Hiv-inhibiting 5-(hydroxymethylene- and aminomethylene)substituted pyrimidines

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

 

This invention relates to derivatives of 5-(hydroxymethylene and aminomethyl)pyrimidine with any abscopal the replication of HIV (human immunodeficiency virus) properties, to receive them and to pharmaceutical compositions containing these compounds.

The resistance of the HIV virus against currently available drugs for the treatment of HIV infection remains a major cause of adverse outcome of therapy. This has led to the introduction of combination therapy of two or more anti-HIV agents, usually having different activity profile. Significant progress made with the introduction of HAART therapy (highly active antiretroviral therapy), which in result leads to a significant reduction of morbidity and mortality in populations of patients with HIV being treated by this therapy. HAART therapy includes various combinations of nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). But even these multi-drug therapy does not completely eliminate HIV and long-term treatment often leads to multidrug resistance. In many cases, the resistant virus is transferred to newly infected individuals, resulting in limited options for therapy DL is not exposed to drug patients.

Therefore, there remains a need for new combinations of active ingredients which are effective against HIV. New types of anti-HIV agents, differing in chemical structure and activity profile, suitable for new types of combined therapy. Detection of such active ingredients, therefore, it is highly desirable to achieve the 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 with any abscopal HIV replication properties.

Compounds according to this invention differ from the compounds of the prior art their chemical structure and their pharmacological profile. Found that the introduction of certain substituents in position 5 specifically substituted pyrimidines leads, resulting in compounds that are not only beneficial from the point of view of their ability to inhibition of replication of human immunodeficiency virus (HIV), but also to their superior ability to inhibit the replication of mutant strains, especially strains that become resistant against one or more known NNRTIS-medicines, and this strain is related to HIV strains resistant against the drug or multiple drugs.

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

their stereochemical isomeric forms, their pharmaceutically acceptable additive salts, their pharmaceutically acceptable hydrate or solvate, N-oxide, where

eachR1independently means hydrogen; aryl; formyl; C1-6-alkylsulphonyl; C1-6-alkyl; C1-6-allyloxycarbonyl;

R2,R3,R7andR8independently mean hydrogen; hydroxy; halogen; C3-7-cycloalkyl; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; cyano; nitro; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl; polyhalogen-C1-6-alkyloxy; -C(=O)R10;1-6-alkyl, optionally substituted with halogen, cyano or-C(=O)R10;2-6alkenyl, optionally substituted with halogen, cyano or-C(=O)R10;2-6-quinil, optionally substituted with halogen, cyano or-C(=O)R10;

R4andR9independently signify hydroxy; halogen; C3-7-cycloalkyl; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; formyl; cyano; nitro; amino; mono - or di(C1-6-alkyl)amino; polyhalogen 1-6-alkyl; polyhalogen-C1-6-alkyloxy; -C(=O)R10; cyano; -S(=O)rR10; -NH-S(=O)rR10; -NHC(=O)H; -C(=O)NHNH2; -NHC(=O)R10; Het; -Y-Het; C1-12-alkyl, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het or1-6-alkyloxy; C2-12alkenyl, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het or1-6-alkyloxy; C2-12-quinil, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het or1-6-alkyloxy;

R5means1-6-alkyl, optionally substituted by Ar or Het; C2-6alkenyl, optionally substituted by Ar or Het; C2-6-quinil, optionally substituted by Ar or Het; C3-7-cycloalkyl; Ar; Het;

R6means hydrogen, C1-6-alkyl, Het;

Ymeans-OR11, -NR12R13;

eachR10independent means1-6-alkyl, amino, mono - or di(C1-6-alkyl)amino or polyhalogen-C1-6-alkyl;

R11means hydrogen or C1-6-alkyl, optionally substituted hydroxy, C1-6-alkyloxy, phenyl or pyridium;

R12means hydrogen or C1-6-alkyl;

R13means hydrogen or C1-6-alkyl; orR12 andR13together with the nitrogen atom, the substituents they are, form pyrrolidinyl; piperidinyl; morpholinyl; piperazinil; piperazinil, optionally substituted C1-6-alkyl or C1-6-alkylcarboxylic; imidazolyl;

Xmeans-NR1-, -O-, -C(=O)-, -CH2-, -CHOH-, -S-, -S(=O)r-;

eachYindependent means-NR1-, -O-, -C(=O)-, -S-, -S(=O)r-;

eachrindependently represent 1 or 2;

Hetmeans 5 - or 6-membered fully unsaturated cycle, where one, two, three or four members of the cycle are heteroatoms, each independently selected from nitrogen, oxygen and sulfur, and where the remaining members of the cycle are carbon atoms; and where possible, any member of the heterocycle with the nitrogen heteroatom may be optionally substituted C1-6-alkyl and 5 - or 6-membered cycle can be optional annylirovan with benzene, thiophene or pyridine cycle; and where any carbon atom of the cycle, including any carbon atom is optionally annulirovano benzene, thiophene or pyridine cycle, each independently, optionally can be substituted by the Deputy selected from the group consisting of halogen, hydroxy, mercapto, cyano, C1-6-alkyl, hydroxy-C1-4-alkyl, carboxy-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-4-alkyloxy the carbonyl-C 1-4-alkyl, cyano-C1-4-alkyl, mono - and di(C1-4-alkyl)amino-C1-4-alkyl, Het1-C1-4-alkyl, aryl-C1-4-alkyl, polyhalogen-C1-4-alkyl, C3-7-cycloalkyl,2-6-alkenyl,2-6-quinil, aryl-C2-4-alkenyl,1-4-alkyloxy, -NH2polyhalogen-C1-4-alkyloxy, aryloxy, amino, mono - and di-C1-4-alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6-alkylpiperazine,1-4-alkylcarboxylic, formyl, C1-4-alkylsulphonyl,1-4-allyloxycarbonyl, aminocarbonyl, mono - and di-C1-4-alkylaminocarbonyl, aryl, Het1;

Het1means pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, chinoline, benzothiazyl, benzofuranyl; and each may be optionally substituted by one or two1-4-alkilani;

eacharylindependent means phenyl or phenyl substituted one, two, three, four, or five substituents, each independently selected from the group consisting of halogen, hydroxy, mercapto, C1-6-alkyl, C2-6-alkenyl,2-6-quinil, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - and di(C1-6-alkyl)amino-C1-6-alkyl, C1-6-alkylsulphonyl,3-7the cyclo is Lila, With1-6-alkyloxy, phenyl-C1-6-alkyloxy,1-6-allyloxycarbonyl, aminosulfonyl,1-6-alkylthio, cyano, nitro, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkyloxy, aminocarbonyl, phenyl, Het and-Y-Het.

Hetis a fully unsaturated cycle which means that the cycle contains the maximum number of double bonds. One type of cycles Het represents an aromatic heterocycles. In one embodiment Het in full, i.e. including optional annelirovannymi benzene, titanovyi or pyridine cycle may be optionally substituted by one, two or three substituents listed above or in the future. In particular, Het contains not more than two atoms of oxygen or sulfur cycle, in particular not more than one oxygen atom or sulfur in the loop.

In one embodiment each Het independently denotes pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, chinoline, benzothiazyl, benzofuranyl, benzoxazolyl, benzothiazolyl, imidazothiazoles; each of which may be optionally substituted by one or two substituents, independently selected from C1-6-alkyl; halogen; hydroxy; cyano; C1-6-alkyloxy; C2-12-alkenyl, substituted with halogen, hydroxy or cyano.

As is used to enter the or in the future, With1-4-alkyl, as a group or part of a group, represents a saturated hydrocarbon radical with a linear or branched chain having 1-4 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl, tert-butyl; C1-6-alkyl, as a group or part of a group, represents a saturated hydrocarbon radical with a linear or branched chain having 1-6 carbon atoms, such as group specified With1-4-alkyl, and 1-pentyl, 2-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methylbutyl, 3-methylpentyl etc.; C1-2-alkyl means methyl or ethyl; With3-7-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The preferred additional To1-6-Akilov are1-4-alkyl or C1-2-alkyl. The preferred additional To3-7-cycloalkyl are cyclopentyl and cyclohexyl.

The term "C2-6alkenyl"as a group or part of a group, means a hydrocarbon radical with a linear or branched chain, having saturated carbon-carbon and at least one double bond and having 2 to 6 carbon atoms, such as, for example, ethynyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 3-GE is senile, 4-hexenyl, 2-methyl-2-pentenyl, 1,2-dimethyl-1-butenyl, etc. are Preferred With2-6alkenyl having one double bond. Interest among2-6-alkenyl radicals are2-4-alkyl radicals. The term "C3-6alkenyl" has the same meaning as2-6alkenyl, but is limited by unsaturated hydrocarbon radical having 3-6 carbon atoms. In cases where C3-6alkenyl associated with a heteroatom, a carbon atom that is associated with the heteroatom preferably is saturated. The term "C2-12alkenyl" means2-6alkenyl, but has 2-12 carbon atoms and includes With2-6-alkeline radicals and the higher homologues, such as 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-methyl-1-hexanol, 1,2-dimethyl-1-pentenyl, 2-methyl-1-hexenyl, 2-ethyl-2-pentenyl, 3-propyl-2-hexenyl, 1-octenyl, 2-octenyl, 1 nonanol, 1-decenyl, 1-undecenyl, 1-dodecenyl etc. Preferred among2-12-alkenyl are2-6alkenyl.

The term "C2-6-quinil"as a group or part of a group, represents a hydrocarbon radical with a linear or branched chain, having saturated carbon-carbon and at least one triple bond and having 2 to 6 carbon atoms, such as, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-2-PROPYNYL, pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl, etc. are Preferred With2-6-alkinyl having one triple bond. Interest among2-6-etkinlik radicals are2-4-alkyl radicals. The term "C3-6-quinil" means2-6-quinil, but is limited by unsaturated hydrocarbon radical having 3-6 carbon atoms. In the case where C3-6-quinil associated with a heteroatom, a carbon atom that is associated with the heteroatom preferably is saturated. The term "C2-12-quinil" has the same meaning as2-6-quinil, but has 2-12 carbon atoms and includes With2-6-alkyline radicals and the higher homologues, such as 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 1-nonenal, 1-decenyl, 1-undecenyl, 1-dodecenyl etc. Preferred among2-12-alkinyl are2-6-alkinyl.

As used in this context before, the element (=O) forms a carbonyl group, when attached to a carbon atom, sulfoxide group, when attached to a sulfur atom, and sulfonyloxy group, when two of the above elements are attached to the sulfur atom.

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

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "polig the lågen-C 1-6-alkyl"as a group or part of a group, for example in polyhalogen-C1-6-alkoxy, means mono - or polyhalogen1-6-alkyl, in particular With1-6is alkyl, substituted with up to one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl with one or more fluorine atoms, for example deformity, trifluoromethyl, triptorelin. Preferred is trifluoromethyl. This also includes PERFLUORO-C1-6-alkyl groups, which are1-6-alkyl groups, where all hydrogen atoms substituted by fluorine atoms, such as pentaverate. In the case where more than one halogen atom attached to the alkyl group within the definition polyhalogen-C1-6-alkyl, - halogen atoms may be the same or different.

Imply that any of the heterocycles mentioned in the definitions of Het, includes any isomer, as, for example, oxadiazole, which can be a 1,2,4-oxadiazole, 1,3,4-oxadiazole or 1,2,3-oxadiazol; the same applies to the thiadiazole, which may be 1,2,4-thiadiazole, 1,3,4-thiadiazole or 1,2,3-thiadiazole; similarly, the imidazole may be 1H-imidazole or 3H-imidazole.

When the radical is found in the definition of compounds of formula (I) or any of the subgroups described in this context, the above Radik the l independently has a value as specified above in the definition of compounds of formula (I) or in a more limited definition, as specified in the future.

You also need to pay attention to the fact that the position of the radical in any molecular residue used in the definitions could be anywhere in this balance, as long as it is chemically stable. For example, pyridine includes 2-pyridine, 3-pyridine and 4-pyridine; pentyl includes 1 pencil, 2-pentyl and 3-pentyl.

When any variable (for example, halogen, C1-6is alkyl, aryl, Het, etc.) occurs more than one time in any residue, each definition is independent.

Imply that any limited definition of the radicals mentioned in this context are suitable for group of compounds of formula (I), as well as for any of the subgroups described or mentioned in this context.

The line going from the substituents in the cyclic systems, indicate that the relationship can be attached to any suitable atoms of the loop.

Assume that the term "compounds of formula (I)or any similar terms, such as "the compounds according to this invention" and the like, and also includes any N-oxide forms of the compounds of formula (I)are compounds of formula (I)where one or more atoms of nitrogen oxidized to N-oxide form.

Pharmaceutically acceptable addition the E. salt, which is able to form compounds according to the present invention can easily be obtained using an appropriate acid, such as, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid, sulfuric acid, semiseria acid, nitric acid, phosphoric acid and the like acids; or organic acids, such as, for example, acetic acid, aspartic acid, modellerna acid, heptane acid, hexanoic acid, nicotinic acid, propanoic acid, hydroxyestra acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, cyclonona acid, salicylic acid, paraaminosalicilovaya acid, pamula acid and the like acids. On the contrary, the above additive salt form of the acid can be converted into a free basic form by treatment with an appropriate base.

The compounds of formula (I)containing acidic protons may be converted into their pharmaceutically acceptable additive salt form with metal or amine by treatment with westwoodone organic or inorganic bases. The corresponding basic salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, such as lithium salts, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, primary, secondary and tertiary aliphatic and aromatic amines, such as salts of methylamine, ethylamine, Propylamine, Isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, research, trimethylamine, triethylamine, Tripropylamine, hinoklidina, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propane diol, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc. on the Contrary, the salt form can be converted into the free acid form by treatment with acid.

The invention also includes hydrates and additive form with a solvent that is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, etc.

You should take into account that some of the compounds of formula (I) and their additive salts can include one or more centers of chirality and exist in the form of stereochemical isomeric forms. Of special interest such soy is inane formula (I), which are the stereochemical clean.

The term "stereochemical isomeric forms"as used above, means all the possible stereoisomeric forms which can have the compounds of formula (I) and their additive salt. Except as otherwise specified or referred to, 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 formula (I) and their salts or solvate, essentially free, i.e. associated with less than 10%, preferably less than 5%, particularly less than 2% and more preferably less than 1% of other isomers. Thus, when the compound of formula (I) represent, for example, as (E), this means that the connection is not essentially contains (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 transconfiguration.

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

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

Imply that the present invention also includes all isotopes of atoms present in the compounds according to this invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon atom include C-13 and C-14.

As used above or in the future, mean that the terms "compounds of formula (I)", "compounds of the present invention", "compounds according to the present invention" or any equivalent terms, like the terms of the subgroups of compounds of formula (I)", "subgroups of the compounds of the present invention, a subgroup of compounds according to the present invention" or any equivalent terms include compounds of General formula (I) or subgroups of compounds of General formula (I)and their salts and stereoisomers.

When, above or in the future, indicate that the substituents, each independently, can be selected from the list of definitions, such as, for example, for R8and R9assume that includes any possible combination, which are chemically possible, or which lead to molecules such chemical stability, they can be obtained using standard pharmaceutical methods.

The embodiment And altoadige of the invention include compounds of formula (I) or any subgroup of compounds of formula (I), where R1means hydrogen.

The embodiment In the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of the incarnation And,

where

(a) R2, R3, R7and R8independently mean hydrogen; hydroxy; halogen; C1-6-alkyl; C3-7-cycloalkyl; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; cyano; nitro; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl; polyhalogen-C1-6-alkyloxy; -C(=O)R10;

(b) R2, R3, R7and R8independently mean hydrogen; hydroxy; halogen; C1-6-alkyl; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; cyano; nitro; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl; -C(=O)R10;

(C) R2, R3, R7and R8independently mean hydrogen; hydroxy; halogen; C1-6-alkyl; C1-6-alkyloxy; cyano; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl;

(d) R2, R3, R7and R8independently mean hydrogen; halogen; C1-6-alkyl; cyano;

(e) R2, R3, R7and R8independently mean hydrogen; halogen; C1-6-alkyl; cyano;

(f) R2and R3mean hydrogen, and R7and R8independently mean hydrogen, Gal is gene cyano.

The embodiment With the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a or b,

where

(a) R4and R9independently signify hydroxy; halogen; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; formyl; cyano; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl; -C(=O)R10; Het; -Y-Het; C1-12-alkyl, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het; C2-12alkenyl, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het; C2-12-quinil, optionally substituted with halogen, cyano, amino, mono - and di(C1-6-alkyl)amino, -C(=O)R10, Het;

(b) R4and R9independently signify hydroxy; halogen; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; formyl; cyano; amino; mono - or di(C1-6-alkyl)amino; polyhalogen-C1-6-alkyl; -C(=O)R10; Het; -Y-Het; C1-12-alkyl, optionally substituted with halogen, cyano, amino, mono - and di(C1-6-alkyl)amino, -C(=O)R10, Het; C2-12alkenyl, optionally substituted with halogen, cyano, amino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het; C2-12-quinil, optionally substituted with halogen, cyano, and the Ino, mono - or di(C1-6-alkyl)amino, -C(=O)R10, Het; and where each Het, in particular, is independently selected from tanila, furanyl, oxazolyl, thiazolyl, optionally substituted with halogen, C1-6-alkyl, cyano, carboxyla, -C(=O)R10;

(C) R4and R9independently signify hydroxy; halogen; C1-6-alkyloxy; carboxyl; C1-6-allyloxycarbonyl; cyano; amino; mono - or di(C1-6-alkyl)amino; -C(=O)R10; Het; -Y-Het; C1-6-alkyl, optionally substituted by cyano, -C(=O)R10, Het; C2-6alkenyl, optionally substituted by cyano, -C(=O)R10, Het; C2-6-quinil, optionally substituted by cyano, -C(=O)R10, Het; and where each Het, in particular, is independently selected from tanila, furanyl, oxazolyl, thiazolyl, optionally substituted with halogen, C1-6-alkyl, cyano, carboxyla, -C(=O)R10;

(d) R4and R9independently denote halogen; carboxyl; C1-6-allyloxycarbonyl; cyano; -C(=O)R10; Het; -Y-Het; C1-6-alkyl, optionally substituted by cyano, -C(=O)R10, Het; C2-12alkenyl, optionally substituted by cyano, -C(=O)R10, Het; and where each Het, in particular, is independently selected from tanila, furanyl, oxazolyl, thiazolyl, optionally substituted with halogen, C1-6-alkyl, cyano, carboxyla, -C(=O)R10;

(e) R4and R9independent iznachalno; -C(=O)R10; Het; C1-6-alkyl, optionally substituted by cyano, -C(=O)R10, Het; C2-6alkenyl, optionally substituted by cyano, -C(=O)R10, Het; and where each Het, in particular, independent means thienyl or furanyl, each optionally substituted by cyano, -C(=O)R10;

(f) R4and R9independently mean cyano; C1-6-alkyl, substituted cyano; C2-6alkenyl, substituted cyano.

Embodiment D of the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a, b or C,

where

(a) R5means1-6-alkyl, substituted by Ar or Het,2-6alkenyl,2-6-quinil, optionally substituted Het,3-7-cycloalkyl, Ar, Het;

R6means hydrogen, C1-6-alkyl, Het;

Y means OR11, NR12R13;

R11means hydrogen or C1-6-alkyl, optionally substituted hydroxy, C1-6-alkyloxy, phenyl or pyridium;

R12means hydrogen or C1-6-alkyl;

R13means hydrogen or C1-6-alkyl; or R12and R13together with the nitrogen atom, the substituents they are, form imidazolyl;

(b) R5means2-6alkenyl,2-6-quinil, substituted Het, Ar, Het;

R6means hydrogen, C1-6-alkyl, Het;

Y OSN which includes OR 11, NR12R13;

R11means hydrogen or C1-6-alkyl, optionally substituted hydroxy, C1-6-alkyloxy;

R12means hydrogen or C1-6-alkyl;

R13means hydrogen;

where in (a) or (b) Ar and Het can have values as described for compounds of formula (I) or formula (I'), or any sub-groups or, in particular, still

Ar denotes phenyl, optionally substituted C1-6-alkyloxy; and/or

(i) Het denotes pyridyl, thiazolyl, imidazolyl, benzothiazolyl, imidazothiazoles, each optionally substituted C1-6-alkyl, halogen; or else, in particular,

(ii) Het denotes pyridyl, thiazolyl, imidazolyl, each optionally substituted C1-6-alkyl, halogen; or else, in particular,

(iii) Het denotes pyridyl, thiazolyl, the latter optionally substituted C1-6-alkyl.

Of particular interest are compounds of formula (I) or any subgroup of compounds of formula (I), where the radical:

The embodiment of E present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a, b, C or D,

where

each of R10independent means1-6-alkyl, amino, mono - or di(C1-6-alkyl)amino.

Embodiment F the present invention, vkluchaetsia the compounds of formula (I) or any subgroup of compounds of formula (I), as such, in the case of embodiments a, b, C, D or E,

where

X is-NR1-, -O-, -S-, -S(=O)r-;

X is-NR1-, -O-;

X is-NR1-;

X means-NH-.

Embodiment G of the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a, b, C, D, E or F,

where

each Y independently means-NR1-, -O-, -S-, -S(=O)ror each Y is independently means-NR1-.

Embodiment H of the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a, b, C, D, E, F or G, where each r independently represents 2.

The embodiment I of the present invention include compounds of formula (I) or any subgroup of compounds of formula (I), such as in the case of embodiments a, b, C, D, E, F, G and H, where each Het independently denotes pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, chinoline, benzothiazyl, benzofuranyl; each of which may be optionally substituted by one or two substituents, each independently selected from the group consisting of C1-6-alkyl, halogen, hydroxy, cyano, C1-6-alkyloxy,2-12-alkenyl, substituted with halogen, hydroxy or cyano.

Embodiment J this is th invention include compounds of formula (I) or any subgroup of compounds of formula (I), as such, in the case of embodiments a, b, C, D, E, F, G, H and I each independently aryl means phenyl or phenyl substituted one, two or three substituents, each independently selected from those mentioned above, or, in particular, from

(a) halogen, hydroxy, C1-6-alkyl, C2-6-alkenyl,2-6-quinil, 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, phenyl-C1-6-alkyloxy,1-6-allyloxycarbonyl, aminosulfonyl, cyano, nitro, polyhalogen-C1-6-alkyl, polyhalogen-C1-6-alkyloxy, aminocarbonyl, phenyl, Het and-Y-Het; or

(b) 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-alkyloxy, phenyl-C1-6-alkyloxy,1-6-allyloxycarbonyl, cyano, polyhalogen-C1-6-alkyl, aminocarbonyl.

One embodiment of the present invention relates to compounds of the formula:

to their pharmaceutically acceptable additive salts or their stereochemical isomeric forms, where X, Y, R1, R4, R5, R6, R7, R8and R9have the meanings as described above.

In a particular embodiment, R 9in the compounds of formula (I) or formula (I'), or any subgroup means-CH2-CH2-CN, -CH=CH-CN or-C≡C-CN. Interest are such compounds where R9is (E)-isomer-CH=CH-CN.

Another embodiment relates to those compounds of formula (I) or formula (I'), or any subgroup where the use of one or more of the following constraints:

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

(ii) R4means hydroxy, halogen, C1-6-alkyl, carboxyl, cyano, -C(=O)R10, nitro, amino, mono - or di(C1-6-alkyl)amino, POLYHALOGENATED;

(iii) X is-NR1-, -O-, -S-, -S(=O)r-;

(iv) R7means hydrogen, C1-6-alkyl, halogen;

(v) R8means hydrogen, C1-6-alkyl, halogen;

(vi) R5means1-6-alkyl, substituted by Ar or Het; C2-6alkenyl; C2-6-quinil, optionally substituted Het; C3-7-cycloalkyl; Ar; Het;

R6means hydrogen, C1-6-alkyl, Het;

Y means-OR11, -NR12R13;

R11means hydrogen or C1-6-alkyl, optionally substituted hydroxy, C1-6-alkyloxy, phenyl or pyridium;

R12means hydrogen or C1-6-alkyl;

R13means hydrogen or C1-6-Ala is l; or R12and R13together with the nitrogen atom, the substituents they are, form imidazolyl;

(vii) each aryl means phenyl or phenyl substituted one, two, three, four, or five substituents, each independently selected from halogen, hydroxy, mercapto, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - and 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.

Another embodiment relates to those compounds of formula (I) or formula (I'), or any subgroup where the use of one or more of the following constraints:

(i) R9means-CH2-CH2-CN or-CH=CH-CN; in particular, where R9means-CH=CH-CN;

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

(ii-a) R1means hydrogen, C1-6-alkyl;

(ii-b) R1means hydrogen, methyl;

(ii-c) R1means hydrogen;

(iii) R4means cyano, aminocarbonyl; or where (iii-a) R2means cyano;

(iv) X is-NR1-, -O-;

(iv-a) X is-NR1-;

(iv-b) X means-NH-, -N(C1-4-Ala is l)-, -O-;

(iv-c) X means-NH-;

(v) R7means hydrogen, C1-6-alkyl, halogen; (v-a) R7means hydrogen, C1-4-alkyl, halogen; (v-b) R7means1-4-alkyl;

(vi) R8means hydrogen, C1-6-alkyl, halogen; (v-a) R8means hydrogen, C1-4-alkyl, halogen; (v-b) R8means1-4-alkyl;

(vii) R5means2-6alkenyl,2-6-quinil, substituted Het; Ar, Het;

R6means hydrogen, C1-6-alkyl, Het;

Y means OR11, NR12R13;

R11means hydrogen or C1-6-alkyl, optionally substituted hydroxy, C1-6-alkyloxy;

R12means hydrogen or C1-6-alkyl;

R13means hydrogen.

Still other subgroups of the compounds of formula (I) or formula (I') are those compounds of formula (I) or formula (I') or any subgroup, where

(a) R10means hydrogen, C1-4-alkyl; or where (b) R10means hydrogen or C1-2-alkyl.

Other subgroups of the compounds of formula (I) or formula (I') are those compounds of formula (I) or formula (I') or any subgroup, where

(a) aryl means phenyl or phenyl substituted one, two or three substituents, each independently selected from halogen, hydroxy, mercapto, C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6 -alkyl, mono - and 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;

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

Link the formula (I-a), which are the compounds of formula (I), where Y means HE, and R6means hydrogen, can be obtained by interaction of pyrimidinediamine formula (II) with the ORGANOMETALLIC compound (M-R5). The thus obtained compounds of formula (I-a) can be converted into the corresponding compounds of formula (I-b), which are compounds of formula (I), where Y means OR11where R11has a different meaning than hydrogen. The group R11you can enter through the formation of a simple ester, such as the reaction of O-alkylation with a reagent W1-R11where W1represents a removable group, such as halogen, in particular chlorine, bromine or iodine, or a sulfate or azide. M M-R5means metal, such as alkali metal, in particular Li, Na or K, or a derivative of magnesium, such as type of Grignard reagent (M-R5means halogen-Mg-R5). These interactions are usually carried out in an inert under the reaction conditions solvent, such as a simple ether (THF, diethyl ether, dioxane) or a halogenated hydrocarbon (CH2CL2, CHCl3).

The compounds of formula (I), where Y means OR11and R5and R6have the same value, can be obtained by reacting the ether pyrimidinecarboxylic acid of formula (III) with ORGANOMETALLIC compounds is receiving (M-R 5that has a value as described above), thereby obtaining the compounds of formula (I-c), which are compounds of formula (I), where Y means HE, and R5and R6have the same value. Ether carboxylic acid in the case of the formula (III), i.e. the group-R can be1-6-alkylbis ether, for example, methyl, ethyl or propyl ether. The compounds of formula (I-c) can be converted into the corresponding compounds of formula (I-d), which are compounds of formula (I), where Y means OR11where R11has a different meaning than hydrogen, and R5and R6of equal importance, by the reaction of formation of simple ether as described above. These interactions are usually carried out in an inert under the reaction conditions, the solvent such as the solvents mentioned in connection with the receipt (I-a) and (I-b).

The compounds of formula (I), where Y means HE further denote (I-e)can be obtained from Ketoprofen (IV) by introducing in the interaction with the ORGANOMETALLIC compound (M-R6as described above, when the conversion of compound (III) into the compound (I-c). Ketoprofene (IV) is produced from compound (I-a) by oxidation reactions, in particular, when using a weak oxidant, such as MnO2. The compound (I-e) is transformed into the compound (I-f), which are the connection of enemy formula (I), where Y means OR11and where R11has a different meaning than hydrogen, by the reaction of formation of simple ether as described above. Also, these interactions are usually carried out in an inert under the reaction conditions solvent (for example, as solvents listed above).

Intermediates of formula (IV), their salts and possible stereoisomers are novel compounds and constitute another aspect of the present invention. Salt intermediates (IV), in particular, are additive salts of acids, more in particular pharmaceutically acceptable additive salts of acids such as the salts mentioned above in connection with compounds of formula (I).

The compounds of formula (I)where Y represents NR11R12in this context represented by formula (I-g), can be obtained by reacting the compounds of formula (I-c) with an agent which introduces the group that you want, such as l3or SOCl2, thereby obtaining an intermediate product (V), which are converted into the corresponding amines with R11R12NH. The group W in the compound (IV) represents a group to delete, which, in particular, means halogen, preferably chlorine or bromine, or tosyl, mesyl or similar. Also, these interactions are usually carried out in an inert under the reaction conditions solvent (such as dissolve and, above).

Intermediates of formula (II) receive a first halogenoalkanes educt of the 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 thus obtained intermediate products of the formula (VII) is then converted into the corresponding intermediates of formula (II), which are group-SNO in position 5 of the pyrimidine residue, by introducing into the interaction of the compound (VII) with pressurized gas, in the presence of sodium formate and a suitable catalyst, such as, for example, dichlorobis(triphenylphosphine)palladium(II).

Intermediate esters of formula (III) can be obtained first by introducing into the interaction of intermediate products of the formula (VII) with pressurized gas, in the presence of ethanol or such lower alkanol and a suitable catalyst, such as, for example, dichlorobis(triphenylphosphine)palladium(II).

The compounds of formula (I) can be converted into the corresponding N-oxide forms by the following well-known in the prior art methods of transformation of the tertiary nitrogen into its N-oxide form. The above reaction of N-oxidized who I am, as a rule, can be done by introducing into the interaction of the parent substance of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include nagkalat, as, for example, Benalmadena acid or halogen-substituted Benalmadena acid, such as 3-chlorobenzylamino acid, alkenylcarbazoles acids, for example peracetic acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like, hydrocarbons such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The compounds of formula (I) can be further transformed into each other using known in the prior art reaction conversion of functional groups. The compounds of formula (I), where R2or R3means hydrogen, can be converted into compounds of formula (I)where one or more of R2, R3, R7or R8means halogen, by entering into interaction with the appropriate introducing halogen agent, such as N-chlorosuccinimide or N-bromosuccinimide, in the presence of a suitable solvent, for example acetic acid. The compounds of formula (I), where R1means1-6-allyloxycarbonyl can be converted to a compound of formula (I), where R1means hydrogen, by entering into cooperation with a suitable base, such as, for example, sodium hydroxide or sodium methoxide. Where R1means tert-butyloxycarbonyl, the corresponding compounds where R1means hydrogen, is produced by processing triperoxonane acid.

Some of the compounds of formula (I) and some of the intermediate products according to the present invention may contain asymmetric carbon atom. Stereochemical pure isomeric forms of the above compounds and the above-mentioned intermediate products can be obtained using known prior art methods. For example, diastereoisomer can be divided by physical methods such as selective crystallization or chromatographic methods, such as countercurrent distribution chromatography, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first transforming the above racemic mixtures using a suitable solvent agents, such as, for example, chiral acids, mixtures of diastereomeric salts or compounds is s; 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 forms may also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that the intermediate 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.

The compounds of formula (I) possess antiviral 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 primarily infects human T-4 cells and destroys them or change their normal function, in particular the coordination of the immune system. As a result, the infected patient has always reduce the n number of T-4 cells, which also behave abnormally. Therefore, immunological protective system is unable to fight infections and tumors, and HIV-infected subject is usually dying caused by conditionally pathogenic microorganisms infections such as pneumonia, or cancer. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system characterized by progressive demyelination, with the result of dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. HIV infection also further associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-associated complex (ARC).

Compounds according to the present invention also show activity against HIV strains that are resistant to (multiple) medicines, in particular HIV-1 strains resistant to multiple drugs, in particular, the compounds according to the present invention show activity against HIV strains, especially against HIV-1 strains that have acquired resistance against one or more known in the prior art non-nucleoside reverse transcriptase inhibitor. Known in the technician level is a non-nucleoside reverse transcriptase inhibitors are nucleoside reverse transcriptase inhibitors, other than the compounds according to the present invention, and known to a qualified specialist in this field, in particular commercially available non-nucleoside reverse transcriptase inhibitor. Compounds according to the present invention also possess a small or neisvaziuosiu the affinity to human α-1-acid glycoprotein and human α-1-acid glycoprotein is not affected or only little effect on anti-HIV activity of the compounds according to the present invention.

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

Compounds according to the present invention, therefore, can be used as drugs against the above-mentioned conditions. The above use as a medicine or method of treatment includes the introduction of HIV-infected subjects an effective amount of the compounds to combat conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1. In particular, the compounds of formula (I) can be used for getting medicines for treating or preventing HIV infection.

In a further aspect this invention relates to a method of treating warm-blooded animals, including humans, suffering from conditions associated with viral infection, particularly HIV infection, the above method includes the introduction of the above warm-blooded animals, including humans, antiviral effective amount of the compounds of formula (I), as described in this context. In addition, it relates to a method for preventing the development of conditions associated with viral infection, particularly HIV infection in warm-blooded animals, including humans, with the above method includes the maintenance of the above-mentioned warm-blooded animals, including people, antiviral effective amount of the compounds of formula (I), as described in this context.

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 can be used for various pharmaceutical forms depending on the route of administration. As appropriate compositions can be called all compositions usually employed for the systematic administration of drugs. To obtain pharmaceutical compositions according to this invention an effective amount of a particular compound, optionally in the form of a salt additive, as an active ingredient, unite by thorough mixing with a pharmaceutically acceptable carrier, and the carrier can be selected from a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in a standard dosage form suitable, in particular, for oral, rectal, subcutaneous injection, or by parenteral injection. For example, upon receipt of the compositions in oral dosage form can be used any out of the ordinary pharmaceutical environments such as, for example, water, glycols, oils, alcohols and the like, in the case of oral liquid finished dosage forms such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, dezintegriruetsja agents, etc. in the case of powders, pills, capsules and tablets. Due to ease their introduction of tablets and capsules represent the most advantageous oral standard dosage forms, in which case use solid pharmaceutical carriers. In the case of parenteral compositions, the carrier typically includes sterile water, at least for the most part, although it may include other ingredients, for example, to aid solubility. Can be obtained, for example, injectable solutions, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can also be obtained injectable suspension, in which case can be used appropriate liquid carriers, suspendresume agents, etc. are Also included preparations in solid form, which are intended for turning, shortly before use, to liquid form. In the compositions suitable for subcutaneous injection, the carrier optional the tion includes enhancing the penetration of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, and additives have no harmful effects on the skin. The above additives can facilitate introduction through 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 droplets, in the form of ointment.

Compounds according to the present invention can also be administered by inhalation or insufflation using methods and dosage forms used in the prior art for introducing this way. Thus, in General, the compounds according to the present invention can enter into the lungs in the form of a solution, suspension or dry powder. Any system designed for the delivery of solutions, suspensions or dry powder by oral or nasal inhalation or insufflation, suitable for administration of the compounds according to the present invention.

To improve the solubility of the compounds of formula (I) can be included in compositions suitable ingredients, such as cyclodextrins. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers or mixed ethers where one or more hydroxyl groups anhydroglucose units of the cyclodextrin Sames the t 1-6-alkyl, in particular the stands, ethyl or isopropyl, e.g. methylated on the occasion of β-CD; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, in particular carboxymethyl or carboxyethyl; C1-6-alkylcarboxylic, in particular acetyl. Especially noteworthy as complexing agents and/or solubilization are β-CD, methylated on the occasion of β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term "simple mixed ether" means derivative of cyclodextrin, where at least two cyclodextrine hydroxyl group is transformed into a simple ether with various 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 groups per mole of anhydroglucose. The average degree of substitution (D.S.) refers to the average number of substituted hydroxyl groups per unit anhydroglucose. Values M.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 slackerslayer values for one of this cyclodextrin derivative. Preferably, as measured by mass spectrometry, M.S. range 0,125-10, and D.S. in the range 0,125-3.

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

The term "solid dispersion", as used hereinafter, describes the system in the solid state (as opposite to the liquid or gaseous state), containing at least two components, in case the connection of the formula (I) and water-soluble polymer, where one component is more or less evenly dispersed in the other component or components (in the case include additional pharmaceutically acceptable agents for the finished dosage forms are generally known in the prior art, such as plasticizers, preservatives and the like). When the above dispersion of the components is such that the system is chemically and physically uniform or homogenous or consists of one phase, as described in thermodynamics, such a solid dispersion is called a "solid solution". Solid solutions are preferred physical systems, as components in them are usually easily bioavailable to organisms in which their input is Yat. 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 juices. Ease of dissolution can be attributed, at least partially, to the fact that the energy required for dissolution of the components of the solid solution, you need less than the energy required for dissolution of the components of the crystalline or microcrystalline solid phase.

The term "solid dispersion" also refers to the dispersions, which are less homogeneous than solid solutions. Such dispersions are not chemically and physically homogeneous or contain more than one phase. For example, the term "solid dispersion" also refers to the system having areas or small areas where amorphous, microcrystalline or crystalline compound of formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both are more or less uniformly dispersed in the other phase comprising a water-soluble polymer, or a compound of formula (I), or a solid solution containing the compound of formula (I) and water-soluble polymer. The above zones are areas in the solid dispersion, clearly visible at a particular physical characteristic (property), small is the size and uniformly and randomly distributed in the solid dispersion.

There are different ways of getting solid dispersions, including extrusion from the melt, spray drying and evaporation of the solution.

The method of evaporation of the solution includes the following stages:

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

b) heating the solution obtained in paragraph (a), optionally in a vacuum until the solvent is evaporated. The solution can also be poured on a large surface so as to form a thin film, and to evaporate the solvent.

According to the method of spray drying, two component, also dissolved in an appropriate solvent and the resulting solution is then sprayed through a nozzle to spray drying with subsequent evaporation of the solvent from the resulting droplets at elevated temperatures.

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

a) mixing the 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 thus obtained mixture to obtain a homogeneous melt,

d) extruding the thus obtained melt through on the but or more nozzles and

e) cooling the melt prior to its solidification.

Assume that the terms "melt" and "melting" refers not only to the transition from solid state to liquid state, but also relate to the transition to the glassy state or kauchukopodobnoe the condition in which it is possible that one component of the mixture is more or less homogeneous included in another. In particular cases, one component is melted, and the other(s) component(s) is dissolved(are) in the melt, thereby forming a solution, which, after cooling, may form a solid solution, having advantageous properties in respect of dissolution.

After obtaining a solid dispersion as described above, the resulting products can optionally be milled and sifted. The product in the form of a solid dispersion can be milled or crushed to particles having a particle size less than 600 microns, preferably less than 400 μm, most preferably less than 125 microns.

Particles obtained as described above can then use standard methods to use to obtain pharmaceutical dosage forms such as tablets and capsules.

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

You can also use one or more cyclodextrins as a water-soluble polymer upon receipt of the above particles, as described in WO 97/18839. The above cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in the prior art, in which W is STI α, β - or γ-cyclodextrins or their pharmaceutically acceptable derivatives.

Substituted cyclodextrins that can be used to obtain the above-described particles include polyethers described in U.S. patent 3459731. Next, substituted cyclodextrins are ethers, where the hydrogen of one or more cyclodextrins hydroxyl groups replaced With1-6-alkyl, hydroxy-C1-6-alkyl, carboxy-C1-6-alkyl or C1-6-allyloxycarbonyl-C1-6-alkyl, or mixed ethers. In particular, such substituted cyclodextrins are ethers, where the hydrogen of one or more cyclodextrins hydroxyl groups replaced With1-3-alkyl, hydroxy-C2-4-alkyl or carboxy-C1-2-alkyl, or, 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, as examples. Such a simple alkilany ether may be a simple methyl ether with a degree of substitution of about 0,125-3, for example about 0.3 to 2. This hydroxypropylcellulose for example, can be obtained by introducing into the interaction of β-cyclodextrin with propylene oxide and may have a value M.S., approximately 0,125-10, for example about 0.3-3. Another type of substituted cyclodextrins that can be used are sulfosalicylate.

The ratio of the compounds of formula (I) to the water-soluble polymer can vary widely. For example, you can use the ratio of from 1/100 to 100/1. Interest ratio of compounds of formula (I) and cyclodextrin are in the range of from about 1/10 to 10/1. Of great interest ratios are within the range of from about 1/5 to 5/1.

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

Another way of using compounds of formula (I) to obtain a finished dosage form comprises a pharmaceutical composition where the compounds of formula (I) are included in the hydrophilic polymer, and the mixture is used as a film coating for many small balls, thereby obtaining a composition which can be easily processed and which is suitable for the production of pharmaceutical dosage forms for oral administration. These balls include Central, rounded or spherical core, a film coating of a hydrophilic polymer and a compound of formula (I), and, optionally, an insulating coating layer. A material suitable for use as cores in the balls, is manifold, provided that the above materials are pharmaceutically acceptable and have the appropriate size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and sugars, and their derivatives.

It is particularly favorable for the above pharmaceutical compositions in a standard dosage form in relation to ease their administration and uniformity of dosage. Standard drugs the military form, as used in this context, refers to physically discrete units suitable as unitary dosages, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated tablets), capsules, pills, packaged powders, pills, suppositories, injectable solutions or suspensions and the like, and segregated multiple forms.

A qualified specialist in the treatment of HIV infection may determine the effective daily amount according to the test results presented in this context. In General, assume that the effective daily amount should be 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. For injection may be assigned to the correct dose in the form of two, three, four or more subds appropriate intervals during the day. The above subdata can be obtained in a standard dosage forms, for example, containing 1 to 1,000 mg, particularly 5 to 200 mg, of the active ingredient at a standard dosage form.

The exact dosage and frequency wedenesday used specific compounds of formula (I), being treated with a specific condition, the severity being treated condition, age, weight and General physical condition of the particular patient, and the individual may be assigned to another medication, as is well known to a qualified specialist in this field. In addition, it is obvious that the above effective daily amount can be reduced or increased depending on the response under treatment of the subject and/or depending on the evaluation of the physician prescribing the compounds according to the present invention. The effective daily amount in the range specified above is therefore only recommended and not mean it in any way limit the scope or application of the present invention.

The compounds of formula (I) can be applied separately 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 for the prevention of viral infections. Compounds according to the present invention can be used in the vaccines and methods of protecting individuals against viral infections over a long period of time. With which organisations can be applied in such vaccines or separately, or together with other compounds according to this invention, or in combination with other antiviral agents in a manner consistent with the normal 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 an extended period of time against HIV infection.

You can also use a combination of one or more antiretroviral compounds and the compounds of formula (I) as a drug. Thus, the present invention also relates to a product containing (a) compound of formula (I) and (b) one or more additional antiretroviral compounds, in the form of combined preparations for simultaneous, separate or sequential use in anti-HIV treatment. Various drugs can be combined in a separate finished medicinal product, together with pharmaceutically acceptable carriers. The above other antiretroviral compounds may be any known antiretroviral compounds, such as suramin, pentamidine, timap is ntin, castanospermine, dextran (textresult), foscarnet-sodium (trinatriumfosfaat); nucleoside reverse transcriptase inhibitors (NRTIs)such as zidovudine (AZT), didanosine (ddI), zalcitabine (dd), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), amdoxovir (DAPD), elvucitabine (ACH-126,443), AVX 754 ((-)-dOTC), voivodinians (FZT), phosphated, HDP-990003, KP-1461, MIV-210, racivir (PSI-5004), UC-781 and the like; non-nucleoside reverse transcriptase inhibitors (NNRTIs)such as delavirdine (DLV), efavirenz (EFV), nevirapine (NVP), dapivirine (TMC), etravirine (TMC), rilpivirine (TMC), DPC-082, (+)-calanolide AND, BILR-355 and the like; nucleotide reverse transcriptase inhibitors (NtRTIs), such as tenofovir ((R)-PMPA) and tenofovirdisproxil (TDF) and the like; competing nucleotide reverse transcriptase inhibitors (NcRTIs), for example NcRTI-1 and the like; inhibitors transactivity proteins, such as TAT-inhibitors, e.g. RO-5-3335, BI-201, etc.; REV inhibitors; protease inhibitors, such as ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), APV (VX-478), TMS, nelfinavir (AG-1343), atazanavir (BMS 232,632), darunavir (TMC), fosamprenavir (GW433908 or VX-175), brecanavir (GW-640385, VX-385), P-1946, PL-337, PL-100, tipranavir (PNU-140690), AG-1859, AG-1776, Ro-0334649 and the like; inhibitors "login", which include inhibitors of hybridization (e.g., enfuvirtide (T-20)), inhibitors prisoedinenie and inhibitors, co-receptor, the latter include R5-antagonists (e.g., antiviral, R5mAb004, maraviroc (UK-427,857), PRO-140, TAK-220, TAK-652, vicriviroc (SCH-D, SCH-417,690) and CXR4 antagonists (e.g., AMD-070, KRH-27315); examples of inhibitors "login" are PRO-542, TNX-355, BMS-488,043, BlockAide/CR™, FP-21399, hNM01, nonacid, VGV-1; inhibitor of maturation represents, for example, RA-457; inhibitors of viral integrase, such as MK-0518, JTK-303 (GS-9137), BMS-538,158; ribozymes; immunomodulators; monoclonal antibodies; gene therapy agents; vaccines; siRNAs; antimyeloma RNA; antibacterial agents; inhibitors of proteins with zinc fingers".

Compounds according to the present invention can also be entered in combination with immunomodulators (e.g., bropirimine, the antibody against human alpha-interferon, IL-2, Medininkai, interferon-alpha and naltrexone), antibiotics (e.g., pentanedinitrile), cytokines (e.g., Th2), modulators of cytokines, chemokines or modulators chemokines, receptors chemokines (e.g., CCR5, CXCR4), modulators of receptors chemokines or hormones (e.g. growth hormone) to improve, fight or eliminate HIV infection and its symptoms. Such combination therapy using various finished dosage forms can be performed simultaneously, sequentially or independently from each other. The alternative, that the second combination can be entered as one finished dosage forms, where the active ingredients are released from the finished dosage forms at the same time or separately.

Compounds according to the present invention can also be entered in combination with modulators of metabolism with subsequent use of the drug for the individual. These modulators include compounds that interfere with the metabolism cytochromes, such as cytochrome P450. It is known that there are some isoenzymes of cytochrome P450, one of which is a cytochrome P450 3A4. Ritonavir is an example of a modulator of metabolism via cytochrome P450. Such combination therapy using various finished dosage forms can be performed simultaneously, sequentially or independently from each other. Alternatively, such a combination can be entered as one of the finished dosage form, where the active ingredients are released from the finished dosage forms at the same time or separately. Such a modulator can be entered in the same or a different ratio, such as the joint according to the present invention. Preferably the mass ratio of such a modulator in relation to the connection according to the present invention (modulator:connection according to the present invention) is 1:1 or below, more preferably the ratio is 1:3 or lower are eligible the way the ratio is 1:10 or less more suitably the ratio is 1:30 or below.

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

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

EXAMPLES

Example 1

Getting connection 1

1.6 M solution of n-BuLi (n-utility) (totaling 3.04 mmol) are added dropwise to a solution of 2-bromopyridine (totaling 3.04 mmol) in THF (5 ml) at -78°C. the Mixture was stirred at -78°C for 1 hour. Then added dropwise intermediate product 1 (0,761 mmol) at -78°C and the mixture stirred at -78°C for 1 hour and at room temperature over night. Water is added and the mixture extracted with ethyl acetate. 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/MeOH/NH4HE = 98/2/0,1 to CH2Cl2/MeOH/NH 4HE = 92/8/0,4; Kromasil, 5 μm). Pure fractions are collected and the solvent is evaporated. Output: of 0.085 g of compound 2 (17%, melting point: 244°C).

Table 1

*Separation of enantiomers using chiral chromatography.

Example 2

Obtaining an intermediate product 2

Manganese dioxide (0.012 mol) are added to a solution of compound2(0,00062 mol) in CH2CL2(20 ml) and the mixture is stirred at room temperature for 24 hours, then filtered over celite. Celite is washed with a mixture of CH2CL2/Meon/THF and the filtrate is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/Meon = 99/1, SiO210 µm). Pure fractions are collected and the solvent is evaporated. Output: to 0.060 g of the intermediate product 2 (20%, melting point: >250°C).

Example 3

Tertiary alcohols

Method And

1.6 M solution of n-BuLi (is 3.08 mmol) are added dropwise to a solution of thiazole (is 3.08 mmol) in THF (5 ml) at -78°C. the Mixture was stirred at -78°C for 1 hour. Then added dropwise intermediate product 2 (0,761 mmol) in which the temperature -78°C, the mixture is then stirred at -78°C for 1 hour and at room temperature over night. Add water and 10%solution of NH4Cl and the mixture extracted with CH2CL2/THF. 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/MeOH/NH4HE = 99/1/0,1 to CH2Cl2/MeOH/NH4HE = 95/5/0,5; Kromasil, 5 μm). Pure fractions are collected and the solvent is evaporated. Output: 0,044 g connection5(11%).

Method:

Commercially available magnesium-containing reagent (3.5 EQ.) added to a solution of the intermediate product2(1 EQ.) in THF (15 ml) at 0°C, the mixture is stirred for 1 hour at 0°C and then at room temperature overnight. Add water and 10%solution of NH4Cl and the mixture extracted with CH2CL2/THF. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is purified by column chromatography on silica gel. Pure fractions are collected and the solvent is evaporated, receiving connection 21-27.

Example 4

Obtaining derivatives of thiazole

Inishmore (1 ml) was added dropwise to a solution of compound 2(of 0.60 mmol) in CH2CL2(5 ml) at 0°C. the Mixture is stirred at 0°C for 3 hours and then at room temperature overnight. The mixture is evaporated to dryness and the resulting solid (intermediate 4) filtered and washed with Et2O. This intermediate product is used in the following reactions without further purification.

Method And

Morpholine (1.2 ml) is added dropwise to a solution of the intermediate product4(0.30 mmol) in THF (15 ml) at room temperature. The mixture is stirred at room temperature overnight. The mixture was poured into water and 10%solution of K2CO3and extracted with a mixture of CH2CL2/Meon/THF. 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 = 98/2/0,2 to CH2CL2/Meon/NH4OH = 94/6/0,6; Kromasil, 5 μm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from Et2O. Output: 0,047 g connection29(28%, melting point: 220°C).

Method In

A mixture of compound 2 (0,00028 mol, 1 EQ.), 1,1'-carbonimidoyl (0,0031 mol, 1.5 EQ.) and methylamine (0,0031 mol, 1.5 EQ.) in THF (2 ml) is stirred for 18 hours. This mixture was poured into water and 1%solution of K 2CO3and extracted with a mixture of CH2CL2/Meon/THF. 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 = 99/1/0,1 to CH2CL2/Meon/NH4OH = 94/6/0,6; Kromasil, 5 μm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from iPr2O. Output: 0,040 g connection30(36%, melting point: 165°C).

Way

1,2-Ethanediol (8,02 mmol, 2 EQ.) added dropwise to a solution of compound6(4,01 mmol, 1 EQ.) triethylamine (8,02 mmol, 2 EQ.) in THF (4 ml) at room temperature. The mixture is stirred at room temperature overnight, then refluxed for 24 hours. The mixture was poured into water and 10%solution of K2CO3and extracted with a mixture of CH2CL2/Meon/THF. 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 = 99/1/0,1 to CH2CL2/Meon/NH4OH = 95/5/0,5; Kromasil, 5 μm). Pure fractions are collected and the solvent is evaporated. The residue is crystallized from iPr2O. Output: 0,048 g connection31(22%, melting point: 120°C).

In the next table lists compounds receive in accordance with the methods described in the above example.

ndmeans is not installed.

Examples of the finished dosage form

Capsules

The compound of formula (I) dissolved in an organic solvent, such as ethanol, methanol or methylene chloride, preferably in a mixture of ethanol and methylene chloride. Polymers such as a copolymer of polyvinylpyrrolidone with vinyl acetate (PVP-VA) or hypromellose (receiver array), usually up to a viscosity of 5 MPa·s, dissolve in organic solvents, such as ethanol, methanol, methylene chloride. Suitably, the polymer is dissolved in ethanol. The polymer solutions and compounds are mixed and then subjected to spray drying. The ratio of compound/polymer chosen from 1/1 to 1/6. The intermediate value may be 1/1,5 and 1/3. A suitable ratio may be 1/6. Dried by spray drying powder, solid dispersion then fill capsule for introduction. Drug fill one capsule in the range of 50 to 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 is then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. 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 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then there is added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated suspension of the coloring matter and it's all homogenized. The core tablets are coated with the thus obtained mixture in an enrobing machine.

Antivirus spectrum

Because of the increasing emergence of drug-resistant HIV strains, the compounds according to the present invention were tested for their efficacy against clinically isolated HIV strains, with some mutations. These mutations are associated with resistance against the reverse transcriptase inhibitors and lead to viruses that exhibit varying degrees, feet the microscopic cross-resistance with respect to commercially available at present, medicines, such as, for example, 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 carrying mutations in the gene for reverse transcriptase. The activity of compounds was evaluated using the cell analysis, which was performed in accordance with the following method.

Human T-cell line MT4 was designed with green fluorescent protein (GFP) and HIV-specific promoter, the long terminal repeat of HIV-1 (LTR sequence). This cell line was designated MT4 LTR-EGFP, and it can be used for in vitro evaluation of anti-HIV activity of the investigated compounds. In HIV-1-infected cells is produced by Tat protein, which activates the LTR-promoter and, in the end, leads to stimulation of the production of GFP-reporter, allowing to measure the ongoing HIV fluorometrically.

Similarly, MT4 cells were designed with GFP and constitutional promoter of cytomegalovirus (CMV). This cell line was designated MT4 CMV-EGFP, and it can be used for in vitro assessment of cytotoxicity of these compounds. In this cell line GFP levels comparable with those infected MT4 cells LTR-EGFP. Cytotoxic investigational compounds reduce the levels of GFP mnemonicindex MT4 cells CMV-EGFP.

Determine the values of the effective concentric and, such as the 50%effective concentration (EC), and, usually expressed in microns. Is ES was defined as the concentration of test compound that reduces the fluorescence of HIV-infected cells by 50%. Concentration in relation to cytotoxicity at 50% (SC in μm) was defined as the concentration of test compound that reduces the fluorescence mnemonicindex cells by 50%. The ratio SS to ES was determined as an index of selectivity (SI), and it is a measure of the selectivity of the anti-HIV activity inhibitor. Performed final monitoring HIV-1 infection and cytotoxicity using a scanning microscope. Analysis "in the image" allows very sensitive detection of viral infection. The measurements were carried out prior to cell necrosis, which typically occurs after approximately five days after infinetly, in particular the measurements were carried out three days after infection.

In columns IIIB, L100I, etc. in the table lists the values RES50against different strains IIIB, L100I, etc.

Strain IIIB is an HIV strain wild-type.

"MDR" refers to a strain that contains mutations L100I, K103N, Y181C, E138G, V179I, L2214F, V278V/I and A327A/V in the reverse transcriptase of HIV.

1. The compound of formula (I):

or its pharmaceutically acceptable additive salt, where
R1means hydrogen;
R2and R3independently mean hydrogen;
R7and R8mean C1-6alkyl;
R4means cyano;
R9means C1-6alkyl, optionally substituted by cyano, C2-6alkenyl, substituted cyano, C2-6quinil, optionally substituted by cyano;
R5means1-6alkyl, optionally substituted AG or Het; C2-6alkenyl, optionally substituted AG or Het; C2-6quinil, optionally substituted AG or Het; C3-7cycloalkyl; AG; Het; R6means H, Het;
Y means-OR11, -NR12R13;
R11means hydrogen or C1-6alkyl, optionally substituted hydroxy, C1-6alkoxy, or pyridyl;
R12means hydrogen or C1-6alkyl;
R13means hydrogen or C1-6alkyl;
or R12and R13together with the nitrogen atom, the substituents they are, form morpholinyl; imidazolyl;
X represents-NR1-;
Het denotes a 5 - or 6-membered fully unsaturated cycle, where one or two members of the cycle are heteroatoms, each independently selected from nitrogen and sulfur, and where the other members of the cycle are carbon atoms; and where possible, any member of the heterocycle with the nitrogen heteroatom optionally can the t to be substituted C 1-6by alkyl; where the 5 - or 6-membered cycle can be optional annylirovan with benzene, thiophene cycle; each independently aryl means phenyl or phenyl substituted by one Deputy, selected from C1-6alkoxy.

2. The compound according to claim 1, where the compound corresponds to the formula (I'):

where X, Y, R1, R4, R5, R6, R7, R8and R9have the meanings as described in claim 1.

3. The compound according to claim 1, where R4independent means cyano; and R9independently mean C1-6alkyl, substituted cyano; C2-6alkenyl, substituted cyano.

4. The compound according to any one of claims 1 to 3, where R5means C1-6alkyl, substituted AG or Het,2-6alkenyl,2-6quinil, optionally substituted Het,3-7cycloalkyl, Ar, Het;
R13means hydrogen or C1-6alkyl; or R12and R13together with the nitrogen atom, the substituents they are, form imidazolyl.

5. The compound according to any one of claims 1 to 4, where R5means2-6alkenyl,2-6quinil, optionally substituted Het; Ar, Het;
R11means hydrogen or C1-6alkyl, optionally substituted hydroxy, C1-6alkyloxy;
R12means C1-6alkyl;
R13means hydrogen.

6. The compound according to any one of claims 1 to 5, where each Het independently denotes pyridyl, tiani is, thiazolyl, each of which may be optionally substituted radical selected from C1-6the alkyl.

7. Pharmaceutical composition having the properties of an inhibitor of HIV replication, containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 6.



 

Same patents:

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel agents for controlling plant fungal diseases, specifically 3,7-dithia-1,5-diazabicyclo[3,3,0]octane as an agent against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger, synthesis of which takes place in a single step using readily available reactants in contrast to multi-step synthesis of existing agents used for controlling fungal diseases of plants and materials.

EFFECT: obtaining novel agents for controlling plant fungal diseases.

1 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

,

where R1 represents CH3; R2 represents halogeno or CN; R3 represents H or CH3; R4 represents H or CH3; n represents 0, 1 or 2; and to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition and to application of the compounds of formula (I) in preparing a drug exhibiting antagonist activity in relation to CX3CR1 receptor.

EFFECT: provided the compounds of formula (I) as CX3CR1 receptor antagonists.

20 cl, 1 tbl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) where the bond b represents a double bond; X represents -S-; each Z1 and Z3 independently represents a direct bond, -N(R5) - or - (CH2)q; Z2 represent -C(O)- or -C(S)-; m represents an integer equal to 1; n represents an integer equal to 1; each of q independently represents an integer varying within 1 to 4; R0 represents hydrogen, halogen, hydroxy, unsubstituted C1-C3alkyl or unsubstituted C1-C3alkoxy; R1 is independently selected from a group consisting of halogen, optionally substituted C1-C3alkyl, -R6OR7, -R6N(R7)2, -R6C(O)R7, -R6C(O)OR7, -R6C(O)N(R7)R9N(R7)2, -R6OC(O)R8, -R6C(O)N(R7)2 or -R6OR9N(R7)2; R2 represents hydrogen; R4 is selected from a group consisting of morpholine, isoxazolyl, thiazolyl, oxazolyl, benzisoxazolyl, benzothiazolyl, dioxynyl, dioxolyl, and optionally substituted phenyl. Also, the invention refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a pharmaceutical composition exhibiting antiproliferative activity and containing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) exhibiting antiproliferative activity.

21 cl, 11 dwg, 5 tbl, 19 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2-piperidino-5-(thienyl-2)-6H-1,3,4-thiadiazines, hydrobromides (of general formula I) and 2-piperidino-5-(thienyl-3)-6H-1,3,4-thiadiazines, hydrobromides (of general formula II) which possess antiaggregant action. wherein R=H; Cl; Br R1=H; Cl.

EFFECT: given compounds may be used for preparing cardiologic drugs and enable better treatment of various cardiovascular diseases, including myocardial infarction and thrombotic apoplexy.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel purified compound PM 181104 of formula I

(with molecular weight 1514 and molecular formula C69H66N18O13S5), pharmaceutically acceptable salts thereof, methods for synthesis via fermentation of a microorganism of the type Kocuria (ZMA B-1 / MTCC 5269), as well as pharmaceutical compositions.

EFFECT: high efficiency of using the composition to produce a medicinal agent for treating bacterial infections.

20 cl, 4 dwg, 4 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or tautomer thereof

or enantiomer or physiologically acceptable salt, where R1 is o-bromo, R2 is n-fluoro, R3 is C1-C4 alkyl, R6 is thiazolyl-2-yl, X is methylene and Z is morpholinyl. The invention also relates to methods of producing (versions) compounds of formula (I) and (Ia). The compound of formula (I) or (Ia) is used to prepare a pharmaceutical composition for treating or preventing HBV infections and HBV-induced diseases such as hepatitis B.

EFFECT: bromophenyl substituted thiazolyl dihydropyrimidines for HBV infection control.

20 cl, 7 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mono-(di-, tetra-)methyl-1,2-bis-(1,3,5-dithiazinan-5-yl)ethanes of general formula (1-3): , (1) R1=CH3, R2, R3, R4=H (2) R1, R3=CH3, R2, R4=H (3) R1, R2, R3, R4=CH3, which involves reaction of hydrogen sulphide-saturated aqueous solution of (37%) formaldehyde and acetaldehyde with 1,2-diaminoethane with molar ratio of initial reagents 1,2-diaminoethane: formaldehyde: acetaldehyde: hydrogen sulphide equal to 10:50:10:40 to obtain (1), 10:40:20:40 to obtain (2), 10:20:40:40 to obtain (3), at temperature 40°C and atmospheric pressure for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as selective sorbents and extraction agents of precious metals, agents for protecting leather, fur and textile from biodeterioration, biologically active substances with respect to different microorganisms and sulphate-reducing bacteria.

1 cl, 1 tbl, 1 ex

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