5-substituted hiv-inhibiting pyrimidines

FIELD: medicine, pharmaceutics.

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

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

7 cl, 2 tbl, 33 ex

 

The present invention relates to the derivatives of pyrimidine with any abscopal the replication of HIV (human immunodeficiency virus) properties. In addition, this invention relates to a process for their preparation and the pharmaceutical compositions. This invention also relates to the use of the above compounds 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 lack of treatment. This leads to the introduction of combination therapy using two or more anti-HIV agents generally have different activity profile. Significant progress is achieved through the introduction of HAART therapy (highly active antiretroviral therapy), which leads to significant morbidity and mortality if exposed to it through treatment of HIV patients. HAART therapy includes various combinations of inhibitors nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside inhibitors of reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Modern methodological recommendations for antiretroviral therapy include the triple combination regimen for initial therapy. However, these multiplikatsionnye terap is not completely destroy HIV and long-term treatment, as a rule, leads to resistance to many drugs. In particular, half of the patients subjected to combination anti-HIV therapy, it is not treatable, mainly due to resistance to one or more used medicines. Also it is shown that the resistant virus is transferred to newly infected individuals, which leads to the choice of a strictly limited therapy for these beyond the effects of medications to patients.

Therefore, there is a continuing need for new combinations of active ingredients which are effective against HIV. New types of active ingredients effective against HIV, differing in chemical structure and activity profile, suitable for new types of combined therapy. Detection of such active ingredients, therefore, is a very desirable achievable purpose.

The present invention relates to the production of specific new series of pyrimidine derivatives having any abscopal HIV replication properties. In WO-99/50250, WO-00/27825 and WO-01/85700 revealed some substituted aminopyrimidine, and in WO-99/50256 and ER-834507 disclosed aminotriazines with any abscopal HIV replication properties.

Compounds according to this invention ex is evidence from well-known in this field of the compounds according to the structure, pharmacological activity and/or pharmacological effectiveness. Found that the introduction of certain substituents in position 5 special way of substituted pyrimidines leads to compounds, not only a positive current from the point of view of their ability to inhibit the replication of human immunodeficiency virus (HIV), but also to their superior ability to inhibit the replication of mutant strains, in particular strains that become resistant to one or more known NNRTIS-medicines (medicines that inhibit non-nucleoside reverse transcriptase), strains which are resistant to drug or many medicines strains of HIV.

Thus, in one aspect, the present invention relates to compounds of formula (I)

their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, where

And means-CH2-CH2-, -CH=CH-, -C≡C-;

each of R1independently means hydrogen, aryl, formyl, C1-6-alkylsulphonyl,1-6-alkyl, C1-6-allyloxycarbonyl;

R2means hydroxy, halogen, C1-6-alkyl, carboxyl, cyano, -C(=O)R6, nitro, amino, mono - or di(C1-6-alkyl)amino, POLYHALOGENATED;/p>

X1means-NR1-, -O-, -S-, -S(=O)p-;

R3means H, C1-6-alkyl, halogen;

R4means H, C1-6-alkyl, halogen;

R5means nitro, amino, mono - and di(C1-4-alkyl)amino, aryl, halogen, -CO-N-CO-R6, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8;

R6means1-4-alkyl, amino, mono - or di(C1-4-alkyl)amino or polyhalogen-C1-4-alkyl;

R7means hydrogen, C1-6-alkyl, aryl-C1-6-alkyl;

R8means hydrogen, C1-6-alkyl, aryl;

each p is 1 or 2;

each aryl means phenyl or phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto,

With1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - or di(C1-6-alkyl)amino-C1-6-alkyl, C1-6-alkylsulphonyl,3-7-cycloalkyl,1-6-alkyloxy,1-6-allyloxycarbonyl,1-6-alkylthio, cyano, nitro, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkyloxy, aminocarbonyl.

As used above or hereinafter, the term "C1-4-alkyl" as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 1-4 carbon atoms, such as the methyl, ethyl, propyl, 1-methylethyl, butyl; the term "C1-6-alkyl" as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 1-6 carbon atoms such as the group defined for C1-4-alkyl, and pentyl, hexyl, 2-methylbutyl and the like; the term "C1-2-alkyl" means methyl or ethyl; the term "C3-7-cycloalkyl" is common to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Most preferred among1-6-Akilov are1-4-alkyl or C1-2-alkyl.

As mentioned above, the radical "(=O)forms a carbonyl residue, when attached to a carbon atom, sulfoxide residue when attached to a sulfur atom, and sulfanilic residue when the above two radical attached to the sulfur atom.

The terms "carboxyl", "carboxy" or "hydroxycarbonyl" refers to the group-COOH.

The term "halogen" is characteristic of fluorine, chlorine, bromine and iodine. As used in this context above and hereinafter, the term "POLYHALOGENATED" as a group or part of a group means a mono - or polyhalogen methyl, in particular methyl with one or more fluorine atoms, for example vermeil, deformity or trifluoromethyl; the term "polyhalogen-C1-4-alkyl" or "polyhalogen-C1-6-alkyl" in ka is estwe group or part of a group means a mono - or polyhalogen 1-4-alkyl or C1-6-alkyl, such as groups defined in the case of halogenmethyl, 1,1-dottorati, 2,2,2-triptorelin, pentafluoroethyl and the like. When more than one halogen atoms attached to the alkyl group within the definition of "POLYHALOGENATED", "polyhalogen-C1-4-alkyl" or "polyhalogen-C1-6-alkyl" they may be the same or different.

When it occurs in the definition of compounds of formula (I) or any of these in this context subgroups, each aryl independently has the meaning as specified above in the definition of compounds of formula (I) or in a more limited definition of aryl specified in the description.

When any variable occurs more than one time in any moiety, each value of such variable is independent.

Imply that any of the limitations in the definitions of radicals, according to the context, applies to a group of compounds of formula (I), as well as to any particular or specified in this context, the sub-group.

The line drawn from the substituents to cyclic systems indicate that the link can be attached to any suitable atoms of the loop.

For therapeutic use of salts of compounds of formula (I) are those where the counterion is pharmaceutically acceptable. However, salts of acids and base is there, which are pharmaceutically unacceptable, may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, whether they are pharmaceutically acceptable or not, are within the scope of the present invention.

Mean pharmaceutically acceptable salt additive, as mentioned above, include therapeutically active non-toxic salt additive form with acids, which are capable of forming compounds of formula (I). Last suitable way can be obtained by processing the basic form of such appropriate acids as inorganic acids, such as halogen acids, 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, cyclohexanesulfamic acid, 2-hydroxybenzo is ina acid, 4-amino-2-hydroxybenzoic acid and the like acids. Conversely, the salt form can be converted into the free base by treatment with alkali.

The compounds of formula (I)containing acidic protons may be converted into their therapeutically active non-toxic salt additive form with metal or amine by treatment with appropriate organic or inorganic bases. The corresponding basic salt forms include, for example, ammonium salts; salts of alkaline and alkaline earth metals, such as lithium salts, sodium, potassium, magnesium, calcium, and the like; salts with organic bases such as primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, Propylamine, Isopropylamine, the four isomeric state of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, Tripropylamine, Hinkley, pyridine, quinoline or isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol, geranamine salt; and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted to the form of the free acid by treatment with acid.

The term "additive salt"also includes hydrates and additive forms with solvents, which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, and the like.

The term "Quaternary amine"as used in this context, higher means of 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 suitable way to remove groups, such as alkylarylsulfonate, alkylarylsulfonate and alkyl-p-toluensulfonate. Quaternary amine contains positively charged nitrogen atom.

Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin and acetate. Selected counterion can be entered using ion-exchange resins.

Assume that the N-oxide forms of the compounds according to the present invention include compounds of formula (I)wherein one or several tertiary nitrogen atoms oxidized to the so-called N-oxide.

You should take into account that some of the compounds of formula (I) and their N-oxides, additive salts, Quaternary amines and stereochemical isomeric form can sod who can't make fun of one or more chiral centers, and exist in the form of stereochemical isomeric forms.

The term "stereochemical isomeric forms"as used in this context above, include all the possible stereoisomeric forms which can have the compounds of formula (I) and their N-oxides, additive salts, Quaternary amines or physiologically functional derivatives. Except as otherwise indicated or specified, the chemical name of the compounds denotes the mixture of all possible stereochemical isomeric forms, with the above mixtures containing all diastereomers and enantiomers of basic molecular structure, and each of the individual isomeric forms of the compounds of formula (I) and their N-oxides, salts, solvate, or Quaternary amines, essentially, free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2%, and highly preferably, less than 1% of other isomers. Thus, when the compound of formula (I), for example, indicated as (E), this means that the compound is essentially free of (Z)-isomer. In particular, stereogenic centers may have the R - or S-configuration; substituents of the divalent cyclic (partially) saturated radicals may have either the CIS-or TRANS-configuration.

Compounds having a double bond may be E(against)or Z("together")-stereochemistry at the above double bond. The terms "CIS", "trance", "R", the S", "E" and "Z" are well known to a qualified specialist in this field.

Stereochemical isomeric forms of the compounds of formula (I) are included in the scope of this invention.

Some of the compounds of formula (I) can also exist in their tautomeric form. Assume that such forms, although not directly referred to in the above formula are within the scope of the present invention.

Whenever used hereinafter, it is assumed that the term "compounds of formula (I)also include their N-oxide forms, their salts, their Quaternary amines and their stereochemical isomeric form. Of particular interest are the compounds of formula (I), which are stereochemical clean.

Specific subgroups of compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context are nesolenym forms, salts, N-oxide forms and stereochemical isomeric forms. Among them interest naselenie forms, salts and stereochemical isomeric form. As used in this context, the term "nosoleva form" refers to a form of connection that is not salt, but which, in most cases, you may be in free base form.

Whenever mentioned above or in the future, the substituents can be selected, each independently, from a list of numerous C is achene, such as, for example, for R9and R10meaning all the possible combinations, which are chemically possible, or which result in a chemically stable molecules.

It should be clear that imply that any of the subgroups of compounds of formula (I), as specified in this context, also include any proletarienne forms, N-oxides, additive salts, Quaternary amines, complexes with metals and stereochemical isomeric forms of such compounds.

Specific subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) a represents-CH2-CH2- or-CH=CH-; or where

(b) a represents-CH=CH-.

In addition, subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R1means hydrogen, formyl, C1-6-alkylsulphonyl,1-6-alkyl, C1-6-allyloxycarbonyl;

(b) R1means hydrogen, C1-6-alkyl;

(C) R1means hydrogen, methyl;

(d) R1means hydrogen.

In addition, subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R2means cyano, amino shall arbonyl; or where

(b) R2means cyano.

In addition, subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) X1means-NR1-, -O-;

(b) X1means-NR1-;

(C) X1means-NH-, -N(C1-4-alkyl)-, -O-;

(d) X1means-NH-, -N(CH3)-, -O-;

(e) X1means-NH-, -N(C1-4-alkyl)-;

(f) X1means-NH-, -N(CH3)- or

(g) X1means-NH-.

Other subgroups of the compounds of formula (I) are the subgroups of compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R3means H, C1-6-alkyl, halogen;

(b) R3means H, C1-4-alkyl, halogen;

(C) R3means H, fluorine, chlorine, bromine, methyl;

(d) R3denotes H, methyl; or where

(e) R3means methyl.

Still other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R4means H, C1-6-alkyl, halogen;

(b) R4means H, C1-4-alkyl, halogen;

(C) R4means H, fluorine, chlorine, bromine, methyl;

(d) R4denotes H, methyl;

(e) R4means methyl.

Still other subgroups of soedineniya (I) are those compounds of formula (I) or any subgroup of compounds of formula (I), mentioned in this context, where

(a) R5means nitro;

(b) R5means amino, mono - and di(C1-4-alkyl)amino, -NH-C(=O)H, -NH-C(=O)R6;

(C) R5means amino, mono - and di(C1-4-alkyl)amino;

(d) R5means aryl;

(e) R5means halogen;

(f) R5means-CO-N-, -CO-R6, -COOR7;

(g) R5means-CO-N-;

(h) R5means-CO-R6;

(i) R5means-COOR7;

(j) R5means-CH=N-O-R8.

Still other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R6means C1-4-alkyl, amino, mono - or di(C1-4-alkyl)amino;

(b) R6means C1-4-alkyl, amino or dimethylamino;

(C) R6means methyl, amino, mono - or dimethylamino;

(d) R6means amino or dimethylamino;

(e) R6means methyl, amino or mono - or dimethylamino, POLYHALOGENATED.

Still other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) R7means hydrogen, C1-4-alkyl; or, where

(b) R7means hydrogen or C1-2-alkyl.

Still other subgroups of the compounds of formula (I) is Vlada those compounds of formula (I) or any subgroup of compounds of formula (I), mentioned in this context, where

(a) R8means hydrogen, C1-4-alkyl; or, where

(b) R8means hydrogen or C1-2-alkyl.

Still other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)mentioned in this context, where

(a) aryl means phenyl or phenyl substituted one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, mercapto, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - or di(C1-6-alkyl)amino-C1-6-alkyl, C1-6-alkylsulphonyl,3-7-cycloalkyl,

With1-6-alkyloxy,1-6-allyloxycarbonyl,1-6-alkylthio, cyano, nitro, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkyloxy, aminocarbonyl;

(b) aryl means phenyl or phenyl substituted one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, mercapto, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - or di(C1-6-alkyl)amino-C1-6-alkyl, C1-6-alkylsulphonyl,1-6-alkyloxy,1-6-allyloxycarbonyl,1-6-alkylthio, cyano, nitro, trifloromethyl, triptoreline, aminocarbonyl;

(C) the aryl oznacza the t phenyl or phenyl, substituted one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - or di(C1-6-alkyl)amino-C1-6-alkyl, C1-6-alkylsulphonyl,1-6-alkyloxy,1-6-allyloxycarbonyl, cyano, nitro, trifloromethyl;

(d) aryl means phenyl or phenyl substituted one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-6-alkyl, C1-6-alkyloxy, cyano, nitro, trifloromethyl.

Of particular interest are the compounds of formula (I) or any subgroup of compounds of formula (I)where a represents-CH=CH - and where the substituents And are in the E-configuration (i.e., the so-called "E-isomers).

The compounds of formula (I) can be obtained by reacting intermediates of formula (II), where W1means of a suitable removable group, such as, for example, halogen, for example chlorine, bromine, tosyl, mesyl and similar groups, with an intermediate product of the formula (III).

The interaction of the pyrimidine derivative (II) with the amine (III) is usually carried out in the presence of a suitable solvent. Suitable solvents are, for example, alcohol such as, for example, ethanol,2-propanol; bipolar aprotic solvent, such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone; simple ether, such as tetrahydrofuran, 1,4-dioxane, onomatology ether of propylene glycol. The interaction can be carried out in the acidic environment generated by adding quantities of a suitable acid, such as, for example, camphorsulfacid, or through the use of proton solvents, such as a solution of hydrogen chloride in alkanol, such as 1 - or 2-propanol.

The compounds of formula (I) can also be obtained through the formation of X1communication or by reacting the compound (IV-a) with compound (V-a) or compound (IV-b) from compound (V-b), as shown in the following diagram.

This reaction scheme W1means the right of the deleted group, which, in particular, has the meaning as specified above.

In particular, the compounds of formula (I), where X1mean NR1the above compounds represented by formula (I-a), can be obtained by reacting the intermediate product of the formula (IV-c), where W1means of a suitable removable group, for example chlorine or bromine, with an intermediate product of the formula (V-c). Remove the group W1you can also type in situ, for example, by transformation of the corresponding hydroxyl group to be deleted is the Rupp, for example, using POCl3. The reaction of the compound (IV-c) with compound (V-c) is preferably carried out in a suitable solvent, in the presence of a base, such as triethylamine. Suitable solvents are, for example, acetonitrile, alcohols, such as, for example, ethanol, 2-propanol, ethylene glycol, propylene glycol, polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, [bmim]PF5; ethers such as 1,4-dioxane, onomatology ether of propylene glycol.

The reaction of the compound (IV-a) or compound (IV-b) with compound (V-a) or compound (V-b) are also suitable in the case where X1means-O - or-S-. In particular, the compounds of formula (I), where X1means Of the above-mentioned compounds represented by the formula (I-b), can be obtained by reacting the intermediate product of the formula (VI), where W1means of a suitable removable group, such as, for example, halogen, for example chlorine, and the like, with an intermediate product of the formula (VII)in the presence of a suitable base, such as, for example, K2CO3or tert-piperonyl potassium (tert-BuOK), and a suitable solvent, such as, for example, acetone or tetrahydrofuran. In a particular implementation, the intermediate product of the formula (VII), first in the W ill result in the interaction, under stirring and at room temperature, with a suitable metal hydride in an organic solvent. Then add the intermediate product of the formula (VI), where W1means suitable to remove the group or the precursor of the deleted group.

The compounds of formula (I-b) can also be obtained by reacting the intermediate product of formula (IV) with an intermediate product of the formula (V-d), in the presence of POCl3suitable base, such as, for example, K2CO3or tert-piperonyl potassium (tert-BuOK), and a suitable solvent, such as, for example, acetone or tetrahydrofuran.

Tizaidine (X1means-S-) can be obtained in a similar way and can be a useful way to transform into the corresponding sulfoxide or sulfon, using known prior art methods of oxidation.

The compounds of formula (I-c), which are compounds of formula (I), where R5means aryl, can also be obtained by reacting the compound (I-d), where W1means of a suitable removable group, such as, for example, halogen, for example chlorine, bromine, aryl radical with special groups, such as boranova acid (ie-IN(OH)2or esters Bronevoy acid (ie-IN(OR)2where R is alkyl or alkylene, for example R oznachaet, ethyl or ethylene). This type of reaction typically can be performed in the presence of a copper salt, in particular of copper acetate (II), and the reaction mixture can be added suitable for termination of the reaction product such as pyridine.

The compound (I-d-1), which are compounds of formula (I-d), where W1means halogen, receive, for example, by halogenation of the corresponding compound of formula (VI), which can be obtained as described in WO-03/016306. Other deleted group can be entered by the replacement of the halogen group, using suitable reagents.

The compound (I-d-1) can be converted into the corresponding compound (I-e), which are group-COOR in position 5 of the pyrimidine residue. The compound (I-e), in turn, can be transformed into the corresponding amides (I-f).

The compound (I-g), which are compounds of formula (I), where R5means the nitrogroup, can be transformed by restoring the nitro group to the amino group into the corresponding compound (I-h)that contain the amino group in position 5 of the pyrimidine residue. The compound (I-h), in turn, can be transformed into the corresponding amides (I-i), using the corresponding acylation reaction.

The connection forms of the crystals (I-j), which are the compounds of formula (I), where R5means SNO, can be obtained by reacting compounds (I-d-1) under high pressure gaseous CO in the presence of sodium formate and a suitable catalyst, for example, dichlorobis(triphenylphosphine)-palladium (II).

The compound (I-j) can be entered into interaction with hydroxylamine to obtain the compounds (I-k), which, in turn, can be alkilirovanii to obtain the compounds (I-l), where R5means alkilirovanny the oxime. The compound (I-j) also can be converted directly into compounds (I-l) by the interaction of the parent compounds (I-j) alkylhydroxylamines.

The compounds of formula (I), below, can be obtained by transformation of compounds of formula (I) in any other, in accordance with the known from the prior art reactions of transformation groups.

The compounds of formula (I) can be converted into the corresponding N-oxide forms, the following is known from the prior art methods of transformation of the tertiary nitrogen into its N-oxide form. The above reaction of N-oxidation usually can be accomplished by reacting the parent compound of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxide is an alkaline or alkaline earth metals, for example, 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, for example 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 R3or R4means hydrogen, can be converted into compounds of formula (I), where R3or R4means halogen, by reacting with a suitable introducing halogen agent such as, for example, N-chlorosuccinimide, or N-biosuccinic, or their combination, in the presence of a suitable solvent, such as, for example, acetic acid.

The compounds of formula (I), where R1means1-6-allyloxycarbonyl, can be converted into compounds of formula (I), where R1means hydrogen, by reacting with a suitable base, such as, for example, the hydroxide or sodium methoxide. Where R1means tert-butyloxycarbonyl thus eastwoodiae connection where R1means hydrogen, can be obtained by processing triperoxonane acid.

Some of the compounds of formula (I) and some of the intermediate products according to the present invention may contain an asymmetric carbon atom. Stereochemical pure isomeric forms of the above compounds and the above-mentioned intermediate products can be obtained by using known from the prior art methods. For example, diastereoisomer can be divided by physical methods such as selective crystallization or chromatographic methods, for example by counter current distribution, liquid chromatography and the like 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 methods, such as 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 form that the same can be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, assuming that carried out the stereospecific reactions take place.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediate products include liquid chromatography, in particular liquid chromatography using a chiral stationary phase.

Some of the intermediates and starting compounds are known compounds and may be commercially available or can be obtained in accordance with known prior art methods.

Intermediate compounds of formula (II) can be obtained by reacting the intermediate product of formula (VIII), where W1has the meaning as described above, with the intermediate product of formula (IX)in the presence of a suitable solvent, such as tetrahydrofuran, and optionally in the presence of a suitable base, such as, for example, Na2CO3.

Intermediates of formula (VIII) can be obtained in accordance with known prior art methods.

Intermediates of formula (V-a) and formula (V-b) can be obtained as follows:

Intermediates of formula (III) or formula (IV-a), where R1means hydrogen or X1means NH, above the tick products represented by formulas (III) and (IV-a-1), can be obtained by reacting the intermediate product of formula (XI) or formula (XII) with a suitable reducing agent such as Fe, in the presence of NH4Cl and a suitable solvent, such as, for example, tetrahydrofuran, N2Oh, and alcohol, for example methanol, and the like.

Intermediate products of the formula (III-a), where a represents-CH2-CH2-the above intermediates represented by formula (III-a-1), can be obtained by reacting the intermediate product of formula (XII-a) Pd/C, in the presence of a suitable solvent, such as alcohol, for example ethanol, and the like.

Intermediates of formula (XII-a) can be obtained by reacting the intermediate product of formula (XIII) with citizen.metropolitan in the presence of a suitable base, such as, for example, NaOCH3and a suitable solvent, such as tetrahydrofuran.

Intermediates of formula (XIII) can be obtained by reacting the intermediate product of formula (XIV) with a suitable oxidant, such as, for example, MnO2in the presence of a suitable solvent, such as, for example, acetone.

About eroticne products of the formula (XIV) can be obtained by reacting the intermediate product of the formula (XV) with NaBH 4in the presence of ethylchloride, a suitable base, such as, for example, N,N-diethylethanamine, a suitable solvent, such as tetrahydrofuran.

Intermediates of formula (XI) and formula (XII) can be obtained by reacting the intermediate product of the formula (XVI), respectively, of formula (XVII), HNO3, NaNO3or KNO3in the presence of H2SO4, AcOH or CH3SO3H.

Intermediates of formula (V-b), where X1means Of and R5means bromine, the above intermediates represented by formula (V-b-1), can be obtained from intermediates of formula (XVIII) by interacting with Br2in the presence of a suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, dimethyl sulfoxide.

Intermediates of formula (V-b-1) can be converted into intermediates of formula (V-a), where R5and W1mean chlorine, the above intermediates represented by formula (V-a-1), by interacting with POCl3.

Intermediate products of the formula (III-a), where a represents-CH=CH - and X1mean NH or O, the above-mentioned intermediate products, is expressed by the formula (III-a-2), respectively, formula (III-a-3)can also be obtained from intermediates of formula (XIX), respectively, of formula (XX), by interacting with H2C=CH-CN in the presence of Pd(OAc)2, P(o-Tol)3suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, CH3-CN.

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

Compounds according to the present invention also show activity against resistant to many drug-resistant HIV strains, in particular, are resistant to many drugs strains of HIV-1, moreover, 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 from the prior art, the 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 a qualified specialist in this field, in particular, as commercially available inhibitors non-nucleoside reverse transcriptase inhibitor. Compounds according to the present invention also have little or no binder" affinity to human α-1-acid glycoprotein; human α1-acid glycoprotein is not exposed or only weakly exposed to anti-HIV activity of the compounds according to the present invention.

Due to their antiretroviral properties, particularly their anti-HIV properties, mainly their anti-HIV-1 activity, the compounds of formula (I), their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines and stereochemical isomeric forms suitable for the treatment of individuals infected with HIV and for the prophylaxis of these infections. Usually the compounds according to the present invention can be used in the treatment of warm-blooded animals infected with viruses whose existence or indirect depends on the enzyme reverse transcriptase. Conditions that can be prevented or treated with the compounds according to the present invention, mainly, are the States associated with HIV and other pathogenic retroviruses, including HIV, is associated with the 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, therefore, can be used as drugs against the above-mentioned conditions. The above use as a medicine or method of treatment involves the introduction of HIV-infected persons with whom bhakta effective amount of the compounds to combat conditions associated with HIV and other pathogenic retroviruses, primarily HIV-1. In particular, the compounds of formula (I) can be used to obtain medications in order to treat or prevent HIV infections.

From the point of view of usefulness of the compounds of formula (I) include a method of treating warm-blooded animals, including humans, suffering from viral infections, or a way of protection of warm-blooded animals, including humans, suffering from viral infections, 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 can be used for various pharmaceutical forms for administration. As appropriate compositions can be called all compositions usually applied to systematically introduce drug with whom edst. To obtain pharmaceutical compositions according to this invention an effective amount of a particular compound, optionally in the form of a salt additive, as an active ingredient, combined with careful mixing with a pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the finished dosage form desired for administration. These pharmaceutical compositions are desirable in a uniform dosage form suitable, in particular, for oral administration, rectal administration, percutaneous injection or parenteral injection. For example, upon receipt of the compositions in oral dosage form can be any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid finished dosage forms such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, dezintegriruetsja agents and the like, in the case of powders, pills, capsules and tablets.

Due to ease their introduction of tablets and capsules represent the most advantageous oral standardized dosage forms, in which case typically use solid headlight is asepticheskie media. In the case of parenteral compositions, the carrier typically includes sterile water, at least for the most part, although there may be other ingredients, for example, to aid solubility. Can be obtained injectable solutions, in which 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 suitable liquid carriers, suspendresume agents and the like. Also included are solid finished dosage forms that are designed for turning, shortly before use, to liquid medicines. In the compositions suitable for percutaneous administration, the carrier optionally includes improving the penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, and the additive does not have a significant detrimental effects on the skin. The above additives can facilitate the introduction into the skin and/or may be useful to obtain the desired compositions. These compositions can be administered in a number of ways, for example in the form of a transdermal patch, in the form of the adjustment, in the form of ointment. Compounds according to the present is obreteniyu can also be administered by inhalation or insufflation, by methods and with the use of finished dosage forms applied in this field for the introduction of this way. Thus, typically, 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 the solubility of the 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 hydroxyl groups anhydroglucose links cyclodextrin substituted With1-6-alkyl, especially stands, ethyl or isopropyl, as, for example, statistically methylated β-CD; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, particularly carboxymethyl or carboxyethyl; C1-6-alkylcarboxylic, especially acetyl. Especially noteworthy as complexing agents and/or solubilization are β-CD, statistically methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, the, in particular, 2-hydroxypropyl-β-CD (2-HP-β-CD).

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

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

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

The term "solid dispersion", as used hereinafter, refers to sist the IU in the solid state (as opposed to liquid or gaseous state), comprising at least two components, for example the compound of formula (I) and water-soluble polymer, where one component is more or less evenly dispersed in the other component or components (when include additional pharmaceutically acceptable agents for the finished dosage form, generally known in this field, such as plasticizers, preservatives, and the like). When the above dispersion of the components is such that the system is chemically and physically completely homogeneous or homogeneous or consists of one phase, as defined in thermodynamics, such a solid dispersion can be called a "solid solution". Solid solutions are preferred physical systems, as components in them are usually easily bioavailable to the organisms in which they 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 that required for dissolution of the components of the crystalline or microcrystalline solid phase.

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

There are various ways to obtain a solid dispersion comprising the extrusion of the melt, spray drying and dissolution-evaporation.

The method of dissolution-evaporation process involves the following stages:

a) dissolving the compounds of formula (I) and water-soluble polymer in a suitable solvent, optionally at elevated temperatures;

b) heating the solution obtained according to paragraph (a), optionally in a vacuum, Placido evaporation of the solvent. The solution can be poured onto a large surface for the formation of a thin film and then evaporate the solvent.

In the case of the method of drying by spraying two component also dissolved in a suitable solvent and the resulting solution is then sprayed through a nozzle spray dryer with subsequent evaporation of the solvent from the resulting droplets at elevated temperatures.

The preferred method of obtaining solid dispersion is the process of extrusion from a melt, comprising the following stages:

a) a mixture of compounds of formula (I) and the corresponding water-soluble polymer;

b) optionally mixing the additives with the thus obtained mixture;

(C) heating and compounding the resulting mixture until a homogeneous melt;

d) punching the thus obtained melt through one or more nozzles; and

e) cooling the melt until it is cured.

The terms "melt" and "melting" can be widely interpreted. These terms refer not only change from a solid state to a liquid state, but may also apply to the transition to the glassy state or kauchukopodobnoe the condition in which it is possible to incorporate one component of the mixture is more or less homogeneous in another component. In some cases, one is omponent melted, and the other(s) component(s) is dissolved(are) in the melt, thereby forming a solution, after cooling, can give a solid solution with favorable dissolution properties.

After the formation of solid dispersions as disclosed above, these products are optional, you can grind and filter.

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 the usual pharmaceutical dosage forms such as tablets and capsules.

You should take into account that a qualified specialist in this field are able to optimize the parameters of the methods of obtaining solid dispersion as described above, such as the most suitable solvent, operating temperature, type of equipment, speed of drying by atomization, the throughput of the extruder to melt.

Water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20°C in aqueous solution with a concentration of 2% (wt./vol.), component 1-5000 MPa·s, more preferably, 1-700 MPa·s, and most predpochtitelno, 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, copolymers based on methacrylates, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, a combination of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene and copolymers of ethylene oxide and propylene oxide. Preferred water soluble polymers are hydroxypropylmethylcellulose.

One or more cyclodextrins can be used as soluble(s) in water of the polymer(s) upon receipt of the above particles, as described in WO-97/18839. The above cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in this region, more preferably, α-, β - or γ-cyclodextrins or their farm is citiesi acceptable derivatives.

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

Particularly suitable are ethers of β-cyclodextrin, for example, dimethyl-β-cyclodextrin, as described by M. Nogradi in Drugs of the Future, volume 9, No. 8, SS-578 (1984), and polyethers, such as hydroxypropyl-β-cyclodextrin, and hydroxyethyl-β-cyclodextrin. So simple alkilany ester may be 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 formed by the interaction of β-cyclodextrin with propylene oxide and may the future value of the MS from about 0.125 to 10, for example, from about 0.3 to 3.

Another type of substituted cyclodextrins are sulfosalicylate.

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

Next, could be capable of obtaining compounds of formula (I) in the form of nanoparticles that include a surface modifier adsorbed on their surface, in a quantity sufficient to maintain an effective average particle size of less than 1000 nm. Assume that suitable surface modifiers include those that are physically linked to a surface of the compounds of formula (I), but not at the expense of the chemical bond with the above connection.

Suitable surface modifiers preferably can be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, oligomers, low molecular weight, natural products, and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting way of using compounds of formula (I) to obtain a finished dosage form comprises a pharmaceutical composition where the compounds of formula (I) is embedded in a hydrophilic polymer, and applying this mixture as a coating film for many small granules, thereby obtaining a composition which can be easily processed and which is suitable for the production of pharmaceutical dosage forms for oral administration.

These granules have a Central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and, optionally, a sealing surface layer.

Substances suitable for use as cores in granules, varied, provided that the above compounds are pharmaceutically acceptable and are of suitable size and density. Examples of such substances are polymers, inorganic substances, organic substances and sugars and their derivatives.

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

The person skilled in the art in the treatment of HIV infection may determine the effective daily amount from the test results presented in this context. It is usually 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 appropriate intervals during the day. The above subdata you can do in the form of a standardized dosage forms, for example, containing 1 to 1,000 mg, and particularly 5-200 mg of the active ingredient of the generic drug form.

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

The compounds of formula (I) according to the present invention can be used 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 separately or in combination with other prophylactic agents to prevent viral infections. Compounds according to the present invention can be used in the vaccines and methods of protecting individuals against viral infections for a long period of time. The compounds can be used in such VA is the care or separately, or together with other compounds according to this invention, or in conjunction with other antiviral agents, to a certain extent compatible with the standard use of reverse transcriptase inhibitors in vaccines. Thus, the compounds according to the present invention can be combined with pharmaceutically acceptable auxiliary means, commonly used in vaccines, and to enter in prophylactically effective amounts to 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, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. Various drugs can be combined in one preparation together with pharmaceutically acceptable carriers. The above other antiretroviral compounds may be known antiretroviral compounds, such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextrans that), foscarnet-sodium (trinatriumfosfaat); inhibitors nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (2',3'-dideoxyinosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (2',3'-dideoxy-3'-thiacytidine, 3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir and the like; inhibitors non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6N-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120, TMC-125, and the like; a phosphonate inhibitors of reverse transcriptase, e.g., tenofovir, 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-APA (α-anilinoquinazoline), for example α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic and the like; inhibitors of TRANS-activating proteins, such as TAT-inhibitors, for example, RO-5-3335, or REV-inhibitors, and the like; protease inhibitors e.g. indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, APV, TMC-126, BMS-232632, VX-175, and the like; fusion inhibitors, for example, T-20, T-1249 and the like; antagonists of CXCR4 receptor, for example, AMD-3100 and the like; inhibitors of viral integrase; inhibitorsinvestigational reverse transcriptase, for example, tenofovir, and the like; inhibitors ribonucleotidic inhibitors, such as hydroxyurea and the like.

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

Compounds according to the present invention can also enter the e in combination with immunomodulatory agents, as, for example, levamisole, bropirimine, the antibody against human alpha-interferon, alpha-interferon, interleukin-2, Medininkai, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, such as pentanedinitrile and the like; cholinergic agents, such as, for example, taken, rivastigmine, donepezil, galantamine and the like; 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 is directed primarily to the use of compounds according to the present invention for the prevention or treatment of HIV infections, the compounds according to the present invention can also be used as inhibitory agents for other viruses that depend on such reverse transcriptase inhibitors in the binding events of their life cycle.

The following examples are intended to illustrate the present invention.

EXAMPLES

In the future, "DMSO" means dimethyl sulfoxide, "TFUK" means triperoxonane acid, "DMF" means N,N-dimethylformamide and "THF" means those is rehydrator.

Example 1

Getting connection 1

N-Bromosuccinimide (0,0393 mol) is added in several portions at room temperature, to the intermediate product 1 (0,0327 mol), the receipt of which is described in WO-03/016306, CH3CN (100 ml). The mixture is stirred at room temperature for 4 hours. The precipitate is filtered off, washed with CH3CN and dried, obtaining 10,08 g of the desired end product. The filtrate is evaporated and purified by column chromatography (eluent: CH2Cl2- 100; 35-70 μm). Pure fractions are collected, the solvent is evaporated and the residue crystallized from CH3CN. Yield: 2.4 g of compound 1. Collect the second fraction. Output: 12,48 g of compound 1 (86%, melting point: >250°C).

Example 2

Getting connection 2

N-Chlorosuccinimide (0,000327 mol) is added in several portions at room temperature, compound 1 (0,000273 mol) in CH3CN (5 ml). The mixture is stirred at room temperature for 4 hours. The precipitate is filtered off, washed with CH3CN and dried. Output: 0,065 g (59%, melting point: >250°C).

Example 3

Obtain compound 3

Use the same procedure as in example 1, from 2-fluoro-6-chloro-analogue of the intermediate product 1 (0,000128 mol) and N-bromac is inimica (0,000154 mol) in CH 3CN (5 ml)to give 0.037 g of compound 3 (62%, melting point: 236°C).

Example 4

Getting connections 4

Suspension of caso3(1.64 g) in water (30 ml) are added to a suspension of intermediate 1 (0,0273 mol) in EtOH (180 ml). Added dropwise chloride iodine (ICl) in CH2Cl2(1 n solution, 22.5 ml). The mixture is stirred at room temperature for 24 hours, then cooled to a temperature of 0°C and filtered. The filtrate is dried in vacuo, then treated with EtOH (180 ml), filtered off, washed with EtOH and CH3CN and dried. Output: 8,5, Part of the filtrate is evaporated. The residue is crystallized from hot CH3CN. The precipitate is filtered off and dried. Yield: 1.54 g (total yield of 78%).

Example 5

The formation of compounds 5 and 6

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0516 mol) and 4-(2-cyanoethyl)-2,6-dimethylphenylamine (0,0516 mol) is stirred at a temperature of 140°C in an oil bath for 45 minutes, then poured into a mixture of water and 10% To2CO3. The precipitate is filtered off and the filtrate is extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2- 100; 35-70 μm). Pure fractions from eraut and the solvent is evaporated, getting 6.0 g of the intermediate product 2 (yield 35%, melting point: >250°C).

Getting connection 5

A mixture of intermediate 2 (0,0182 mol) and 4-cyanoaniline (0,0182 mol) heat of melting for 5 minutes, then poured into a mixture of water and 10% To2CO3. Add CH2Cl2and a small amount of the Meon and the precipitate is filtered off and dried. Output: 7,4 g of compound 5 (95%, melting point: >250°C).

Getting connection 6

A mixture of compound 5 (0,0180 mol) and chloride dihydrate tin-(II) (0.125 mol) in ethanol (100 ml) is stirred at 70°C overnight, then poured into a mixture of water and 10% To2CO3. The precipitate is filtered off through celite. The filtrate is removed and the precipitate is washed with CH2Cl2and THF. The solvent is evaporated. Yield: 6.0 g of compound 6 (87%, melting point: >250°C).

Example 6

Getting 2-fluoro-6-chlorophenyl-analogues of compounds 5 and 6

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0153 mol) and 4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine (0,0153 mol) heat of melting for 5 minutes, then poured into a mixture of water and 10% To2CO3and extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel eluent: CH 2Cl2- 100; 35-70 μm). Pure fractions are collected and the solvent is evaporated. Yield: 1.9 g of 2-chloro-4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidine, the intermediate product 3 (35%, melting point: 217°C).

A mixture of intermediate 3 (0,000424 mol) and 4-cyanoaniline (0,000424 mol) heat of melting for 5 minutes, then poured into a mixture of water and 10% To2CO3. Add CH2Cl2and a small amount of the Meon and the precipitate is filtered off and dried. Output: of 1.34 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidin]amino]benzonitrile, compound 7 (73%, melting point: >250°C).

A mixture of compound 7 (0,00306 mol) and chloride dihydrate tin-(II) (0,0214 mol) in ethanol (20 ml) is stirred at 70°C overnight, then poured into a mixture of water and 10% To2CO3. The precipitate is filtered off through celite. The filtrate is removed and the precipitate is washed with CH2Cl2and THF. The solvent is evaporated. Yield: 1.1 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-aminopyrimidine]amino]benzonitrile, compound 8 (89%, melting point: >250°C).

Example 7

Obtaining the compound (9)

A mixture of compound 1 (0,0247 mol), dichlorobis(triphenylphosphine)palladium (II) (0,00494 mol) and triethylamine (0,107 mol) in ethanol (100 ml) is stirred at a temperature of 100°C during the course the e to 72 hours when the pressure of carbon monoxide at 15 bar. The mixture was poured into water. The precipitate is filtered off. Output: 6, the Filtrate is extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/Meon=99,5/0,5; 15-40 μm). Pure fractions are collected and the solvent is evaporated. Output: 1,9, Collect the second fraction. Total yield: 7.9 g of compound (9) (73%, melting point:>250°C).

The connection 26 is produced from compound 3, using the same technique.

Example 8

The connection 10

A mixture of compound 9 (0,00456 mol), monohydrate of lithium hydroxide (0,0137 mol) in THF (20 ml) and water (7 ml) is stirred at a temperature of 50°C during the night. THF is evaporated. The residue is diluted with water and add 3 HCl solution to until the pH value becomes equal to 2-3. The precipitate is filtered off, washed with water and dried. Yield: 1.78 g of compound 10 (95%, melting point: >250°C).

Example 9

Obtaining the compound (11)

1-Hydroxybenzotriazole (0,548 mmol) is added to a mixture of compound 10 (0,365 mmol) in THF (3 ml). To the mixture successively added dichloromethane (3 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,548 mm is eh). To this solution was added 1-Propylamine (0,548 mmol). The mixture is stirred at room temperature for 24 hours, then poured into a mixture of water and 10% To2CO3and extracted with a mixture of CH2Cl2and methanol (90/10). The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent:CH2Cl2=100 and CH2Cl2/Meon = 95/5; Kromasil, 5 μm). Output: 0,116 g of compound 11 (70%, melting point: >250°C).

The connection 30 receive, using the same methodology, based on connection 3.

Example 10

The connection 12

Thionyl chloride (5 ml) is added to compound 10 (0,000365 mol) and the mixture refluxed for 1 hour. Thionyl chloride is removed in vacuo and the residue diluted with CH2Cl2(5 ml). The mixture is cooled to a temperature of 0°C and added dropwise 30%ammonia solution (2 ml). The mixture is stirred at 0°C, at least for 1 hour and the precipitate is filtered off, washed with water and diisopropylethylamine ether and dried. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/Meon/NH4OH=95/5/0,1; 35-70 μm). Pure fractions are collected and Rast is oritel is evaporated. Output: 0,071 g of compound 12 (47%, melting point: >250°C).

Example 11

The formation of compounds 13, 14 and 15

Formic acid (10 ml) is added, at room temperature, compound 6 (0,00215 mol) in ethyl formate (30 ml). The mixture is stirred at the boiling point under reflux for 4 hours. The mixture is evaporated to dryness, then bring in a mixture of water and 10% To2CO3and extracted with a mixture of CH2Cl2and Meon. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is crystallized from CH2Cl2and Meon. Output: 0,48 g of compound 13 (55%, melting point: >250°C).

The connection 14

Cyanoborohydride sodium (0,00262 mol) are added, at room temperature, to a mixture of compound 6 (0,000524 mol) and paraformaldehyde (0,00524 mol) in acetonitrile (10 ml). Add a few drops of acetic acid and the mixture is stirred at room temperature for 2 hours. This mixture is then poured into a mixture of water and 10% To2CO3and extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2=100 and CH2Cl2/Meon=99/1; 10 μm). Pure fractions sobi is up and the solvent is evaporated. Output: 0,070, This fraction is crystallized from a mixture of diisopropyl ether and diethyl ether. The precipitate is filtered off and dried. Output: 0,059 g of compound 14 (27%, melting point: >250°C).

The connection 15

Acetylchloride (0,000315 mol) are added dropwise, at room temperature, to a mixture of compound 6 (0,000262 mol) and triethylamine (0,000524 mol) in CH2Cl2(2 ml) and THF (2 ml). The mixture is stirred at room temperature for 4 hours, then poured into a mixture of water and 10% To2CO3and extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/Meon/NH4OH=95/5/0,1; 35-70 μm). Pure fractions are collected and the solvent is evaporated. Output: 0,061 g of compound 15 (55%, melting point: >250aboutC).

The connection 28 receive, using the same methodology, based on connection 8.

Example 12

Getting 5-aryl-substituted compounds

Connection 1 (0,449 mmol) are added to a solution of tetrakis(triphenylphosphine)palladium (0) (0,0449 mmol) in 1,2-dimethoxyethane at room temperature. Add a solution of 2-chloraniline acid (0.15 mmol) in methanol (3 ml) at room temperature. The mixture is stirred at a temperature of 95°C for 24 hours and then poured into water, extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/Meon=99/1; Kromasil Si, 10 μm). Pure fractions are collected and the solvent is evaporated. Output: 0,130 g of compound 16 (60%, melting point:168-170°C).

Compound 17 is obtained by interaction of compound 16 with hydrogen in the presence of Pd/C in methanol/THF.

Example 13

The connection 18

Formic acid (2 ml) is added, at room temperature, compound 8 (0,000370 mol) in ethyl formate (6 ml). The mixture is stirred at the boiling point under reflux for 3 hours. The mixture is then poured into a mixture of water and 10% To2CO3. The precipitate is filtered off, washed with a mixture of diisopropyl ether and diethyl ether and dried. The residue is crystallized from CH2Cl2and Meon. Output: 0,72 g of compound 18 (45%, melting point: 250°C).

Example 14

The connection 19

A mixture of compound 1 (0,0112 mol), dichlorobis(triphenylphosphine)palladium (II) (0,00228 mol), sodium formate (0,0336 mol) and magnesium sulfate (1 g in DMF (50 ml) was stirred at 100°C for 20 hours under a pressure of carbon monoxide 8 bar. The mixture is filtered through celite and poured into water. The precipitate is filtered off, washed with water and Et2O, and dried. Yield: 2.9 g of compound 19 (65%, melting point: >250°C).

Example 15

The connection 20

A mixture of compound 19 (0,000254 mol) and hydroxylaminopurine (0,000380 mol) in pyridine (3 ml) was stirred at room temperature for 20 hours, then poured into water. The precipitate is filtered off, washed with water and Et2O, and dried. Output: 0,048 g of compound 20 (39%, melting point: >250°C).

Example 16

The connection 31

A suspension of compound 19 (0,0003 mol) and methoxyacetanilide (of 0.0004 mol) in pyridine (4 ml) was stirred at room temperature overnight, poured into water, filtered off, washed with water and dried at a temperature of C in vacuum. The residue (0,128 g) purified by column chromatography using a kromasil (eluent: CH2Cl2/CH3HE=from 100/0 to 95/5; 5 μm). Pure fractions are collected and the solvent is evaporated, getting 0,065 g (46%) of compound 31 (melting point: >250°C).

Example 17

The connection 26

A mixture of compound 12 (0.0001 mol) and 10%Pd/C (0.1 g) in THF (5 ml) and Meon (5 ml) hydronaut at room temperature overnight, at 3 bar pressure, then filtered over celite. F is ltrat is evaporated. The residue is crystallized from DIPE. The precipitate is filtered off and dried, obtaining 0,065 g (81%) of compound 26 (melting point: 180°C).

Example 18

The connection 33

A mixture of compound 6 (of 0.0005 mol) and 10%Pd/C (0.2 g) in THF (8 ml) and Meon (6 ml) hydronaut at room temperature over night at 3 bar pressure, then filtered over celite. The filtrate is evaporated. This fraction is purified by column chromatography on silica gel (eluent: CH2Cl2/CH3HE= 95/5; 35-70 μm). Pure fractions are collected and the solvent is evaporated. Output: 0,071 g (35%, melting point: 180°C).

The following tables list compounds that have already obtained or which can be obtained in accordance with the techniques described in the above examples.

Table 1

Examples of the finished dosage forms

Capsules

The compound of formula (I) dissolved in an organic solvent, such as ethanol, methanol or methylene chloride, preferably a mixture of ethanol and methylene chloride. Polymers such as a copolymer of vinylpyrrolidone and vinyl acetate (PVP-VA) or hydroxypropylmethylcellulose (receiver array), typically with a viscosity of 5 MPa·s, rest the accelerate in organic solvents, such as ethanol, methanol and methylene chloride. Suitable way, 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 in the range of from 1/1 to 1/6. Intermediate ranges can be 1/1,5 and 1/3. A suitable ratio may be 1/6. The powder obtained by spray drying, the solid dispersion is then filled capsule for introduction. The amount of drug contained in one capsule is 50-100 mg, depending on the size of the capsule.

Tablets film coated

Obtain core tablets

A mixture of 100 g of compound of formula (I), 570 g lactose and 200 g starch are thoroughly mixed and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried and again sieved. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All this is thoroughly mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Floor

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 of 1.23-propantriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the previous one and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye stuff and put it all together homogenized. Core tablets cover the thus obtained mixture in the enrobing machine.

Antivirus spectrum

Because of the increasing emergence of drug-resistant strains of HIV, the 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 wild-type HIV and HIV mutants with mutations in the gene for reverse transcriptase. The activity of compounds was evaluated using cytological analysis, and the residual activity was expressed in values RES50. In table 3, columns IIIB and A-G lists the values RES50p is otiv 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;

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;

Strain G contains mutations L100I, K103N, Y181C, V179I, Y181C, E138G, V179I, L2214F, V278V/I and A327A/V in the reverse transcriptase of HIV.

Table 3
Connection, No.IIIBABCDEFG
26the 9.79the 9.7108,69,29,26,4
139,48,69,2 9,28,58,28,46
277,93,37,97,36,56,56,64,6
288,87,98,68,37,377,3the 4.7
298,478,27,76,276,44,6
307,77,37,26,96,56,46,55
318,58,28,5 8,58,28,28,25,1
328,58,58,79,38,68,68,76

1. The compound of the formula

its pharmaceutically acceptable additive salt or a stereochemical isomeric form, where:
And means-CH2-CH2-, -CH=CH-;
each of R1independently means hydrogen;
R2means cyano;
X1means-NR1-;
R3means H, C1-6-alkyl, halogen;
R4means H, C1-6-alkyl, halogen;
R5means nitro, amino, mono - and di(C1-4-alkyl)amino, phenyl, possibly substituted with halogen, halogen, -CO-N-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8;
R6means1-4-alkyl, amino, mono - or di(C1-4-alkyl)amino or polyhalogen-C1-4-alkyl;
R7means hydrogen, C1-6-alkyl;
R8means hydrogen, C1-6-alkyl.

2. The compound according to claim 1, where a represents-CH=CH-; X1means-NH-; R3means methyl or halogen; R4means methyl or halogen; R6 represents amino or dimethylamino.

3. The compound according to claim 1, where
R5means nitro or
R5means amino, mono - and di(C1-4-alkyl)amino, -NH-C(=O)H, -NH-C(=O)R6.

4. The compound according to claim 1, where
R5means phenyl, possibly substituted with halogen; or
R5means halogen.

5. The compound according to claim 1, where
R5means-CO-N-, -COOR7.

6. The compound according to claim 1, where
R5means-CH=N-O-R8.

7. Pharmaceutical composition having antiviral 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 to 6.



 

Same patents:

FIELD: medicine, pharmaceutics.

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

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

5 cl, 7 dwg, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

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

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

5 cl, 7 tbl, 14 ex

FIELD: medicine.

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

EFFECT: improvement of the method.

5 cl, 4 tbl, 6 ex

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

The invention relates to a new crystalline modification D dicyclanil (2 cyclopropylamino-4,6-diaminopirimidina-5-carbonitrile) of formula I

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula I, as well as to their diastereoisomers, enentiomers and/or pharmaceutically acceptable salts, which possess inhibiting action with respect to cyclin-dependent kinases and/or tyrosinekinases of VEGF receptor. In compound of general formula (I) Q stands for group where D, E, G, L, M and T in each case represent carbon, R1 represents hydrogen, halogen or CF3, R2 represents C1-C10-alkyl, which can optionally be disrupted with one group-C(O), C2-C10-alkinyl, C3-C10-cycloalkyl or phenyl, which is optionally substituted in one or more places in similar or different way by hydroxyl, halogen, C1-C6-alkoxy, C1-C6-alkyl, C3-C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl or -COR8, X represents oxygen, sulphur or group -NH-, R3 represents hydroxy, halogen, CF3 or C1-C6-alkoxy, m represents 0-4, R4 represents hydrogen or group -COR8, NO2 or -SO2R7, or represents C1-C10-alkyl or C3-C10-cycloalkyl, R5 represents C1-C10-alkyl, which can be optionally substituted in one or more places, in similar or different way, by hydroxyl or C3-C10-cycloalkyl, or C3-C10-cycloalkyl, R7 represents C1-C10-alkyl, which is optionally substituted by group trimethylsilanyl (TMS), R8 represents C1-C6-alkyl, C1-C6-alkoxy. Invention also relates to intermediate compounds.

EFFECT: compounds can be applied for obtaining medication intended for treatment of cancer, selected from Kaposhi's sarcoma, Khodgkin's disease, leukemia or solid tumour, such as carcinoma of mammalian gland, kung, large intestine or prostate gland, autoimmune disease, such as psoriasis, and/or proliferative diseases, such as hemangioma or angiofibroma.

21 cl, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 2,4-di(hetero)arylaminopyrimidine of general formula I or its pharmaceutically acceptable salt, possessing properties of ZAP-70 inhibitors. In compounds of formula I: Z stands for =CR2-; each of radicals R0 and R1 represents hydrogen; R2 represents (C1-C4)alkoxy; R3 represents -SO2NH2; or R1 and R2 form together with C-atoms, to which they are bound, 5-7-member non-aromatic carbocyclic or heterocyclic residue, where said heterocyclic residue includes 1 or 2 heteroatoms, selected from N and O, and heterocyclic residue, containing 1-2 atoms of oxygen can be substituted with fluorine atoms; R4 and R6 represent hydrogen, R5 represents hudrogen, halogen, (C1-C4)alkyl or CF3; one of R7, R8 and R9 represents NR10R11, and one or two others represent hydrogen, halogen, COOH, CF3 or (C1-C4)alkyl; R10 and R11 independently represents hydrogen or (C1-C4)alkyl. Invention also relates to methods of obtaining compounds.

EFFECT: compounds can be applied, for instance in case of acute or chronic rejection of organ or tissue, in treatment of atherosclerosis and other diseases, when inhibition of ZAP-70 is of importance.

9 cl, 7 tbl, 150 ex

FIELD: medicine, pharmaceutics.

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

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

5 cl, 7 tbl, 14 ex

FIELD: 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: chemistry.

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

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: medicine.

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

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: medicine, pharmaceutics.

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

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

4 cl, 7 dwg, 1 tbl, 3 ex

FIELD: chemistry.

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

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

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

7 cl, 155 ex

FIELD: chemistry.

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

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

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses pharmaceutical composition for controlled release regarding toxic active compounds, in particular, bioactive proteins from class of interferons. Composition contains bio-degradable block-copolymer made of poly(ethyleneglycol)terephthalate (PEGT) in amount from 50 to 95%, and poly(butyleneterephthalate) (PBT). Agent may be represented as injection microparticles, injection liquid, capable of independent gel or solid implant formation. Besides, invention provides a pharmaceutical set, including specified composition, methods of composition making and pharmaceutical versions of its application.

EFFECT: invention provides for initial release within 4 hours of not more than approximately 10% of included amount of one or more alpha-interferons and at least 80% of one or more alpha-interferons are released in monomer non-aggregated form.

31 cl, 8 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to a spray drying production process of a solid pharmaceutical powder containing microcrystalline cellulose in a solid dispersion of the anti-HIV compound etravirine (TMC125) in a water-soluble polymer. In a parent mixture, the relation of the water-soluble polymer to TMC 125 makes 10:1 to 1:1, and of microcrystalline cellulose to TMC 125 - 1:1 to 1:3. Said parent mixture of microcrystalline cellulose, a solution of the water-soluble polymer and etravirine is sprayed in the form of drops into a drying chamber by atomisers to form a solid dispersion of TMC 125 powder.

EFFECT: better solubility and bioavailability of the antiviral compound etravirine.

10 cl, 9 dwg, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

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