroviral compounds such as suramin, pentamidine, thymopentin, castanospermine, dextran (textresult), foscarnet-sodium (trinatriumfosfaat); inhibitors nucleoside reverse transcriptase inhibitors (NRTIs)such as zidovudine (AZT), di is ansin (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ACH-126,443) and the like; inhibitors non-nucleoside reverse transcriptase inhibitors (NNRTIS), such as delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine (CPV), calanoid AND TMS, etravirine (TMC), DMS, BMS-561390, DPC-083, and the like; inhibitors nucleotide reverse transcriptase inhibitor (NtRTI), such as tenofovir (TDF) and tenofovirdisproxil and the like; compounds of the type TIBO (tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-he 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-ARA (α-anilinoquinazoline), for example α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic and the like; 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, BMS-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, co-receptor; the latter include antagonists of CCR5 and ant is honesty CXR4 (for example, AMD-3100), examples of inhibitors of infiltration are enfuvirtide (ENF), GSK-873140, PRO-542, SCH-417690, TNX-355, maraviroc (UK-427857); inhibitors 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 anti-viral agents which are aimed at different events in the viral life cycle, therapeutic effect of these compounds can be enhanced. 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 of this standard antiretroviral agent that is required to achieve 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 activity. Such combinations reduce potential resistance to therapy with a single agent, while going minimizing any associated with this toxicity. These comb the nation 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 levamisole, bropirimine, the antibody against human alpha-interferon, alpha-interferon, interleukin-2, Medininkai, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, such as pentanedinitrile etc.; cholinergic agents, such as, for example, taken, rivastigmine, donepezil, galantamine and the like; with blockers of the NMDA channel, such as memantine; to prevent or combat infection and diseases or symptoms of diseases associated with HIV infections, such as AIDS and ARC, as, for example, dementia. The compound of formula (I) can be combined with another compound of the formula (I).

Although the present invention focuses on the use of the 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.

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

EXAMPLES

Example 1

Getting 4-the Mino-3,5-dimethylbenzonitrile

Mix 75 g of the intermediate product And, 180 ml of DMF and 40.2 g of CuCN and heated for 4 hours at a temperature of 150°C. Then the entire mixture is cooled to a temperature of 90°C, add 500 ml of 1,2-diaminopropane and the mixture is stirred for 30 min, then cooled to a temperature of 20°C. the Formed precipitate is removed by filtration and the filtered product was dissolved in 3.0 liters of dichloromethane. To the resulting solution was added 200 g of silica gel and the whole mixture is stirred for 30 minutes, the Silica gel was removed by filtration and the solvent is evaporated at 50°C receives 43 g of 4-amino-3,5-dimethylbenzonitrile (intermediate product).

Feature: LC (liquid chromatography), size, %: >95%.

Example 2

Mix 77,98 g of the intermediate product, which is a known product, 43 g of the intermediate product In 300 ml of NMP and 43.7 g of diisopropylethylamine and stirred for 48 hours at a temperature of 155°C. the Mixture is cooled to a temperature of 90°C and add 90 ml of water. The final product is left to crystallize slowly cooling to a temperature of 25°C. Then the final product produce by filtration and dried at 50°C. the Selected product is purified column chromatography on silica gel. Yield: 2.8 g between the exact product D.

Feature: LC, area, %: >98%.

Example 3

Mix 2.16 g of the intermediate product D and 200 ml nanometrology ether of propylene glycol (PGMME) and then add gaseous NH3at a pressure of 1 bar. The mixture is heated to a temperature of 145°C and add another NH3until the pressure reaches to 4.5 bar. The whole mixture is stirred for 20 hours at a temperature of 145°C, all the while maintaining the atmosphere of NH3at a pressure of 4.5 bar. The mixture is then stirred for 6 days at a temperature of 120°C and in an atmosphere of NH3at a pressure of 7 bar. The mixture is then cooled to a temperature of 20°C and the solvent is removed by evaporation, obtaining 3.2 g of the intermediate product that is

Feature: LC, area, %: 95.3 per cent.

Example 4

Getting connection 1

3.2 g of the intermediate product E is mixed with 150 ml of THF, 50 ml of water and 1.6 g2CO3at 25°C. After cooling to a temperature of 0°C. to this mixture of 1.03 g Br2within 10 minutes, all the while maintaining the temperature at 0°C. Then the excess Br2decompose aqueous solution of Na2S2O4. The aqueous layer was removed and the organic layer is evaporated. The residue is purified column chromatography, obtaining 1.3 g of compound 1.

Feature: LC, %mass.: 98,8%.

Example 5

The mixture to 21.91 g of the intermediate product F, 200 ml of DMA and 14.9 g of NaH (60%dispersion in oil) and stirred for 1 hour at 70°C. After cooling to a temperature of 25°C. the mixture is then poured into 2 l of water. The pH value of the thus obtained aqueous mixture was adjusted to pH=2 by addition of hydrochloric acid. The end product of G are filtering, receiving 36,92 g of compound G.

Feature: GC (gas chromatography), size, %: 100%.

Example 6

36,92 g of the intermediate product G is heated at a temperature of 220-240°C for 1 hour. After cooling to room temperature, to the mixture are added 50 ml of THF, 50 ml Meon and 16.9 g of KOH. After stirring for 1 hour at a temperature of 50°C. the reaction mixture is decomposed with 2 l of water. The pH value of the thus obtained aqueous mixture was adjusted to pH=2 by addition of hydrochloric acid. The final product is filtered off, getting 13,25 g of compound N.

Feature: GC, %: 100% of the product.

Example 7

The mixture 17,23 g of the intermediate product, to 11.61 g of the intermediate product N, 52 ml of NMP and 9.9 g2CO3stirred for 45 min at 40°C. After adding 44 ml of water desired end product is left to crystallize slowly cooling to a temperature of 25°C. the Final product is t allocate by filtration and dried at 50°C. The wet product is re-suspended in 65 ml of acetone, the product produce by filtration and dried at 50°C receives 19,43 g of the intermediate product I.

Feature: LC, area, %: 77% of the product.

Example 8

A mixture of 3 g of the intermediate product I received in the previous example, and 30 ml of NMP is heated to a temperature of 145°C. Add gaseous NH3until then, until the pressure reaches to 4.5 bar. After stirring for 4 hours at a temperature of 145°C, all the while maintaining the atmosphere of NH3at a pressure of 4.5 bar, the solvent is removed by evaporation, obtaining 1.8 g of intermediate product j

Feature: LC, area, %: 81%.

Example 9

A mixture of 1.46 g of intermediate product J is mixed with 150 ml of CH2Cl250 ml water and 0.68 g2CO3at 25°C. After cooling to a temperature of 0°C add 0,93 g Br2at 0°C for 10 minutes the resulting mixture is stirred for 1 hour at 0°C. an Excess of Br2decompose aqueous solution of Na2S2O4. The aqueous layer was removed and the organic layer is evaporated. The residue is purified column chromatography, obtaining 1 g of compound 2.

Feature: LC, area, %: 98%.

Example 10

A mixture of 9 g of the intermediate product I, 500 ml of CH2Cl2and 7,28 g m-chlormadinone acid (MSRV) is stirred for 16 hours at boiling temperature under reflux. The mixture was then washed with NaOH solution at room temperature and the solvent is evaporated, receiving of 11.45 g of the intermediate product K.

Feature: LC, area, %: 62.3% of the intermediate product To and 24.9% of the corresponding SO2product.

Example 11

A mixture of 11 g of the intermediate product (obtained in the previous example) and 300 ml of THF is heated to a temperature of 40°C and add gaseous NH3until then, until the pressure reaches to 4.5 bar. After stirring for 2 hours at 40°C and in an atmosphere of NH3at a pressure of 4.5 bar add 50 ml of NMP, and the whole mixture is stirred for 4 hours at 40°C and in an atmosphere of NH3at a pressure of 4.5 bar. After completion of the reaction the solvent is evaporated. The product is extracted from the remainder of the 2.5 l CH2Cl2and washed with 2 l of water. After separation of the solvent from the organic layer is evaporated, receiving 6 g of the product L.

Feature: LC, area, %: 34% product L.

Example 12

Mix 3.5 g of the intermediate product L (obtained in the previous example), 150 ml of THF, 10 ml of water and 1.1 g2With the 3at 25°C. After cooling to a temperature of 0°C type of 4.04 g Br2at 0°C for 10 minutes the Mixture is stirred for 1 hour at 0°C and then the excess Br2decompose aqueous solution of Na2S2O4. The separated organic layer is evaporated and the residue purified column chromatography, obtaining of 0.58 g of compound 3.

Feature: LC, area, %: 98%.

Example 13

Finished products

Capsules

Compound 1 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. Preferably 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 drying powder, solid dispersion, then fill capsule for introduction. The amount of drug loaded in one capsule, the stake is letsa ranging from 50 mg to 100 mg, depending on the size of the capsule.

Tablets film coated

Obtain core tablets

A mixture of 1000 g of compound 1, 2850 g of lactose and 1000 g of starch is mixed well and then moisturize with a solution of 25 g of sodium dodecyl sulfate and 50 g of polyvinylpyrrolidone in about 1000 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 500 g of microcrystalline cellulose and 75 g of hydrogenated vegetable oil. The entire mixture is well mixed and pressed into tablets, receiving 10,000 tablets, each containing 100 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 the thus obtained mixture in an enrobing machine.

Example 14

Antivirus spectrum

Because of the increasing emergence of drug resistant among the properties of strains of HIV, compounds according to the present invention were tested for their efficacy against clinically isolated strains of HIV with some 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 table below, columns IIIB and A-G lists the values RES50against different strains IIIB, A-G.

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

Strain And contains the Y181C mutation in the reverse transcriptase of HIV;

The strain contains the V106A mutation in the reverse transcriptase of HIV;

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

Strain D contains the Y188L mutation in the reverse transcriptase of HIV;

Strain F contains mutations L100I and K103N in the reverse transcriptase of HIV;

Strain F contains mutations K103N and Y181C in the reverse transcriptase of HIV.

Room connection.IIIBAInDEF
19,28,49,49,19,18,48,4
28,57,88,57,78,48,17,7
38,37,18,15,87,45,26,6

1. The compound of formula (I)

its pharmaceutically acceptable additive salt, where X is NH.

2. The compound according to claim 1, having antovic-1-activity, to obtain the drug.

3. Pharmaceutical composition having antovic-1-activity, containing headlight is asepticheski acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to claim 1.

4. A method of obtaining a composition according to claim 3, including a thorough mixing of the active ingredient and carrier.

5. The method of obtaining the compounds of formula (I) according to claim 1, where
the original product (X) bromilow free bromine or a bromine donor compound, such as N-bromosuccinimide, as shown in the following diagram, where X is the same as specified in claim 1:

and the compound of formula (I) is transformed into its pharmaceutically acceptable additive salt form of the acid by treatment of the corresponding acid and, on the contrary, pharmaceutically acceptable additive salt form of the acid compounds of formula (I) is transformed into the form of a free base by treatment of the salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

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

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5 cl, 7 tbl, 14 ex

FIELD: medicine.

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

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5 cl, 4 tbl, 6 ex

The invention relates to organic chemistry and can find application in medicine

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FIELD: medicine, pharmaceutics.

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

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FIELD: medicine, pharmaceutics.

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13 cl, 2 dwg, 14 tbl, 7 ex

FIELD: medicine, pharmaceutics.

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22 cl, 2 tbl, 6 ex

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

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

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

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EFFECT: increased effectiveness of the compounds.

4 cl, 2 dwg, 4 tbl, 1 ex

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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: medicine.

SUBSTANCE: invention refers to medicine and concerns a microbicidal agent delivery systems including a microbicidal composition containing a microbicidal compound which represents a dendrimer including one or more surface groups of formula (IV); its microbicidally active derivative or its pharmaceutically acceptable salt or solvate; and a carrier, an excipient or a diluent for the active compound; and also a preventive device. And the microbicidal composition is applied on a surface of the preventive device and is compatible therewith.

EFFECT: invention provides effective delivery of the microbicidal compositions which are structurally and chemically compatible with the preventive device.

22 cl, 5 ex, 3 tbl

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology, specifically to obtaining a human immunoglobulin based preparation, and can be used in medicine. The preparation is obtained via purification of class G, A and M immunoglobulins isolated from the blood of HIV infected patients through affinity chromatography on a column with integrase-sepharose.

EFFECT: invention enables to obtain class G, A and M immunoglobulins isolated from the blood of HIV infected patients, capable of selectively splitting HIV integrase only.

7 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) or its pharmaceutically acceptable salt, mediated by glutamate receptor, and to based on them pharmaceutical composition. (I), where R1 stands for C1-6alkyl; R2 and R3 stand for hydrogen; p stands for 0; n stands for 1; R5 and R6 stand for hydrogen, and Het stand for thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidozolyl, each of which can be substituted with one or two groups, independently selected from the list, which consists of C1-6alkyl, C1-6alkoxy, acetyl, halogen, halogenC1-6alkyl, cyano.

EFFECT: creation of compound which has property to enhance response reaction.

4 cl, 2 tbl, 6 dwg, 38 ex

FIELD: medicine, veterinary science.

SUBSTANCE: invention concerns veterinary. The preparation contains the following drugs: L-arginine monohydrochloride in amount 48-72 mg/l, L-lysine monohydrochloride in amount 48-72 mg/l, L-histidine monohydrochloride in amount 13.8-20.8 mg/l, L-isoleucine in amount 13.8-20.8 mg/l, L-leucine in amount 41.6-62.4 mg/l, L-methionine in amount 10.4-15.6 mg/l, L-phenylalanine in amount 17.2-25.8 mg/l, L-threonine in amount 20.8-31.2 mg/l, L-tryptophan in amount 7.9-10.3 mg/l, L-glutamine in amount 68.8-103.2 mg/l, L-valine in amount 17.2-25.8 mg/l, L-tyrosine in amount 27.7-41.5 mg/l, L-cystine monochloride in amount 17.9-26.9 mg/l, L-serine in amount 17.2-25.8 mg/l, glycine in amount 34.4-54.6 mg/l, L-alpha-alanine in amount 17.2-25.8 mg/l, L-proline in amount 25.6-38.4 mg/l, L-aspartic acid in amount 18.0-30.0 mg/l, L-oxyproline in amount 7.9-10.3 mg/l, L-glutamic acid in amount 48-72 mg/l, L-cysteine monohydrochloride in amount 0.12-0.70 mg/l, choline chloride in amount 0.4-3.0 mg/l, folic acid in amount 0.01-0.09 mg/l, calcium pantothenate in amount 0.01-0.09 mg/l, thiamine hydrochloride in amount 0.01-0.09 mg/l, nicotinic acid in amount 0.03-0.22 mg/l, pyridoxal monohydrochloride in amount 0.03-0.22 mg/l, riboflavin in amount 0.012-0.09 mg/l, nicotinamide in amount 0.03-0.22 mg/l, D-biotin in amount 0.01-0.09 mg/l, myoinositol in amount 0.06-0.45 mg/l, pyridoxine hydrochloride in amount 0.03-0.22 mg/l, calciferol in amount 0.01-0.09 mg/l, ascorbic acid in amount 0.06-0.45 mg/l, p-amino-benzoic acid in amount 0.06-0.45 mg/l, glucose in amount 800-1200 mg/l, and the following inorganic salts: sodium chloride in amount 7.2-8.8 g/l, potassium chloride in amount 360-440 mg/l, one-substituted potassium phosphate in amount 54-66 mg/l, two-substituted 12-aqueous sodium phosphate in amount 13.5-16.5 mg/l, 6-aqueous calcium chloride in amount 24.8-30.4 mg/l, 6-aqueous magnesium chloride in amount 9.9-11.6 mg/l, 7-aqueous magnesium sulphate in amount 9.0-11.0 mg/l, 9-aqueous ferrous nitrate in amount 0.65-0.79 mg/l, 3-aqueous sodium acetate in amount 7.1-8.7 mg/l. The method for prevention and correction of diseased conditions in animals consists in the injection introduction in an animal of said preparation in the form of an aqueous solution for prevention 2 times a week for a month in dosage 1.5-2.0 ml per 10 kg of body weight, for therapy in dosage 3.0-5.0 ml per 10 kg of body weight 2 times a day for 3-5 days, at synthetic and/or food poisoning intoxications - in a tenfold therapeutic dose. And, if a dose of the preparation exceeds 20 ml, it is injected in more points.

EFFECT: invention provides higher therapeutic and preventive effectiveness.

6 cl, 8 tbl

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

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 of the formula (I) where: A is an aryl or a 5-member heteroaryl containing a S heteroatom, possibly substituted with one or two substitutes selected from a group consisting of halogen, C1-6-alkyl or C1-6-alkoxy; n equals 1 or 2; p equals 1, 2, 3 or 4; q equals 1; r equals 0 or 1; R1 is C2-6-alkynyl substituted with aryl, or C1-6-alkyl possibly substituted with one-five substitutes selected from a group consisting of halogen, hydroxy, C1-6-alkyl, C1-6-halogenoalkyl, -OC(O)-C1-6-alkyl, C3-10-cycloalkyl, C1-6-alkoxy, possibly substituted with one, two or three halogens or aryl, aryl which is possibly substituted with a halogen or C1-6-alkoxy, 5-9-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N or O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl, and phenoxyl, or is C1-6-alkoxy, or is C3-10-cycloalkyl which is possibly substituted with one or more Ra, or is a 5- or 6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with one or more Ra, or is an aryl possibly substituted with one or more Ra, or is a 5-10-member heteraryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, possibly substituted with one or more Ra, or is -NRbRc, where Rb is H or C1-6-alkyl and where Rc is H, C1-6-alkyl or aryl, possibly substituted with one or more Ra, where Ra is selected from: halogen, cyano, oxo, hydroxy, halogenobenzenesulfonyl, C1-6-alkyl, possibly substituted with one, two or three substitutes selected from a group consisting of 5-10-member heterocycloalkyl and aryl, which is possibly substituted with halogen or C1-6-alkoxy, C1-6-halogenoalkyl, C1-6-halogenoalkoxy, C1-6-alkoxy, possibly substituted with aryl or 5-10-member heteroaryl, one, two or three ring atoms of which are heteroatoms selected from N, O and S, and the rest of the ring atoms are C atoms, which is possibly substituted with C1-6-alkyl, aryloxy, -NH(CO)-C1-6-alkyl, -O(CO)-C1-6-alkyl, C1-6-alkylsulfonyl, aryl, 4-6-member heterocycloalkyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-6-alkyl or oxo, 5-10-member heteroaryl,one, two or three ring atoms of which are heteroatoms selected from N and O, and the rest of the ring atoms are C atoms, possibly substituted with C1-6-alkyl or oxo, and di(C1-6)alkylamino; R2 is H, OH, C1-6-alkyl or halogen; as well as their pharmaceutically acceptable salts. The invention also relates to medicine and to use of the compounds in any of paragraphs 1-24.

EFFECT: obtaining novel biologically active compounds with affinity to dopamine D3 receptor and to serotonin 5- HT2a receptor.

27 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dermatovenerology and can be used for treatment of syphilis. For this purpose simultaneously with traditional antibacterial therapy perorally introduced is solution of probiotic Bactisporin not less than 4 doses 3 times a day during 3-5 days. After that 1 dose is introduced 2 times a day during 10-15 days. Also introduced is oxymethyluracyl in dose 0.5 g 2 times a day during 10 days.

EFFECT: method ensures accelerating negativation of complex of serologic reactions.

2 tbl

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