Hiv-inhibiting 2-(4-cyanophenylamino)-pyrimidine-oxide derivatives
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
The present invention relates to derivatives of pyrimidine-oxide having the property of inhibiting the replication of HIV (Human Immunodeficiency Virus), to receive them and to pharmaceutical compositions containing these compounds.
Resistance of HIV to currently available drugs against HIV continues to be the primary cause of failure in the treatment. This has led to the introduction of combination therapy with two or more anti-HIV agents, usually having different activity profile. Significant progress has been achieved through the introduction of HAART (Highly Active Anti-Retroviral Therapy HAART Highly Active Anti-Retroviral Therapy), which has led to a significant reduction of morbidity and mortality among patients with HIV, affected by this treatment. HAART consists of various combinations of nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). Modern guidance on antiviral therapy recommend this triple combination regimen even in the case of the initial treatment. However, such politicalscience treatment is not always effective and never completely cure HIV. It is reported that half of patients receiving combination anti-HIV treatment, responds to treatment is not completely mainly due to steady the particular virus to one or more of the used drugs. Transition to alternative combination usually gives temporary relief, but any form of long-term treatment is ultimately unsuccessful, as it develops politikarena stability. Moreover, it is shown that resistant virus is transferred to the newly infected individuals, resulting in severely limited treatment options in case-insensitive drugs for patients.
Thus, there remains a need for new drug combinations that are effective against HIV. In such new combinations, new types of HIV inhibitors that differ in chemical structure and activity profile. Therefore, the discovery of new active ingredients is highly desirable.
The present invention offers particular attention to the new series of derivatives of biaryl-substituted pyrimidine, which may find application in the treatment of HIV, especially as a new component of drug combinations. In the publication WO 00/27825 describe the individual biaryl-substituted pyrimidines having the properties of inhibiting HIV replication. Compounds of the present invention behave is excellent from the viewpoint of inhibiting HIV replication and exhibit improved ability to inhibit the replication of mutant strains, especially strains that have become Usto is sustainable to one or more known NNRTIS, these strains are referred to as strains resistant to the drug or multiple drugs.
The present invention relates to compounds of the formula:
to pharmaceutically acceptable additive salts or their stereochemical isomeric forms, where
R1represents a halogen atom;
R2and R3each independently from each other represents C1-6-alkyl.
As used in this case, the definition of "C1-4-alkyl" means a linear or branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, etc.; "C1-6-alkyl" covers1-4-alkyl radicals and their higher analogues containing 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. are Preferred from1-6-Akilov are1-4-alkyl radicals.
The term "halogen" includes fluorine atoms, chlorine, bromine and iodine.
Compounds of the present invention contains N-oxide bond, which may be represented by NO, N=O or N+-O-or, as mostly used in this application and in the claims, N→O.
In the case of therapeutic use of salts of compounds of formula(I) are salts, where the counterion is pharmaceutically acceptable. However, salts which are pharmaceutically unacceptable, can also find use, for example, upon receipt or when cleaning pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or not, are included in the scope of the present invention.
The definition of "pharmaceutically acceptable salt additive"used in this description, covers therapeutically active non-toxic acid additive salt form, which are capable of forming compounds of formula (I). Salt forms can usually be obtained by processing the main form with appropriate acids such as inorganic acids, for example halogen acid, i.e. hydrochloric, Hydrobromic acid, etc.; sulfuric acid; nitric acid; phosphoric acid and so on; or organic acids, for example, acetic, propanoic, hydroxyestra, 2-hydroxy-propane, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be excellent asana by treatment with alkali in the free basic form. The compounds of formula (I)containing acidic protons may be converted into their therapeutically active non-toxic salt additive forms of metals and amines by treatment with appropriate organic and inorganic bases.
The definition of the additive salt also comprises the hydrates and additive form with a solvent that is able to form compounds of formula (I). Examples of such forms are the hydrates, the alcoholate and other
Some compounds of formula (I) and their additive salts may contain one or more chiral centers and may exist in the form of stereochemical isomeric forms. Stereoisomer may exist when R2and R3represent4-6-alkyl. The definition of "stereochemical isomeric forms"as used in this description, defines all the possible stereoisomeric forms which the compounds of formula (I) and their salt additive may have. Assume that the stereochemical isomeric forms of the compounds of formula (I) are included in the scope of the present invention.
Preferred subgroups of compounds are the compounds of formula (I)defined above, or any subgroup of compounds of formula (I)defined herein, where R1represents a chlorine atom or bromine, more preferably where R1represents the ATO is bromine.
Other preferred subgroup of compounds are the compounds of formula (I)defined above, or any subgroup of compounds of formula (I)defined herein, where R2and R3represents a C1-4-alkyl, more preferably where R2and R3represent1-2-alkyl, even more preferably where R2and R3represent methyl.
Special attention is given to the compounds of formula (I), where R1represents bromine and R3represents methyl.
In General, compounds of formula (I) can be obtained by N-oxidation of the corresponding compounds of the formula (II) using known in the field of methods of transformation of the tertiary nitrogen atom in its N-oxide form.
The reaction of N-oxidation with the aim of obtaining compounds of formula (I) can be carried out by introducing into a reaction starting material of formula (II) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxide of an alkali metal or alkaline earth metal, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may be nagkalat, such as, for example, natantia acid or halogen-substituted on the benzoic acid, for example 3-chlormadinone acid; peroxo-alcamovia (Nedelcheva) acids, such as peracetic acid; alkylhydroperoxide, for example, tert-botellita peroxide. Preferred is 3-chlormadinone acid (m-HNBK). The reaction of N-oxidation is usually carried out in a suitable solvent, such as, for example, water, lower alcohol, for example ethanol and others; hydrocarbons such as toluene; a ketone, for example acetone or 2-butanone; halogenated hydrocarbons such as dichloromethane or chloroform; and any mixtures of such solvents. Preferred are halogenated hydrocarbons, in particular dichloromethane. The final products can be purified using methods generally known in the art, such as extraction, crystallization, rubbing and chromatography.
The initial compounds of the formula (II) are known compounds, which can be obtained in accordance with the techniques described in the publication WO 00/27825. They can be obtained by the reaction of intermediate compounds of formula (III) or (V) with an intermediate compound of formula (IV) or (VI), as shown in the following reaction scheme, where the substituents R1, R2and R3have the meanings defined for compounds of formula (I) or any subgroup, and W represents a suitable leaving group,such as, for example, a chlorine atom, etc.
The reaction of the pyrimidine derivative (III) and (V) cyanoaniline (IV) and, respectively, with cyanophenyl derivative (VI) is preferably carried out in a suitable solvent, such as, for example, an alcohol, such as methanol, ethanol, 2-propanol; N,N-dimethylformamide; N,N-dimethylacetamide and 1-methyl-2-pyrrolidinone; 1,4-dioxane; onomatology ether of propylene glycol; acetonitrile. The reaction can be carried out in acidic conditions, which can be obtained by adding a suitable acid, for example camphorsulfonic acid, to a suitable solvent, such as tetrahydrofuran or an alcohol, e.g. ethanol, 1 - or 2-propanol, or by using acidified solvents, for example, hydrochloric acid, dissolved in alkanol, such as ethanol, 1 - or 2-propanol.
The compounds of formula (II) can be also obtained by the reaction of cyanoaniline derivative (VII) with a pyrimidine derivative (VIII) or reaction cyanophenyl derivative (IX) with a pyrimidine derivative (X), as shown in the following schema.
In the above reaction schemes, R1, R2and R3have the meanings given above for compounds of formula (I) or any subgroup, and W represents a suitable the walking group, such as, for example, halogen atom, e.g. a chlorine atom, etc. These reactions are preferably carried out in a suitable solvent, in particular in any of the solvents mentioned above in connection with reaction (III) c (IV).
Another way of obtaining compounds of formula (II) is galogenirovannyie source material (XI) - free halogen, for example chlorine or bromine, or a halogen donor such as N-bromo - or N-chlorosuccinimide. The above halogenation reaction is preferably carried out in a suitable inert reaction solvent such as simple air, especially in THF. N-bromo or N-chlorosuccinimide can be used in the presence of acetic acid.
The compounds of formula (I) can also be obtained by transformation of compounds of formula (I) into each other in accordance with well-known in this field reactions of transformation groups. For example, chlorinated analogs can be converted into the corresponding brominated analogues or, on the contrary, the exchange reaction of halogen.
The compounds of formula (I) can also be obtained using any methods known or described in this paper to obtain the compounds of formula (II), but replacing, where possible, pyrimidine starting materials the corresponding pyrimidine-oxides. The latter compound can be floor is obtained similarly by the reaction of N-oxidation, described for the conversion of (II) in (I).
Some compounds of formula (I) and some previous intermediate compounds may contain an asymmetric atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained by applying known in the field of methods.
The synthesis of certain intermediates used in the preceding reaction schemes described below, where the following reaction schemes, R1, R2and R3have the meanings given above for compounds of formula (I) or any subgroup, and W represents a suitable leaving group, particularly chlorine atom or bromine. The radical R1represents a halogen atom, but the following reaction schemes it can also be a predecessor of halogen, for example, the hydroxy-group or a protected hydroxy-group (for example, benzyloxy), which can be converted into a halogen using a halogenation agent such as POCl3or POBr3. It may be preferred to avoid side reactions.
Intermediate compounds of formula (III) can be obtained by the reaction of a derivative of phenol (XII) with a pyrimidine derivative (XIII), as described in the following reaction scheme.
Similarly, the intermediate compound (V) can be obtained based on pyrimidine (XV), as described in the following diagram:
In the above reaction, the amino group may be protected or not protected with suitable protecting group.
Intermediate compound (X) can be obtained by condensation of the pyrimidine derivative (XVI) with a 4-aminobenzonitrile, as shown in the diagram below. If it is desirable to prevent adverse reactions, HE - and/or amino group can be protected, and R1can be a precursor of halogen, as described above.
Intermediate compounds of formula (XI) can be obtained as described in the reaction scheme below. First 4-aminobenzonitrile enter into reaction with cyanamide to obtain 4-cyanopyrimidine (XVII). The above reaction can be carried out in water in the presence of a strong acid, for example hydrochloric acid, at elevated temperature, for example at a temperature of approximately from 50 to 70°C., for example, at approximately 60°C. the Latter compound is introduced into reaction with di-C1-6-alkyl-malonic ester of the formula (XVIII), where each substituent R is independently represents a C1-6-alkyl, preferably each R is a methyl. This reaction can be conducted is in a suitable solvent, for example in an alcohol, such as methanol, in the presence of a strong base such as an alkali metal alkoxide such as sodium methoxide, at elevated temperatures such as the boiling temperature under reflux. The resulting 4,6-dihydroxypyrimidine (XIX) make pyrimidine derivative (XX), where W represents a leaving group and in particular a halogen atom, preferably a chlorine atom or bromine. This transformation can be carried out using a suitable halogenation agent such as POCl3or POBr3, in a suitable solvent, in particular in polar aprotic solvent, for example, DMF, DMA, HMPA, N-organic, DMSO, etc., preferably in acetonitrile. Other leaving groups can be introduced by known in this field reactions of transformation of the alcohol into a leaving group. Derived pyrimidine (XX) is then injected into the reaction with 4-substituted benzonitrile (XXI) to give the desired intermediate compound (XXI). The reaction of (XX) (XXI) can be held in a suitable solvent, such as a simple ether, for example THF, halogenated hydrocarbon, for example, CH2Cl2, CHCl3and , in particular, in a polar aprotic solvent, for example, DMF, DMA, HMPA, acetonitrile, DMSO, etc. and preferably in N-organic. To bind the acid which is liberated during the reaction, can be added to the basis, for example, a carbonate of an alkali metal such as potassium carbonate.
The compounds of formula (I) possess antiviral properties (properties of inhibiting reverse transcriptase inhibitors), in particular, they are active against HIV, which is the etiologic agent of acquired immunodeficiency syndrome (AIDS) in humans. HIV primarily infects the T-4 cells and then destroy them or change their normal function, particularly the coordination of the immune system. In the infected patient has permanently reduced the number of T-4 cells, which, in addition, behave abnormally. Therefore, protective immune system unable to fight off infections and tumors, and HIV-infected subject usually die from opportunistic 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, leading to dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. HIV infection is also associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL, PGL) or AIDS-associated complex (ADC ARC).
Connect the means of the present invention also show activity against mutant strains of HIV, including once, twice, three times and repeatedly mutated strains. Compounds of the present invention is active against HIV strains resistant to many drugs, particularly against resistant to many drug-resistant HIV-1, more preferably the considered compounds exhibit activity against HIV strains, especially strains of HIV-1 that have acquired resistance to one or more known in the field of non-nucleoside reverse transcriptase inhibitor. Known non-nucleoside reverse transcriptase inhibitors represent a non-nucleoside reverse transcriptase inhibitors, non of the considered compounds and known to experts in this field, in particular in the sale of non-nucleoside reverse transcriptase inhibitor. Compounds of the present invention have a slight affinity binding or do not have the affinity of binding to human α-1 acid glycoprotein; human α-1 acid glycoprotein may not influence or only weakly affect the anti-HIV activity of the considered compounds.
Thanks to antiretroviral properties, particularly anti-HIV properties, especially anti-HIV-1 activity, the compounds of formula (I), their pharmaceutically acceptable salt additive and stereochemical isomeric fo what we are useful in the treatment of individuals, infected with HIV and for the prophylaxis of these infections. In General, compounds of the present invention can be used in 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 using the compounds of the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-associated 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.
Thus, the compounds of the present invention or any subgroup can be used as drugs against the above-named States. The specified application as a medicine or method of treatment includes the introduction of HIV-infected subject number of compounds effective to combat the conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1. In particular, the compounds of formula (I) can be used in the manufacture of a medicinal product for treating or preventing HIV infection.
In it is one aspect of the present invention provides a method of treating warm-blooded animals, including humans, suffering from viral infections, or the means of preventing warm-blooded animals, including humans, from viral infections, especially HIV infections. This method consists of the administration, preferably oral administration, of an effective amount of compound (I), its pharmaceutically acceptable salt or additive it is possible stereochemical forms of warm-blooded animals, including humans.
According to another aspect of the compounds of formula (I) or any of their subgroups can be used in the method of preventing, treating or combating infection or disease associated with infection of a mammal mutant virus HIV, which includes an introduction to the specified mammal an effective amount of the compounds of formula (I) or any of its subgroups.
In another aspect, the compounds of formula (I) or any subgroup can be used in the method of preventing, treating or combating infection or disease associated with infection mammals HIV multidrug resistance, which includes the introduction of the specified mammal an effective amount of the compounds of formula (I) or any of its subgroups.
In another aspect the compounds of formula (I) or any subgroup can be used in the method of inhibiting HIV replication in h is particularly HIV, having a mutant reverse transcriptase of HIV, more preferably a mutant reverse transcriptase of HIV multidrug resistance, which includes the introduction of the specified mammal an effective amount of the compounds of formula (I) or any of its subgroups.
Preferably mammals, referred to in the present invention, is the man.
The present invention also provides compositions for the treatment of viral infections, containing a therapeutically effective amount of the compounds of formula (I), and pharmaceutically acceptable carrier or diluent.
Compounds of the present invention or any subgroup for the purposes of the introduction can be obtained in various pharmaceutical forms. As appropriate compositions can be called all compositions usually employed for systematic drug. To obtain pharmaceutical compositions of the present invention an effective amount of a particular compound, optionally in the acid-additive form, as the active ingredient is mixed into a homogeneous mixture with a pharmaceutically acceptable carrier, and this carrier can have a wide variety of forms depending on the form required for drug administration. Such pharmaceutical compositions are desirable in a single dosiro the authorized form, acceptable, preferably for administration orally, rectally, subcutaneously, or by parenteral injection. For example, upon receipt of a composition in oral dosage form may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, etc. in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, thinners, latrikunda, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules are the most preferred oral unit dosage forms, in which, of course, are for solid pharmaceutical carriers. In the case of parenteral compositions, the carrier will usually be a sterile water, at least in the most part, although there may be other ingredients, for example, to facilitate solubility. Can be prepared, for example, injectable solutions, in which the carrier is a saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared injectable suspension, which can be used suitable liquid carriers, suspe gerousia agents etc. In addition, there are drugs in solid form, which, as implied, immediately before the application was transferred to the medication liquid form. In the compositions suitable for subcutaneous administration, the carrier optionally contains an agent that enhances the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, and such additives do not have a strong negative impact on the skin. These supplements can facilitate application to the skin and/or can provide the required composition. Such compositions can be introduced by any means, for example, in the form of a transdermal patch, in the form of a label in the form of ointment. Compounds of the present invention can be introduced through inhalation or by injection using the methods and drugs used in this area for the introduction of so. Therefore, in General, compounds of the present invention can be introduced 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 the introduction of the considered compounds.
To facilitate the solubility of the compounds of formula (I) in the composition can be add the received appropriate ingredients, for example cyclodextrins. Appropriate cyclodextrins are α-, β-cyclodextrins or ethers and mixed ethers, where one or more hydroxyl groups of glucose units of the cyclodextrin substituted With1-6-alkyl, especially stands, ethyl or isopropyl, e.g. randomly methylated β-cyclodextrin; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, particularly carboxymethyl or carboxyethyl; C1-6-alkylcarboxylic, especially acetyl. Especially significant 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-GP-β-CD). Another type of substituted cyclodextrins are sulfosalicylate.
The definition of "mixed ethers" means derivative of cyclodextrin in which at least two hydroxy-groups of the cyclodextrin tarifitsirovana different groups, for example, hydroxypropyl and hydroxyethyl.
The average molar substitution (MS) is used as a measure of the average number of moles of alkoxy units per mole glucose residues. The average degree of substitution (SZ) refers to the average number of sameindividualas per mole glucose residues. Values MZ and SZ can be determined using various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectrometry (IR). Depending on the method used may be several different values obtained for one of this cyclodextrin derivative. Preferably when measured using mass spectrometry value MS are in the range from 0.125 to 10 and the values of SZ are in the range 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 appropriate pharmaceutically acceptable water-soluble polymers.
The definition of "solid dispersion", as used herein, refers to a system in a solid state (as opposed to liquid or gaseous state), containing at least two components, i.e. the compound of formula (I) and water-soluble polymer, where one component is distributed more or less evenly throughout the other component or components (in the case when additional pharmaceutically acceptable prescription agents known in this field, such as plasticizers, preservatives, etc). When this variance component is akova, that the system is chemically and physically uniform or homogenous throughout or consists of one phase, as defined in thermodynamics, this dispersion is called a "solid solution". Solid solutions are preferred physical systems, as components in them are usually readily bioavailable to organisms in which they entered.
The definition of "solid dispersion" also includes dispersion, which are less homogeneous throughout the volume than solid solutions. Such dispersions are not chemically and physically homogeneous throughout the volume or contain more than one phase; for example, systems having domains or small region where amorphous, microcrystalline or crystalline compound of formula (I) or amorphous, microcrystalline or crystalline water-soluble polymer, or both are more or less equal in the other phase containing water-soluble polymer or the compound of formula (I), or a solid solution containing the compound of formula (I) and water-soluble polymer. These domains represent the area within the solid dispersion, clearly marked by some physical feature, small in size and evenly and statistically distributed throughout the solid dispersion.
There are various methods of obtaining the solid is x dispersions, including extrusion from the melt, spray drying and dissolution-evaporation. After receiving the solid dispersions obtained products may not necessarily be crushed and sifted. The solid dispersion may be subjected to a milling or grinding to particles having a size less than 600 microns, preferably less than 400 μm and most preferably less than 125 microns. Particles obtained above can then be converted using conventional methods in the pharmaceutical dosage forms such as tablets or capsules.
Water-soluble polymers in the particles are polymers having an apparent viscosity, when dissolved at 20°C in aqueous solution at a concentration of 2% (wt./vol.), from 1 to 5000 MPa·s, more preferably from 1 to 700 MPa·s and most preferably from 1 to 100 MPa·s. For example, suitable water-soluble polymers are 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 its salts with alkali metal or ammonium salts, carragenan, galactomannan, tragakant, agar-agar, Ara is the Iisko gum and xanthan gum, polyacrylic acids and their salts, polymethacrylic acids and their salts, copolymers of methacrylate, 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.
In addition, one or more cyclodextrins can be used as the water-soluble polymer when receiving the above-described particles, as disclosed in the publication WO 97/18839. These cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in this field, more specifically, α-, β - and 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 No. 3459731. In addition, the substituted cyclodextrins are cyclodextrins described as agents that promote the solubility of the compounds of formula (I).
The ratio of the compounds of formula (I) to a water-soluble polymer may vary within wide limits. For example, can be used relations from 1:100 to 100:1. Imagine what their interest is the relationship of the compounds of formula (I) to the cyclodextrin are in the range from about 1:10 to 10:1. More preferably are in the range of from 1:5 to 5:1.
In addition, it is also convenient to make the composition of the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface in sufficient quantity to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include modifiers that are physically attached to the surface of the compounds of formula (I), but not chemically associated with the specified connection and can be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface modifiers are non-ionic and anionic surfactants.
Another interesting method of preparation of compounds of formula (I) includes a pharmaceutical composition, whereby the compounds of formula (I) is introduced into the hydrophilic polymer, and applying this mixture as a covering film over many small beads; the result is a composition that can be conveniently manufactured and which is suitable for producing pharmaceutical dosage Faure is for oral administration. These balls have a Central, rounded or spherical core, covering the film of the hydrophilic polymer and the compounds of formula (I) and optional insulating covering layer. Materials suitable for use as a core in the beads are different, provided that these materials are pharmaceutically acceptable and have the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and sugars, and their derivatives.
Especially preferably to be named pharmaceutical composition in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form in this description are called physically discrete elements, suitable as single doses, each element contains a predetermined quantity of active ingredient calculated to produce 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, sachet powders, pills, suppositories, injectable solutions or suspensions, etc. and a separate composite structure.
Specialist in the treatment of HIV infection can op is adelite effective daily amount presented in the description of the test results. In General implies that the effective daily amount may be from 0.01 to 50 mg/kg body weight, more preferably from 0.1 to 10 mg/kg of body weight. It may be acceptable to enter the desired dose in the form of two, three, four or more sub-doses at appropriate intervals throughout the day. These sub-doses may be prepared as unit dosage forms, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of active ingredient in a unit dosage form.
The exact dosage and frequency of injection depend on the specific compounds of formula (I), the condition treated, the severity of the condition treated, age, weight and General physical condition of the particular patient, and other medications that the individual may accept, which is well known to specialists in this field. Moreover, it is obvious that the effective daily amount may be reduced or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the present invention. Therefore, the ranges of effective daily amounts mentioned above are reference only and in no way are intended to limit the scope the invention or its application.
Consider the compounds of formula (I) can be used alone 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 alone or in combination with other prophylactic agents for the prevention of viral infections. Compounds of the present invention can be used in the vaccines and methods of protecting the individual against viral infections over a long period of time. The compounds may be used in such vaccines or separately, or together with other compounds of the present invention, or in combination with other antiviral agents in accordance with usual practice, the use of reverse transcriptase inhibitors in vaccines. Therefore, the compounds can be combined with pharmaceutically acceptable adjuvants commonly used in vaccines, and put in prophylactically effective amounts to protect individuals from HIV infection for an extended period of time.
In addition, as the drugs you can use one or more additional antiviral compounds and a compound of formula (I). Therefore, the present invention also relates to the product that contains Adamu (a) compound of formula (I) and (b) one or more additional antiviral compounds in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of HIV. Various medications can be combined in one preparation together with pharmaceutically acceptable carriers. These other antiviral compounds can be any known antiviral compounds, such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran-sulfate), foscarnet-sodium (trinatriumfosfaat); nucleoside reverse transcriptase inhibitors (NRTIs)such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (ReversetTM), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ASN-126443) and so on; 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, etc.; nucleotide reverse transcriptase inhibitors (NtRTI), such as tenofovir (TDF) and fumarate tenofovir-disoproxil etc.; compounds of the TIBO (tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2-(1H)-about-tinawag) type, for example, (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; compounds of the α-APA (α-anilinoquinazolines) type e.g. α-[(2-nitro-phenyl)amino]-2,6-dichlorobenz the acetamid etc.; inhibitors of TRANS-activating proteins, such as TAT-inhibitors, e.g., RO 5-3335; inhibitors REV; 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-756432, tipranavir (PNU-140690), BILA 1096BS, U-140690, etc.; entry inhibitors, which include fusion inhibitors (e.g., T-20, T-1249), attachment inhibitors and inhibitors of co-receptors; the latter include antagonists of CCR5 and CXR4 antagonists (e.g., AMD-3100); examples of entry inhibitors are enfuvirtide (ENF), GSK-873,140, PRO-542, SCH-417,690, TNX-355, maraviroc (UK-427,857); inhibitor of suppuration, for example, is PA-457 (Panacos Pharmaceuticals); inhibitors of viral integrase; inhibitors ribonucleotidic reductase (cellular inhibitors), for example, hydroxyurea and other
By introducing compounds of the present invention with other antiviral agents that target different events in the development cycle of the virus, can be potentiated therapeutic effect of these compounds. Combined treatment, which is described above, provides a synergistic effect in the inhibition of HIV replication, because each component of the combination acts on different sites of HIV replication. Applied to the e of these combinations can reduce the dosage of this conventional antiviral agent, which would be required to achieve the desired therapeutic or prophylactic effect in comparison with when the agent is introduced in monotherapy. Such combinations can reduce or eliminate the side effects of conventional separate anti-retroviral therapy without interfering with antiviral agents. Such combinations reduce potential resistance to treatment with one agent, while minimizing any associated toxicity to a minimum. These combinations can also increase the effectiveness of conventional agents without increasing the associated toxicity.
In addition, the compounds of the present invention can be introduced in combination with immunomodulatory agents such as levamisole, bropirimine, the antibody against human alpha-interferon, interferon-alpha, interleukin 2, methionine-enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone and so on; antibiotics such as pentamidine isetionate etc.; cholinergic agents such as takin, rivastigmine, donepezil, galantamine, etc.; blockers of the NMDA channel, such as memantine; to prevent or eliminate infection and diseases or symptoms related to HIV infection, such as AIDS and ARC, for example, dementia. The compounds of formula (I) can also be combined with other compounds of the formula (I).
Although the present invention focuses on the application of the compounds for the prevention or treatment of HIV infection, consider the connection can also be used as inhibitory agents for other viruses that depend on such reverse transcriptase inhibitors in their reproduction.
The following examples are intended to illustrate the present invention and do not limit its scope.
Example 1: Synthesis of N-oxide 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy] - for 3,5-dimethylbenzonitrile
A mixture of 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy] - for 3,5-dimethylbenzonitrile (intermediate compound 1; 5,00 g; 11.5 mmol) and m-HNBK (3 EQ., 34.5 mmol, 8,50 g, 70 wt.%) refluxed in dichloromethane (100 ml). 10 minutes later formed a clear solution, and after 5 minutes, a precipitate may form. The mixture is refluxed for a further 15 minutes, cooled to room temperature and the white solid filtered off and washed with dichloromethane. A solid connection is stirred in acetic acid for 1 hour, filtered and dried, to obtain 1.7 g (33%) of compound 1.
Physical characteristics: TPL 271°C (Asón);
Range1H NMR (300 MHz, DMSO) δ ppm: 1,90 (s, 2,25N, Asón), 2,12 (C, 6N), 7,39 (d, 2H), 7,40 (d, 2H), 7,76 (s, 2H), 7.95 is ush. s, 1H), 10,2 (ush. s, 1H). The product contains 0.75 equivalents of acetic acid.
Data analysis LC-MS (linear gradient, 1 ml/min from t095% 10 mm aqueous HCOOH/acetonitrile to t155% 10 mm aqueous HCOOH/acetonitrile, UV-DAD): purity 95%, t=9,49 min, mass spectrum m/z 449, 451 [M-N]-.
Example 2:The form of pharmaceutical compositions.
Compound 1 described in example 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 polyvinyl pyrrolidone and vinyl acetate (PVP-VA) or hydroxypropylmethyl-cellulose (HPMC), typically with a viscosity of 5 MPa·sec, dissolved in organic solvents, such as ethanol, methanol, methylene chloride. The corresponding 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 ratio can be 1:1.5 and 1:3. A suitable ratio may be 1:6. Dried spray dried powder, solid dispersion, is then filled capsules, intended for insertion. Download drugs on one capsule is in the range from 50 to 100 mg depending on the size of the used capsules.
Tablets film coated
Receipt the core tablets
A mixture of 100 g of compound 1, 1,750 g of lactose and 200 g starch is thoroughly mixed and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 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 whole mixture was thoroughly mixed and pressed into tablets, get 10,000 tablets each containing 10 mg of active ingredient.
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. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first, and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinyl-pyrrolidone and 30 ml of concentrated suspensions of the dye, and then all homogenized. Core tablets cover the mixture in the device for applying the coating.
Example 3:Spectrum of antiviral activity
Due to the increasing emergence of drug-resistant HIV strains examined compounds were tested for their potential activity against clinically isolated strains of HIV that have accumulated multiple mutations. Such mutations include what are stated resistance to reverse transcriptase inhibitors and lead to viruses, which show various degrees of phenotypic cross-resistance to modern commercially available drugs, such as AZT and delavirdine.
Antiviral activity of the compounds of the present invention estimate in the presence of wild-type HIV and HIV mutants carrying mutations in the gene for reverse transcriptase. The activity of the compounds evaluated using cell analysis, and the residual activity is expressed in values RES50. In the table in columns IIIB and A-G are 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 K103N mutation in the reverse transcriptase of HIV,
Strain C contains the L100I mutation in the reverse transcriptase of HIV,
Strain D contains mutations Y1881L and S162K in the reverse transcriptase of HIV,
Strain F contains mutations L100I and K103N in the reverse transcriptase of HIV,
Strain F contains mutations K101E and K103N in the reverse transcriptase of HIV.
|1||9,24||9,20||cent to 8.85||9,20||which 9.22||8,97||8,98|
The compound a is a compound of comparison, is a compound, referred to in example 1, "intermediate connection 1", and is described in the publication WO 00/27825.
1. The compound of the formula
its pharmaceutically acceptable additive salt, where
R1represents a bromine atom;
R2and R3each independently from each other represents C1-6-alkyl.
2. The compound according to claim 1, where R2and R3represent methyl.
3. Pharmaceutical composition having activity against HIV, containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 and 2.
4. A method of obtaining a pharmaceutical composition according to claim 3, including a thorough smashin the e active ingredient and carrier.
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
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
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
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
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
SUBSTANCE: in general formula , R is unsubstituted or substituted with -OH, C1-4alkyl or -O-C1-4alkyl, straight or branched alkyl C1-C4; R1 has formula -(L)x-R3; R3 is a fragment, chosen from a group consisting of substituted or unsubstituted phenyls, where the substitute is chosen from C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl or fluorine; R2 has formula -(L1)y-R4; R4 is a fragment, chosen from a group consisting of i) hydrogen atom; ii) substituted with -OH, -O-C1-4alkyl or phenyl or unsubstituted straight or branched hydrocarbyls C1-C10, where the hydrocarbyl is C1-6alkyl; L and L1 are bridge fragments -NR5-; each of the fragments R5 is a hydrogen atom, straight or branched alkyl C1-C4; indices x and y can independently assume values 0 and 1.
EFFECT: compounds can be used for curing diseases, mediated by activity of phlogistic cytokines, such as arthritis.
10 cl, 4 dwg, 3 tbl, 200 ex
SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.
EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.
13 cl, 1 tbl, 540 ex
FIELD: medicine; pharmacology.
SUBSTANCE: invention relates to the pyrimidine derivatives with general formula I and their pharmaceutically acceptable salts, which possess tyrosine kinase ZAP-70, FAK and Syk-inhibiting activity, and to their application. The compounds can be used for treatment or prevention of diseases or conditions, where the activation of tyrosine kinase ZAP-70, FAK and/or Syk is involved, e.g., heart failure, chronic obstructive pulmonary disease, Alzheimer's disease et al. In general formula (I) , X is for CR0; R0, R1, R2, R3 and R4 - each identifies independently hydrogen; C1-C8alkyl; hydroxyC1-C8 alkyl; or R3 and R4 together with the adjoined nitrogen and carbon atoms create the 5-10-term heterocyclic ring and, besides, contain 1, 2 or 3 heteroatoms, chosen from N, O and S; or R1 , R2 and R3 each identifies independently the halogen; C1-C8alcoxy; hydroxyC1-C8 alcoxy; C1-C8 alcoxy -C1-C8 alcoxy; phenyl; 5-6-term heterocyclic ring; containing 1-4 heteroatoms, chosen from N and O; nitro; carboxy; -N(C1-C8alkyl)C(O)-C1-C8 alkyl; -CONR10R11; -SO2N(R10)R11; where R10 and R11 each identifies independently the hydrogen; hydroxy; C1-C8 alkyl; C2-C8alkenyl; C3-C8cycloalkyl; C3-C8 cycloalkyl -C1-C8 alkyl; C2-C8 alcoxy -C1-C8 alkyl; hydroxy C1-C8 alcoxy -C1-C8 alkyl; hydroxyC1-C8 alkyl; or 5-10-term heterocyclic ring, containing up to two heteroatoms, chosen from N and S; or R1 and R2 together with the adjoined carbon atoms create the aryl or 5-10-term heteroaryl radical, containing one or two heteroatoms, chosen from N, O and S; or R5 and R6 identifies independently from each other the hydrogen; halogen; cyano; C1-C8 alkyl; haloC1-C8alkyl; R7, R8 and R9 identifies independently from each other the hydrogen; hydroxy; C1-C8alkyl; haloC1-C8alkyl; C1-C8alcoxy; -Y-R12, where Y means the simple link or O and R12 means C1-C4alkyl, substituted or unsubstituted 5-, 6- or 7-term heterocyclic ring, containing 1, 2 or 3 heteroatoms, chosen from N, O and S; carboxy; -N(C1-C8 alkyl)-CO-NR10R11; - -N(R10)(R11); R7 and R8 or R8 and R9, correspondingly, together with the adjoined carbon atoms create the 5- or 6-term heteroaryl containing 1, 2 or 3 heteroatoms, chosen from N; or 5- or 6- term carbocyclic ring; or R7 means hydrogen, hydroxyl, C1-C4alkyl, unsubstituted or terminally substituted hydroxyl group; C1-C8alcoxy group, unsubstituted or terminally substituted by hydroxyl, C1-C4 alcoxy group or unsubstituted or substituted C1-C4alkyl 5-6-term heterocyclic ring, containing 1-3 heteroatoms, chosen from N and O; Provided, one R1, R2 or R3 means -CON(R10)R11; or -SO2N(R10)R11.
EFFECT: therapeutic efficiency is increased.
7 cl, 14 tbl, 184 ex
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
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
SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.
EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.
11 cl, 181 ex
SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. In formula I R1 is a halide, (C1-C6)alkyl or (C1-C6)alkoxy group; R2 is hydrogen; R3 is phenyl, substituted with one or two substitutes independently selected from a group comprising halide(C1-C6)alkyl, halide and a cyano group; R4 is CH2OH, CH2OC(=O)(CH2)2C(=O)OH or CH2OC(=O)(C1-C6)alkyl; R5 is (C1-C6)alkyl. The invention also relates to use of the compounds to make a medicinal agent, to a pharmaceutical composition containing a therapeutically effective amount of the compound and to a method of obtaining formula I compounds.
EFFECT: obtaining compounds with HIV reverse transcriptase inhibiting properties.
9 cl, 2 tbl,11 ex
SUBSTANCE: invention pertains to biotechnology. Described is an anti-HIV monoclonal antibody or its functional fragment which has in the variable region of the H-(heavy) chain regions which determine complementarity, CDR1, CDR2 and CDR3, which have sequences given in the description, and CDR1, CDR2 and CDR3 regions with sequences given in the description in the variable region of the L-(light) chain. Expression vectors which code fragments of the heavy and light chain of the described antibody and host cells which are transformed by the said vectors are disclosed. A method for detecting the HIV strain and a method for individual passive immunotherapy are disclosed.
EFFECT: invention enables to obtain an antibody which enables neutralisation of HIV infection without an autoimmune side effect.
17 cl, 9 dwg, 2 tbl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine and aims at HIV-infection treatment. That is ensured by introduction of a T-cell depletor which effectively disintegrates all T-cells of the patient. Said depletor is a CD52 monoclonal antibody Alemtuzumab.
EFFECT: invention allows suppressing the immune system by the controlled method.
8 cl, 2 ex, 2 dwg
FIELD: chemistry; biochemistry.
SUBSTANCE: present invention relates to biochemistry and specifically to a modified polypeptide of a HIV-1 gp41 envelope glycoprotein, a polynucleotide which codes the modified polypeptide and an expression vector which contains a coding modified polypeptide of the HIV-1 gp41 envelope glycoprotein. The modified polypeptide of the HIV-1 gp41 envelope glycoprotein contains an amino acid sequence SEQ ID NO: 1 or SEQ ID NO: 14, where the sequence between positions 603 and 615 or 598 and 622 SEQ ID NO: 1 or the sequence between positions 530 and 542 or 525 and 549 SEQ ID NO: 14 is replaced by a linker fragment which is an oligopeptide SEQ ID NO: 2.
EFFECT: improved solubility of a modified polypeptide of the HIV-1 gp41 envelope glycoprotein without changing its immunogenic reactivity.
10 cl, 8 dwg, 1 tbl, 3 ex
SUBSTANCE: invention relates to new compounds of formula , to their salts, where R1 and R2 each independently is hydrogen or C1-10alkyl which can be optionally substituted with substitutes selected from a group comprising a hydroxyl group, NR4R5, pyrrolidinyl, piperidinyl, morpholinyl; R3 is a radical of formula , where n equals 1; R3a is nitro; X is -NR7 - or -O-; R4 and R5 each independently is C1-6alkyl; R7 is hydrogen, C1-6alkyl, optionally substituted with pyrrolidinyl. The invention also pertains to use of the compounds, to a pharmaceutical composition, to a method of preparing the pharmaceutical composition, as well as to a method of obtaining the chemical compound in any of paragraphs 1-3.
EFFECT: obtaining new biologically active compounds with antiviral activity.
7 cl, 4 ex, 2 tbl
SUBSTANCE: present invention relates to novel compounds of formula , where X is -O-; values of Ar, R1-R5, R11 are given in the formula of invention. The said compounds have inhibitory effect on HIV reverse transcriptase. The invention also relates to a pharmaceutical composition containing the invented compounds or their pharmaceutically acceptable salts.
EFFECT: obtaining new compounds and a pharmaceutical composition containing said compounds.
8 cl, 61 ex, 2 tbl
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