Hiv-inhibiting 5-carbo- or heterocyclic substituted pyrimidines

FIELD: medicine, pharmaceutics.

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

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

5 cl, 7 tbl, 14 ex

 

Description

The invention relates to pyrimidine derivative having any abscopal the replication of HIV (human immunodeficiency virus) properties. The invention also relates to methods for their preparation and the pharmaceutical compositions. The invention also relates to the use of these compounds for the prevention or treatment of HIV infection.

The resistance of the HIV virus to existing drugs for the treatment of HIV is the main cause of treatment failure. This led to the introduction combinational treatment two or more anti-HIV agents, usually having different activity profile. Considerable success has been achieved with the introduction of HAART therapy (highly active antiretroviral therapy, Highly Active Anti-Retroviral Therapy), which led to a significant reduction of morbidity and mortality in HIV-infected patients treated by this method. HAART consists of various combinations of inhibitors nucleoside reverse transcriptase inhibitors (NRTIs), inhibitors of-nukes reverse transcriptase inhibitors (NNRTIS) and protease inhibitors (PI). Current guidelines for antiretroviral therapy recommend this mode of triple combination therapy for initial treatment. However, these types of therapy that involves using multiplepart, fully n the destroy HIV and long-term treatment usually is addictive to these multiplepart. In particular, half of the patients taking anti-HIV combination therapy, not fully respond to treatment, mainly due to resistance to one or more used drugs. It was also shown that the resistant virus is transmitted to newly infected people, which leads to a strictly limited treatment options such does not take the drug patients.

So there is a constant need for new combinations of active ingredients which are effective against HIV. New types of anti-HIV effective active ingredients, differing in chemical structure and activity profile can be used in new types of combination therapies. Therefore, the finding of such active ingredients is highly desirable task for the decision.

The present invention is directed to providing a completely new pyrimidine derivatives possessing any abscopal HIV replication properties. WO 99/50250, WO 00/27825 and WO 01/85700 reveal some substituted aminopyrimidine, and WO 99/50256 and EP-834507 reveal aminotriazines with any abscopal HIV replication properties.

Compounds according to the invention differ from the compounds of the prior art in structure is re, pharmacological activity and/or pharmacological effect. It is established that the introduction of a carbocyclic or heterocyclic groups attached to the specifically substituted the pyrimidine at position 5, leads to the formation of compounds, not only acting favorably from the point of view of their ability to inhibit the replication of human immunodeficiency virus (HIV), but also with improved ability to inhibit the replication of mutant strains, in particular, strains that have become resistant to one or more known NNRTIS drug (drug-based reverse transcriptase inhibitors of-nukes), and these strains are strains of HIV that are resistant to the drug or multiplepart.

Thus, in one aspect the present invention relates to a compound of the formula

(I)

its N-oxide, pharmaceutically acceptable additive salt, Quaternary amine or the stereochemical isomer, in which

-and1=and2-and3=and4- represents a bivalent radical of the formula

-CH=CH-CH=CH- (a-1);

-N=CH-CH=CH- (a-2);

-N=CH-N=CH- (a-3);

-N=CH-CH=N- (a-4);

-N=N-CH=CH- (a-5);

-b1=b2-b3=b4- represents a bivalent radical of the formula

-CH=CH-CH=CH- (b-1);

-N=CH-CH=CH- (b-2);

-N=CH-N=CH- (b-3);

-N=CH-CH=N- (b-4);

-N=NCH=CH- (b-5);

n is 0, 1, 2, 3, and when-a1=and2-and3=and4- is (a-1), n can take a value of 4;

m is 0, 1, 2, 3 in the case when-b1=b2-b3=b4- is (b-1), m may take a value of 4;

each of the radicals R1independently means a hydrogen atom; aryl; formyl; C1-6alkylsulphonyl; C1-6alkyl; C1-6allyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarboxylic,1-6allyloxycarbonyl or1-6alkylcarboxylic;

each of the radicals R2independently from each other mean a hydroxy-group; a halogen atom; C1-6alkyl, optionally substituted by one, two or three substituents, each independently selected from the group comprising halogen atom, cyano or-C(=O)R6;3-7cycloalkyl; C2-6alkenyl, optionally substituted one, two or three substituents, each independently selected from the group comprising halogen atom, cyano or-C(=O)R6;2-6quinil, optionally substituted one, two or three substituents, each independently selected from the group comprising halogen atom, cyano or-C(=O)R6;1-6allyloxycarbonyl; carboxyl; cyano; nitro; amino; mono - or di(C1-6alkyl)amino; POLYHALOGENATED; poly is algometry; -S(=O)rR6; -NH-S(=O)rR6; -C(=O)R6; -NHC(=O)H; -C(=O)NHNH2; -NHC(=O)R6; -C(=NH)R6;

R2ameans cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;1-6alkyl, substituted hydroxy-group and the second Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;1-6alkalosis1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6alkenyl substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6quinil, replaced by one that is two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

X1means-NR1-, -O-, -C(=O)-, -CH2-, -CHOH-, -S-, -S(=O)r-;

R3represents cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;1-6alkyl, substituted hydroxy-group and the second Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;1-6alkalosis1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6alkenyl substituted one, two or three substituent and, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6quinil substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

X3means-NR1-, -O-, -C(=O)-, -S-, -S(=O)r-;

R4means a halogen atom; a hydroxy-group; C1-6alkyl, optionally substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano or-C(=O)R6; C2-6alkenyl, optionally substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano or-C(=O)R6;2-6quinil, optionally substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, cyano or-C(=O)R6;3-7cycloalkyl; C1-6alkyloxy; cyano; nitro; polyhalogen1-6alkyl; polyhalogen1-6alkyloxy; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6Ala is carbonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

R5represents a radical of the formula-Y-Alk-L, -Alk'-Y-L or-Alk'-Y-Alk-L;

each of the radicals Alk or Alk' independently represents a bivalent1-6alkyl or C2-6alkenylphenol group;

L is aryl or Het;

Y represents O, S, -S(=O)r-, NR1; -CH=N-O-;

Het denotes a 5 - or 6-membered fully unsaturated ring system in which one, two, three or four ring element are heteroatoms, each of which is independently selected from the group comprising nitrogen, oxygen and sulfur, and in which the remaining ring elements are carbon atoms; and, if possible, any nitrogen ring member may be optionally substituted C1-6the alkyl, where the ring system may not necessarily be linked with the benzene ring, and in which any carbon atom of the ring, including any optional carbon atom attached to the benzene ring, each independently may be substituted by the Deputy selected from such groups as halogen atom, hydroxy, mercapto, cyano, C1-6alkyl, hydroxys1-4alkyl, carboxy1-4alkyl, C1-4alkalosis1-4alkyl, C1-4allyloxycarbonyl1-4alkyl, tsianos1-4alkyl, mono - and di(C1-4alkyl)amino1-4alkyl, et 1C1-4alkyl, aryls1-4alkyl, polyhalogen1-4alkyl, C3-7cycloalkyl,2-6alkenyl, aryl-C2-4alkenyl,1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and di-C1-4alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6alkylpiperazine,1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl,1-4allyloxycarbonyl, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, aryl, Het1;

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

Q means a hydrogen atom, a C1-4alkyl, halogen atom, polyhalogen1-6alkyl or-NR9R10;

R6means1-4alkyl, amino, mono - or di(C1-4alkyl)amino or polyhalogen1-4alkyl;

R7means a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, and each of the said carbocyclic or heterocyclic is olcovich systems optionally may be substituted by one, two, three, four, or five substituents, each of which is independently selected from among such groups as halogen atom, hydroxy, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, formyl, C1-6alkylsulphonyl,3-7cycloalkyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, nitro, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8), R7a, -X3-R7aor R7a-C1-4alkyl-;

R7ameans a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, and each of the said carbocyclic or heterocyclic ring systems optionally may be substituted by one, two, three, four, or five substituents, each of which is independently selected from among such groups as halogen atom, hydroxy, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, formyl, C1-6alkylsulphonyl,3-7cycloalkyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, tzia is about, nitro, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8);

R8means a hydrogen atom, a C1-4alkyl, aryl or arils1-4alkyl;

R9and R10each independently mean a hydrogen atom; C1-6alkyl; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; amino; mono - or di(C1-6alkyl)aminocarbonyl; -CH(=NR11or R7moreover , each of the above With1-6the alkyl groups optionally and each individually may be substituted by one or two substituents, each of which is independently selected from among such groups as hydroxy, C1-6alkyloxy, hydroxys1-6alkyloxy, carboxyl,1-6allyloxycarbonyl, cyano, amino, imino, mono - or di(C1-4alkyl)amino, POLYHALOGENATED, POLYHALOGENATED, POLYHALOGENATED, -S(=O)rR6, -NH-S(=O)rR6, -C(=O)R6, -NHC(=O)H, -C(=O)NHNH2, -NHC(=O)R6, -C(=NH)R6, R7; or

R9and R10can be taken together with the formation of the bivalent or trivalent radical of the formula

-CH2-CH2-CH2-CH2(d-1)

-CH2-CH2-CH2-CH2-CH2(d-2)

-CH2-CH2-O-CH2-CH2(d-3)

-CH2-CH2-S-CH2-CH2(d-4)

-CH2-CH2-NR12-CH2-CH2(d-5)

-C 2-CH=CH-CH2(d-6)

=CH-CH=CH-CH=CH- (d-7)

R11means cyano; C1-4alkyl, optionally substituted C1-4alkyloxy, cyano, amino, mono - or di(C1-4alkyl)amino group or aminocarbonyl; C1-4alkylsulphonyl; C1-4allyloxycarbonyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl;

R12means a hydrogen atom or a C1-4alkyl;

R13and R14each independently denote With1-6alkyl, optionally substituted by cyano or aminocarbonyl,2-6alkenyl, optionally substituted by cyano or aminocarbonyl,2-6quinil, optionally substituted ceanography or aminocarbonyl;

R15means1-6alkyl substituted by cyano or aminocarbonyl;

R16means1-6alkyl, optionally substituted by cyano or aminocarbonyl or R7;

each of r is 1 or 2;

each aryl represents phenyl or phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from among such groups as halogen atom, hydroxy, mercapto, C1-6alkyl, C2-6alkenyl,2-6quinil, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, C1-6alkylsulphonyl; C3-7cyclea the keel; With1-6alkyloxy, panels1-6alkyloxy,1-6allyloxycarbonyl, aminosulfonyl,1-6alkylthio, cyano, nitro, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, phenyl, Het1or-X3-Het1.

The present invention also relates to the use of compounds to obtain drugs for treating or preventing HIV infection, and the compound has the formula (I)as described above.

As stated in the description, With1-4alkyl as a group or part of a group denotes a linear or branched chain saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl; C1-6alkyl as a group or part of a group denotes a linear or branched chain saturated hydrocarbon radicals containing from 1 to 6 carbon atoms such as the group defined for C1-4of alkyl, and pentyl, hexyl, 2-methylbutyl etc.; C2-6alkyl as a group or part of a group denotes a linear or branched chain saturated hydrocarbon radicals containing from 2 to 6 carbon atoms, such as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl etc.; C3-7cycloalkyl is a General formula to refer to such groups as cyclopropyl, cyclobutyl, cyclopentyl, C is clohessy and cycloheptyl; With2-6alkenyl denotes a linear or branched chain hydrocarbon radicals containing from 2 to 6 carbon atoms containing a double bond, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; C2-6quinil, refers to linear and branched chained hydrocarbon radicals containing from 2 to 6 carbon atoms and having a triple bond, such as ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl etc. Among2-6alkenyl and C2-6etkinlik groups preferred unsaturated analogues containing 2 to 4 carbon atoms, for example, With2-4alkenyl and C2-4quinil, respectively. With2-6alkeneamine and C2-6alkyline groups, which are connected to the heteroatom, preferably connected with this atom through a saturated carbon atom and therefore limited With3-6alkenylamine and C3-6alkenylamine groups.

The term "bivalent1-6alkyl or C2-6alkenyl" refers to divalent radicals, which can also be attributed to C1-6Alcantara or2-6alcantera. The term "bivalent1-6alkyl or C1-6alcander" denotes a linear or branched chain saturated bivalent hydrocarbon radicals containing from 1 to 6 carbon atoms, such as methylene, 1,2-ethandiyl or 1,2-ethylene, 1,3-about anvil or 1,3-propylene, 1,2-PROPANEDIOL or 1,2-propylene, 1,4-butanediyl or 1,4-butylene, 1,3-butanediol or 1,3-butylene, 1,2-butanediol or 1,2-butylene, 1,5-pentandiol or 1.5-pentile, 1,6-hexanediol or 1,6-hexylen etc, also including alkylidene radicals, such as ethylidene, propylidene, etc. the Term "bivalent1-4alkyl or C1-4alcander" denotes a similar linear or branched chain saturated bivalent hydrocarbon radicals containing from 1 to 4 carbon atoms. The term "bivalent2-6alkenyl or2-6alcander" denotes a linear or branched chain bivalent hydrocarbon radicals containing from 1 to 6 carbon atoms and having one or more (e.g. one, two, three) and preferably one double bond, such as ethen-1,2-diyl, propene-1,3-diyl, propene-1,2-diyl, butene-1,4-diyl, 2-butene-1,4-diyl, butene-1,3-diyl, butene-3,4-diyl, butene-4,4-diyl, pentan-1,5-diyl, 2-penten-1,5-diyl, hexene-1,6-diyl, 2-hexene-1,6-diyl, 3-hexene-1,6-diyl etc. the Term "bivalent3-6alkenyl or3-6alcander" denotes a similar linear or branched chain unsaturated divalent hydrocarbon radicals containing from 3 to 6 carbon atoms, while the term "bivalent3-4alkenyl or3-4alcander" denotes a similar linear or branched apachecon the e divalent unsaturated hydrocarbon radicals, containing 3 to 4 carbon atoms. Particularly preferred divalent3-6alkeneamine or bivalent3-4alkeneamine radicals, in particular those in which the carbon atom directly connected to the heteroatom represents a saturated carbon atom.

In some cases, radicals With1-6alkyl, C2-6alkenyl,2-6quinil or1-6alkalosis1-6the alkyl can be substituted one, two or three substituents. Preferably, these radicals substituted by substituents in an amount up to 2, more preferably one Deputy.

Monocyclic, bicyclic or tricyclic saturated carbocycle represent a ring system consisting of 1, 2 or 3 rings, the specified ring system consists only of carbon atoms of the ring system contains only simple communication; monocyclic, bicyclic or tricyclic partially saturated carbocycle represent a ring system consisting of 1, 2 or 3 rings, the specified ring system consists only of carbon atoms and contains at least one double bond provided that the ring system is not aromatic ring system; monocyclic, bicyclic or tricyclic aromatic carbocycle represents an aromatic ring system consisting of 1, 2 or 3 to the EC, the specified ring system consists only of carbon atoms; the term "aromatic" is well known to specialists in this field and means cyclically conjugated system of 4n+2 electrons, that is with 6, 10, 14, etc. π-electrons (rule of Galela); monocyclic, bicyclic or tricyclic saturated the heterocycle represents a ring system consisting of 1, 2 or 3 rings, and contains at least one heteroatom selected from O, N or S, the specified ring system contains only a single bond; monocyclic, bicyclic or tricyclic partially saturated a heterocycle represents a ring system consisting of 1, 2 or 3 rings and containing at least one heteroatom selected from O, N or S, and at least one double bond provided that the ring system is not aromatic ring system; monocyclic, bicyclic or tricyclic aromatic heterocycle is an aromatic ring system consisting of 1, 2 or 3 rings and containing at least one heteroatom selected from O, N or S.

Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,2,0]octenyl, cyclogeranyl, cyclodecane, decahedron liner, tetradecahydrophenanthrene, etc. are Preferred cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; more preferred are cyclopentyl, cyclohexyl, cycloheptyl.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated carbocycle are cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl, bicyclo[4,2,0]octenyl, cyclododecyl, cyclodecene, octahydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 1,2,3,4,4A,9,9a,10-octahydronaphthalene etc.

Specific examples of monocyclic, bicyclic or tricyclic carbocyclic are phenyl, naphthalenyl, anthracenes. Preferred is phenyl.

Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, imidazolidinyl, diazolidinyl, tetrahydrothieno, dihydrooxazolo, isothiazolinones, isoxazolidine, oxadiazolidine, diazolidinyl, thiadiazolidine, pyrazolidine, piperidine, hexahydropyridine, hexahydropyrazino, dioxane, morpholinyl, dithienyl, thiomorpholine, piperazinil, tritional, decahydroquinoline, octahedrally, etc. are Preferred tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, imidazolidinyl, t is Soldini, dihydrooxazolo, diazolidinyl, piperidinyl, dioxane, morpholinyl, thiomorpholine, piperazinil. Especially preferred are tetrahydrofuranyl, pyrrolidinyl, DIOXOLANYL, piperidinyl, dioxane, morpholinyl, thiomorpholine, piperazinil.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles are pyrrolidyl, imidazolyl, pyrazolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, indolinyl, etc. are Preferred pyrrolidyl, imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, indolyl.

Specific examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are ezetil, acetimidoyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, cinnoline, hemolysins, phthalazine, honokalani, hintline, naphthyridines, paride the sludge, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine, isoxazolidine, oxazolopyridine, pyrazolopyrimidine, imidazopyridine, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyridine, thienopyridines, properidine, isothiazolinones, triazolopyridazines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazolidine, triazolopyrimidines, oxadiazolidine, thiadiazolidine, triazolopyridazines, imidazolidinyl, imidazothiazoles, imidazolidinyl, isoxazolidine, isothiazolinones, pyrazoloacridine, oxazolidinyl, diazolidinyl, imidazolidinyl, oxadiazolidine, thiadiazolidine, triazolopyridazines, carbazolyl, acridines, phenazines, phenothiazines, phenoxazines etc.

Preferred the romantic heterocycle is monocyclic or bicyclic aromatic heterocycles. Preferred monocyclic, bicyclic or tricyclic aromatic heterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline, benzopyranyl, pyrrolopyridine, cyanopyridyl, properity, isothiazolones, triazolopyridine isoxazolidine, oxazolopyridine, pyrazolopyrimidine, imidazolidinyl, pyrrolopyrazine, thienopyridines, foroperational, isothiazolinones, triazolopyridines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, pyrrolopyrimidine, thienopyrimidines, properidine, isothiazolinones, triazolopyrimidines, isoxazolidine, oxazolopyridine, pyrazolopyrimidines, imidazopyridines, oxadiazolidine, thiadiazolidin, triazolopyridine, oxadiazolidine, thiadiazolidine, triazolopyridines, oxadiazolidine, thiadiazole imaginal, triazolopyrimidines, carbazolyl, acridines, phenothiazinyl, phenoxazines etc.

Particularly preferred aromatic heterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, purinol, chinoline, ethenolysis, phthalazine, honokalani, hintline etc.

As described above, the group (=O) forms a carbonyl residue, when attached to a carbon atom, sulfoxide residue when attached to a sulfur atom, and sulfanilic the remainder when two of these groups attached to the sulfur atom.

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

The term "halogen atom" is shared by atoms of fluorine, chlorine, bromine or iodine. As indicated above, and below, POLYHALOGENATED as a group or part of a group denotes a mono - or polyhalogen methyl, in particular methyl with one or more fluorine atoms, for example, deformity or trifluoromethyl; polyhalogen1-4and the keel or polyhalogen 1-6alkyl as a group or part of a group is defined as mono - or polyhalogen1-4alkyl or C1-6alkyl, for example, the groups defined as halogenmethyl, 1,1-dottorati etc. when attached to more than one halogen atom to an alkyl group within the definition of POLYHALOGENATED, polyhalogen1-4the alkyl or polyhalogen1-6of alkyl, they may be the same or different.

The radical Het represents a 5 - or 6-membered fully saturated ring system, which may be linked with the benzene ring, as described above. The term "fully saturated"used in this definition, means that the ring contains the maximum number of double bonds. In many cases, this 5 - or 6-membered ring system is aromatic. Therefore, particular subgroups of the compounds according to the present invention are those groups or subgroups that are defined in the description, where Het represents a 5 - or 6-membered aromatic ring system, as defined in the description. The radical Het, in particular, can be any of the heterocycles mentioned in the groups, monocyclic, bicyclic or tricyclic heterocycles described above, which are covered by the General definition of Het, for example, pyrrolyl, furyl, thienyl, imidazolyl, Oxus is poured, isoxazolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuran, isobenzofuran, benzothiazyl, isobenzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazoles, benzisoxazole, benzisothiazole, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, chinoline, ethenolysis, cinnoline, phthalazine, honokalani, hintline, naphthyridine, benzopyranyl.

The radical Het may be substituted by pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6alkylpiperazine. Preferably, these radicals are connected with the remainder of Het through the nitrogen atom.

When it occurs in the definition of compounds of formula (I) or any of the subgroups described in the description, each aryl independently means that the above definition of the compounds of formula (I), or each aryl may have any of the values described below, in particular, under the numbers (22), (22A), etc.

The term "heterocycle" in the definitions of the radicals R7or R7aincludes all possible isomeric forms of the heterocycles, for example, pyrrolyl includes 1H-pyrrolyl and 2N-pyrrolyl.

Carbocycle or heterocycle in the definition of the radicals R7and R7acan be attached properly to the rest frequent the molecules of formulas (I) through any carbon atom or ring heteroatom, if not stated otherwise. Thus, for example, when the heterocycle is imidazolyl, they can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc. or when carbocycle is naphthalenyl, they can be 1-naphthalenyl, 2-naphthalenyl etc.

When any variable (for example, R7X2) appears more than once in any component, each definition this variable is independent.

Any limitations in the definitions of radicals of this description imply applicability to the group of compounds of formula (I), as well as to any subgroup defined or mentioned in this specification.

A line drawn from substituents in ring systems, mean that the relationship can be established between any suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are those salts in which the counterion is pharmaceutically acceptable. However, these salts and bases that are not farmatsevticheskii acceptable may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of claims of the present invention.

Assumes pharmaceutically acceptable salt additive, as mentioned is use, include forms of therapeutically active non-toxic additive salts of acids which are capable of forming compounds of formula (I). The latter can be simply obtained by treating the base with such appropriate acids as inorganic acids, for example, halogen acids, e.g. hydrochloric, Hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be converted into the free base by treatment with a base.

The compounds of formula (I)containing acidic protons may be converted into their therapeutically active non-toxic additive metal salts or amine by treatment with appropriate organic or inorganic bases. The additive form of salts of the respective bases include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, Kallai etc., salts of organic bases, for example, primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, Propylamine, Isopropylamine, the four isomeric state of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, Diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, Tripropylamine, Hinkley, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propandiol, geranamine salts, and salts of amino acids such as, for example, arginine, lysine and the like And, on the contrary, the form of salts can be converted in the form of free acids by treatment with an acid. The term "additive salt" also includes a hydrate and a solvate additive form, which can form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, etc.

The term "Quaternary amine"used in the description, defines the Quaternary ammonium salts that can form the compounds of formula (I) by the reaction between a basic nitrogen-containing compound of the formula (I) and the corresponding quaternization agent such as, for example, optionally substituted alkylhalogenide, aryl halides or arylalkylamine, for example, methyliodide or benzylated. Can also be used with other reagents with easy atmasamyama groups is mi, such as alkylarylsulfonate, alkylarylsulfonate and alkyl-p-toluensulfonate. Quaternary amine contains positively charged nitrogen atom. Pharmaceutically acceptable counterions include chloride ions, bromine, iodine, triptoreline and acetate. Selected counterion can be introduced using ion-exchange resins.

Form N-oxides of the compounds of the present invention include compounds of formula (I)in which one or several tertiary nitrogen atoms oxidized to the so-called N-oxide.

It will be understood that certain compounds of formula (I) and their N-oxides, additive salts, Quaternary amines and stereochemical isomeric form can contain one or more centers of chirality and exist as a stereochemical isomeric form.

The term "stereochemical isomeric forms"used in the description refers to all possible stereoisomeric forms which can form compounds of formula (I), and which can have their N-oxides, additive salts, Quaternary amines or physiologically functional derivatives. If not mentioned otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms of the compounds, containing all diastereomers and enantiomers of basic molecular structure as well as each Department is different isomeric forms of formula (I) and their N-oxides, salt, solvate or Quaternary amines essentially does not contain, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1%, other isomers. Thus, when the compound of formula (I) represents, for example, (E), this means that the connection is not essentially contains (Z)-isomer. In particular, stereogenic centers may have the R - or S-configuration; substituents or a divalent cyclic (partially) saturated radicals may have either the CIS-or TRANS-configuration. Compounds containing double bonds, can have E (entgegen) or Z (zusamman) stereochemistry at the specified double bond. The terms "CIS, TRANS, R, S, E and Z" is well known to specialists in this field. It is assumed that the stereochemical isomeric forms of the compounds of formula (I) are covered by the scope of claims of the present invention.

Some compounds of formula (I) can also exist in tautomeric form. Such forms, although detail is not specified in the above formula, is included in the scope of claims of the present invention.

The term "compounds of formula (I)" in the description also include their N-oxide forms, their salts, their Quaternary amines and their stereochemical isomeric form. Particularly preferred are those compounds of formula (I), which are stereochemical clean.

To ncrete subgroups of compounds of formula (I) or any subgroup of compounds of formula (I), which are naselenie form, salt form of N-oxides and stereochemical isomeric forms, listed in the description. Which one is preferable naselenie forms, salts and stereochemical isomeric form. According to the description, the term "nosoleva form" refers to a form of connection that is not salt, which in most cases will represent a form of free base.

According to the description of the substituents can be selected each independently from each other from a list of multiple values, such as, for example, for R9and R10that means that it includes all possible combinations, which are chemically possible or lead to the formation of chemically stable molecules.

It should be understood that any of the subgroups of compounds of formula (I)as defined in the description, also includes any prodrugs, N-oxides, additive salts, Quaternary amines, metal complexes and stereochemical isomeric forms of such compounds. Assumes that any additional subgroup containing a permutation of any of the many specific definitions of the subgroups of compounds of formula (I), as mentioned, also forms part of the being of the present invention.

Particular subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I), is certain in the description, in which-a1=and2-and3=and4- represents-CH=CH-CH=CH- (a-1).

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which-b1=b2-b3=b4- represents-CH=CH-CH=CH- (b-1).

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I), as defined in the description, in which (a) n is 0, 1, 2, 3; or (b) n is 0, 1 or 2; or (C) n is 0.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which (a) m is 0, 1, 2, 3, or in which (b) m is 0, 1 or 2; or (C) m is 2.

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) R1represents a hydrogen atom; a formyl; C1-6alkylsulphonyl; C1-6alkyl; C1-6allyloxycarbonyl or

(b) R1represents a hydrogen atom; C1-6alkyl; or

(C) R1represents a hydrogen atom.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of the compounds is of the formula (I), defined in the description, in which

(a) R2means a hydroxy-group; a halogen atom; C1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;3-7cycloalkyl; C2-6alkenyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;2-6quinil, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;1-6allyloxycarbonyl; carboxyl; cyano; nitro; amino; mono - or di(C1-6alkyl)amino; POLYHALOGENATED; POLYHALOGENATED; -S(=O)pR6; -NH-S(=O)pR6; -C(=O)R6; -NHC(=O)H; -C(=O)NHNH2; NHC(=O)R6; C(=NH)R6;

(b) R2means a hydroxy-group; a halogen atom; C1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;2-6alkenyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;2-6quinil, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;1-6allyloxycarbonyl; carboxyl cyano; nitro; amino; mono - or di(C1-6alkyl)amino; trifluoromethyl;

(C) R2means a halogen atom; C1-6alkyl, optionally substituted by such a group, as cyano, C2-6alkenyl, optionally substituted by such a group, as cyano; C1-6allyloxycarbonyl, carboxyl, cyano, amino, mono(C1-6alkyl)amino; di(C1-6alkyl)amino;

(d) R2means halogen atom, cyano, aminocarbonyl,1-6alkyloxy,1-6alkyl, C1-6alkyl substituted by cyano, or C2-6alkenyl substituted by cyano;

(e) R2means halogen atom, cyano, aminocarbonyl,1-4alkyl substituted by cyano, or C2-4alkenyl substituted by cyano;

(f) R2means cyano, aminocarbonyl; or

(g) R2means cyano.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) R2ameans cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected the number of such groups, as the halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; C1-6alkyl, substituted hydroxy-group and the second Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6alkenyl substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6quinil substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7;

(b) R2ameans cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6the alkyl may be optionally substituted by cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from among the groups, as the halogen atom, cyano, -C(=O)-NR9R10C1-6alkyl, substituted hydroxy-group and the second Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10C1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;2-6alkenyl substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;2-6quinil substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;

(c) R2ameans halogen atom, cyano, aminocarbonyl,1-6alkyl, optionally substituted by cyano or aminocarbonyl,2-6alkenyl, optionally substituted by cyano or aminocarbonyl;

(d) R2ameans halogen atom, cyano, aminocarbonyl,1-6alkyl substituted by cyano or aminocarbonyl or2-6alkenyl substituted by cyano or aminocarbonyl;

(e) R2ameans cyano, aminocarbonyl,1-6alkyl substituted by cyano, or C2-6alkenyl substituted by cyano;

(f) R2ameans cyano, aminocarbonyl,1-4alkyl substituted by cyano,or C 2-4alkenyl substituted by cyano;

(g) R2ameans cyano, C1-4alkyl substituted by cyano, or C2-4alkenyl substituted by cyano, or (h) R2ameans cyano.

Further subgroup of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, where

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

(b) X1means-NH-, -N(C1-4alkyl)-, -O-, -S-, -S(=O)p-;

(C) X1means-NH-, -N(CH3)-, -O-, -S-;

(d) X1means-NH-, -O-, -S-;

(e) X1means-NH-, -O-

or (f) X1means-NH-.

Further subgroup of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, where

(a) R3means cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6alkyl optionally may be substituted with cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; C1-6alkyl substituted hydroxypropyl and the second Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6alkenyl substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7;2-6quinil substituted by one Deputy, selected from among such groups as halogen atom, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7; -C(=N-O-R8)-C1-4alkyl; R7or-X3-R7; in particular,

(b) R3means cyano; aminocarbonyl; amino; C1-6alkyl; a halogen atom; C1-6alkyloxy, where C1-6alkyl optionally may be substituted with cyano; other13; NR13R14; -C(=O)-other13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl, substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10; C1-6alkyl, substituted hydroxy-group and the second Deputy, selected from among such g is UPP, as the halogen atom, cyano, -C(=O)-NR9R10;1-6alkalosis1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;2-6alkenyl substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;2-6quinil substituted by one Deputy, selected from among such groups as halogen atom, cyano, -C(=O)-NR9R10;

(C) R3means halogen atom, cyano, aminocarbonyl,1-6alkyl, optionally substituted by cyano or aminocarbonyl,2-6alkenyl, optionally substituted by cyano or aminocarbonyl;

(d) R3means halogen atom, cyano, aminocarbonyl,1-6alkyl substituted by cyano or aminocarbonyl or2-6alkenyl substituted by cyano or aminocarbonyl;

(e) R3means cyano, C1-4alkyl substituted by cyano, or C2-4alkenyl substituted by cyano;

(f) R3means1-4alkyl substituted by cyano, or C2-4alkenyl substituted by cyano;

(g) R3means2-4alkyl substituted by cyano, or C2-4alkenyl substituted by cyano;

(h) R3means2-4lceil, substituted by cyano;

(i) R3means ethynyl, substituted by cyano;

(j) R3means (E)-2-cyanoethyl.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) R4means a halogen atom; a hydroxy-group; C1-6alkyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6; C2-6alkenyl, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;2-6quinil, optionally substituted by one Deputy, selected from among such groups as halogen atom, cyano or-C(=O)R6;3-7cycloalkyl; C1-6alkyloxy; cyano; nitro; polyhalogen1-6alkyl; polyhalogen1-6alkyloxy; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

(b) R4means a halogen atom; a hydroxy-group; C1-6alkyl, optionally substituted by one Deputy, selected from among groups such as cyano; C2-6alkenyl, optionally substituted by cyano; C2- quinil, optionally substituted by cyano; C3-7cycloalkyl; C1-6alkyloxy; cyano; nitro-group; trifluoromethyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino, or R7;

(C) R4means a halogen atom; a hydroxy-group; C1-6alkyl, optionally substituted by cyano; C2-6alkenyl, optionally substituted by cyano; C2-6quinil, optionally substituted by cyano; C1-6alkyloxy; cyano; nitro; trifluoromethyl; aminocarbonyl; mono - or di(C1-4alkyl)aminocarbonyl; C1-6allyloxycarbonyl; C1-6alkylsulphonyl; formyl; amino; mono - or di(C1-4alkyl)amino;

(d) R4means a halogen atom, a hydroxy-group, With1-6alkyl, C2-6alkenyl; C2-6quinil; C1-6alkyloxy; cyano; nitro; amino;

(e) R4means a halogen atom, a hydroxy-group, With1-4alkyl, C1-4alkyloxy, cyano; or

(f) R4means a halogen atom, a C1-4alkyl, C1-4alkyloxy.

Additional subgroup of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) R5represents radika the formula-Y-Alk-L or-Alk'-Y-Alk-L;

(b) R5represents a radical of the formula-Y-Alk-L or-Alk'-Y-Alk-L, where L is Het;

(c) R5represents a radical of formula-Alk'-Y-L;

(d) R5represents a radical of formula-Alk'-Y - L; where L represents aryl.

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which R5represents a radical of the formula-Y-CpH2p-L or-CqH2q-Y-CpH2p-L, where L is aryl or Het; aryl, Het and Y have the meanings indicated in the description, and

p is 1-6;

q is 1-6; where, in particular,

(a) Y means O, S, NR1; -CH=N-O-; (b) Y represents O, NR1; -CH=N-O-; (c) Y represents NR1or-CH=N-O-;

(b) p is 1-4; or, in particular, R is 1-2;

(C) q is 1-4; or, in particular, q is 1-2.

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) Het denotes a 5 - or 6-membered fully unsaturated ring system in which one, two, three or four ring element are heteroatoms, each of which is independently selected from the group comprising nitrogen, oxygen and sulfur, and in which the remaining ring elements to provide the amount carbon atoms; and, if possible, any nitrogen ring member may be optionally substituted C1-6the alkyl, where the ring system may not necessarily be linked with the benzene ring: while any carbon atom of the ring, including any optional carbon atom attached to the benzene ring, each independently may be substituted by the Deputy selected from such groups as halogen atom, hydroxy-group, mercapto, cyano, C1-6alkyl, hydroxys1-4alkyl, carboxy1-4alkyl, C1-4alkalosis1-4alkyl, tsianos1-4alkyl, di(C1-4alkyl)amino1-4alkyl, Het1C1-4alkyl, aryls1-4alkyl, polyhalogen1-4alkyl, C3-7cycloalkyl, aryl-C2-4alkenyl,1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and di-C1-4alkylamino,1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl, aryl, Het1;

(b) Het means a heterocycle selected from such compounds as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, tetrazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazol, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, benzothiadiazin the sludge, benzofurazanyl, benzoxadiazole, indazoles, chinoline, said heterocycle optionally substituted on carbon atoms by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy, mercapto, cyano, C1-6alkyl, hydroxys1-4alkyl, carboxy1-4alkyl, C1-4alkalosis1-4alkyl, C1-4allyloxycarbonyl1-4alkyl, tsianos1-4alkyl, mono - and di-(C1-4alkyl)amino1-4alkyl, Het1With1-4alkyl, aryls1-4alkyl, polyhalogen1-4alkyl, C3-7cycloalkyl, arils2-4alkenyl,1-4alkyloxy, -OCONH2polyhalogen1-4alkyloxy, aryloxy, amino, mono - and di-C1-4alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil, 4-C1-6alkylpiperazine,1-4alkylcarboxylic, formyl, C1-4alkylsulphonyl, aryl, C1-4allyloxycarbonyl, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, Het1;

(C) Het means a heterocycle selected from such compounds as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, triazolyl, tetrazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl, benzothiazolyl, chinoline, this heterotic is optionally substituted at carbon atoms by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, cyano, C1-6alkyl, C1-4allyloxycarbonyl1-4alkyl, amino, mono - and dis1-4alkylamino, morpholinyl,1-4alkylcarboxylic, aminocarbonyl, mono - and dis1-4alkylaminocarbonyl, aryl, Het1;

(d) Het means a heterocycle selected from such compounds as pyrrolyl, furanyl, thienyl, isothiazolin, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzofuranyl, chinoline, said heterocycle optionally substituted on carbon atoms by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, cyano, C1-6alkyl, C1-4allyloxycarbonyl1-4alkyl, amino, mono - and di-C1-4alkylamino, morpholinyl,1-4alkylcarboxylic, aminocarbonyl, arylvinyl, Het1(the latter, in particular, represents pyridyl);

(e) Het means a heterocycle selected from such compounds as pyrrolyl, furanyl, thienyl, oxadiazolyl, pyridyl, said heterocycle optionally substituted on carbon atoms by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, With1-6alkyl, f the Nile, Het1(the latter, in particular, represents pyridyl).

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) Het1means pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, each of which may be optionally substituted by one or two1-4alkyl radicals;

(b) Het1means pyridyl, thienyl, furanyl, each of which may be optionally substituted by one or two1-4alkyl radicals; or

(C) Het1means pyridyl, thienyl, furanyl;

(d) Het1means pyridyl.

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) Q means a hydrogen atom, a C1-6alkyl or-NR9R10; (b) Q means a hydrogen atom or-NR9R10; (c) Q means a hydrogen atom, amino group, mono - or di-C1-4alkylamino; or (d) Q means a hydrogen atom.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) R6oz ACHAT 1-4alkyl, amino group, mono - or di(C1-4alkyl)amino; in particular,

(b) R6means1-4alkyl or amino group; or (C) R6means1-4alkyl.

Additional subgroups of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)as defined in the description, in which

(a) R7means a monocyclic or a bicyclic partially saturated or aromatic carbocycle or monocyclic or bicyclic partially saturated or aromatic heterocycle, and each of the said carbocyclic or heterocyclic ring systems optionally may be substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, C1-6alkylsulphonyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy or aminocarbonyl, in particular,

(b) R7means any of the specific monocyclic or bicyclic partially saturated or aromatic carbocyclic or monocyclic or bicyclic partially saturated or aromatic heterotic is s, specifically mentioned in the present description, each of these carbocyclic or heterocyclic ring systems optionally may be substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, C1-6alkylsulphonyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy or aminocarbonyl;

(C) R7ameans a monocyclic or a bicyclic partially saturated or aromatic carbocycle or monocyclic or bicyclic partially saturated or aromatic heterocycle, and each of the said carbocyclic or heterocyclic ring systems optionally may be substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, mercaptopropyl,1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, C1-6alkylsulphonyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy or aminocarbonyl; the company is and,

(d) R7ameans any specific monocyclic or bicyclic partially saturated or aromatic carbocycle or monocyclic or bicyclic partially saturated or aromatic heterocycle, specifically indicated in the present description, each of these carbocyclic or heterocyclic ring systems optionally may be substituted by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, C1-6alkylsulphonyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy or aminocarbonyl.

Additional subgroup of compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) X3means-NR1-, -O - or-S-; (b) X3means-NR1- or-O-; (c) X3means-NH-, -N(C1-4alkyl)-, -O-; (d) X3means-NH-, -N(CH3)-, -O-; or (e) X3means-NH-,-O-.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) R8means a hydrogen atom, a C1-4alkyl or arils1-4alkyl; or (b) R8means a hydrogen atom or a C1-4alkyl.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) R9and R10each independently mean a hydrogen atom; C1-6alkyl; C1-6alkylsulphonyl; C1-6allyloxycarbonyl; mono - or di(C1-6alkyl)aminocarbonyl; -CH(=NR11), each of the above With1-6alkyl groups optionally can be substituted by one or two substituents, each of which is independently selected from groups such as the hydroxy-group, With1-6alkyloxy, hydroxys1-6alkyloxy, carboxyl,1-6allyloxycarbonyl, cyano, amino group, mono - or di(C1-4alkyl)amino, POLYHALOGENATED, POLYHALOGENATED;

(b) R9and R10each independently mean a hydrogen atom; C1-6alkyl; C1-6alkylsulphonyl or1-6allyloxycarbonyl;

(C) R9and R10each independently means a hydrogen atom or a C1-6alkyl;

(d) R9and R10means a hydrogen atom.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) R13and R14each independently denote With1-6alkyl, optionally substituted by cyano, C2-6alkenyl, optionally substituted by cyano, C2-6quinil, optionally substituted by cyano;

(b) R13and R14each independently represent a hydrogen atom or a C1-6alkyl;

(C) R13and R14represent hydrogen atoms.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which R15means1-6alkyl, optionally substituted by cyano.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which (a) R16means1-6alkyl, optionally substituted by cyano or aminocarbonyl, or in which (b) R16means1-6alkyl, optionally substituted by cyano.

Other subgroups of the compounds of formula (I) are those compounds of formula (I) or any subgroup of compounds of formula (I)specified in the description, in which

(a) aryl means phenyl or phenyl substituted one, two, three, four, or five substituents, each of which is independently selected from num is of such groups, as the halogen atom, the hydroxy-group, mercaptopropyl,1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, C1-6alkylsulphonyl,3-7cycloalkyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, Het1or-X3-Het1;

(b) aryl means phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, mercaptopropyl,1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, C1-6alkylsulphonyl,3-7cycloalkyl,1-6alkyloxy,1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, polyhalogen1-6alkyl, polyhalogen1-6alkyloxy, aminocarbonyl, phenyl, thienyl or pyridyl;

(C) aryl means phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, mercapto, C1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, C1-6alkylsulphonyl,1-6and is Biloxi, With1-6allyloxycarbonyl,1-6alkylthio, cyano, a nitro-group, trifluoromethyl, triptoreline, aminocarbonyl, phenyl;

(d) aryl means phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, With1-6alkyl, hydroxys1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, C1-6alkylsulphonyl,1-6alkyloxy,1-6allyloxycarbonyl, cyano, a nitro-group, a trifluoromethyl;

(e) aryl means phenyl or phenyl substituted one, two or three substituents, each of which is independently selected from among such groups as halogen atom, hydroxy-group, With1-6alkyl, C1-6alkyloxy, cyano, a nitro-group, a trifluoromethyl.

Regardless of whether there is a radical or group more than once in the definition of the compounds of formula (I), in each case specified radical or a group independently can be any of the definitions listed in the description.

One variant of the invention refers to a subgroup of compounds of formula (I)having the formula

(I')

their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, where b1=b2-b 3=b4-, R1, R2, R2a, R3, R4, R5, m, n and X1have the meanings indicated above in the General definitions of the compounds of formula (I) or their various subgroups.

Another variant of the invention, refers to a subgroup of compounds of formula (I)having the formula

(I)

their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, and1=and2-and3=and4-, R1, R2, R2a, R3, R4, R5, m, n and X1have the meanings indicated above in the General definitions of the compounds of formula (I) or their various subgroups.

Another variant implementation of the invention refers to a subgroup of compounds of formula (I)having the formula

(I”')

their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, where R1, R2, R2a, R3, R4, R5, m, n and X1have the meanings indicated above in the General definition of the compounds of formula (I) or their various subgroups.

An additional variant embodiment of the invention refers to a subgroup of compounds of formula (I)having the formula

(I””)

their N-oxides, Pharm is citiesi acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, where R1, R2a, R3, R4, R5and X1have the meanings indicated above in the General definition of the compounds of formula (I) or their various subgroups.

Also preferred variant embodiment of the invention encompasses a sub-group of compounds of formula (I)having the formula

(I””')

their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines or a stereochemical isomeric forms, where R1, R2, R2a, R3, R5and X1have the meanings indicated above in the General definitions of the compounds of formula (I) or their various subgroups.

The compounds of formula (I) can be obtained by the reaction of intermediate compounds of formula (II), where W1is suitable tsepliaeva group, such as, for example, halogen atom, e.g. a chlorine atom and the like, with an intermediate compound of formula (III).

The reaction of the pyrimidine derivative (II) with the amine (III) is usually carried out in the presence of a suitable solvent. Suitable solvents are, for example, alcohol such as ethanol, 2-propanol; bipolar aprotic solvent, such as acetonitrile, N,N-dimethylformamide; N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone; this then it is carbonated as return, 1,4-dioxane, onomatology simple ether of propylene glycol. The reaction can be performed in an acidic environment, which may be obtained by adding a quantity of a suitable acid, for example, camphorsulfonic acid, and a suitable solvent, such as tetrahydrofuran or an alcohol, for example, 2-propanol, or when using acidified solvents, for example, hydrochloric acid, dissolved in alcohol, such as 1 - or 2-propanol.

The compounds of formula (I) can also be obtained by forming the X1communication or interaction (IV-a) with (V-a)or (IV-b) with (V-b), as shown in the following diagram

In this reaction scheme, W2means appropriate functional group, which, when combined with a group-X1N, can be transformed into an element X1. This method is the most convenient to obtain the compounds of formula (I)in which X1means heteroatom, such as-NR1, -O-, -S-.

In particular, the compounds of formula (I)in which X1mean NR1these compounds are represented by formula (I-a)can be obtained by the interaction of the intermediate derivative of the formula (IV-c), where W1means corresponding tsepliaeva group, for example, chlorine atoms or bromine, with Premiata the major compound of the formula (V-c). Tsepliaeva band W1may also be entered in situ, for example, by conversion of the corresponding hydroxyl functional groups in tsepliaeva group, for example, under the action of POCl3. The reaction of (IV-c) with (V-c) is preferably carried out in an environment suitable solvent in the presence of a base, such as triethylamine. Suitable solvents are, for example, acetonitrile, alcohols, such as, for example, ethanol, 2-propanol, ethylene glycol, propylene glycol, polar aprotic solvents such as N,N-dimethylformamide; N,N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, [bmim]PF5; such ethers as 1,4-dioxane, onomatology simple ether of propylene glycol.

This reaction scheme is also suitable in the case when X1means-O - or-S-. In particular, the compounds of formula (I)in which X1means Of specified compounds represented by formula (I-b)can be obtained by the interaction of the intermediate compounds of formula (VI)in which W1means suitable tsepliaeva group such as halogen atom, e.g. a chlorine atom and the like, with an intermediate compound of formula (VII) in the presence of a suitable base, such as, for example, K2CO3or tert-piperonyl potassium (KOt-Bu)), and a suitable solvent, such as, for example, ACET is h or tetrahydrofuran. In a particular implementation of the intermediate compound (VII) first interacts with stirring at room temperature with a suitable metal hydroxide in the medium of organic solvent. Then add the intermediate compound (VI), where-W1means suitable tsepliaeva group.

The compounds of formula (I-b) can also be obtained by the interaction of the intermediate compounds of formula (IV-b)in which-X1N means HE specified intermediate compound represented by formula (IV-d), with an intermediate compound of formula (VII) in the presence of POCl3suitable base, such as, for example, K2CO3or tert-piperonyl potassium (KOt-Bu), and a suitable solvent, such as, for example, acetone or tetrahydrofuran.

Tizaidine (X1means-S-) can be obtained similarly and simply can be transformed into the corresponding sulfoxide or sulfon known in this field oxidation methods.

The compounds of formula (I)in which X1differs from a heteroatom, can be obtained by the interaction of (IV-a) with (V-a) or (IV-b) c (V-b), as shown in the diagram above, the selection of the appropriate functional groups-X1H and-W2.

In particular, when X1means-C(=O)-, source the th material (V-a) or (IV-b), where the group-X1N represents a group of the Grignard type (-Mg-halogen) or lithium interacts with the source material (IV-a) or (V-b), where W2represents an ester (-Coolkill). The last ester can also be restored to alcohol, for example, LiAlH4and then oxidised mild oxidizing agent, such as MnO2to the corresponding aldehyde, which then communicates with the appropriate starting material, in which the group-X1N represents a group of the Grignard type (-Mg-halogen) or lithium. Compounds in which-X1means-C(=O)-, can be converted in-NON - analogues of the corresponding reaction recovery, for example, in the presence of LiAlH4.

When X1represents-CH2-this link may be introduced by reaction of the Grignard reagent, for example, the interaction of the source material (V-a) or (IV-b), where-X1N group is-CH2-Mg-halogen, with an intermediate compound (IV-a) or(V-b), where W2represents a halogen group. Methylene group may be oxidized to a group-C(=O)- (X1means-C(=O)-), for example, selenium dioxide. Group-C(=O)-, in turn, can be restored with a suitable hydride, such as LiAlH4to group-SNON-.

The compounds of formula (I)in which R means a radical-Y1CpH2p-L, gdau 1means O, S or NR1specified intermediate compound represented by formula (1-C), can also be obtained by the interaction of the intermediate compound (VIII-a), where W1means suitable tsepliaeva group, such as, for example, halogen atom, e.g. chlorine, bromine, reagent HY1-CpH2p-L. the Compound (I-c) can also be obtained by the interaction of the intermediate compound (VIII-b) with a reagent W1-CpH2p-L.

The compounds of formula (I-d), which are compounds of formula (I-c), where Y1means NH, can also be obtained by reductive amination of the intermediate compound (VIII-a)in which Y represents NH, hereinafter represented as (VIII-a-1), with a reagent O=CH-Cp-1H2p-1-L. This reaction is conducted in the medium of a suitable solvent, in the presence of reductants, such as hydrogen, in the presence of a catalyst based on a noble metal (such as Pd) or a metal hydride, for example, cyanoborohydride sodium.

Intermediate compound (VIII-a) can be obtained by halogenoalkanes the appropriate starting material (IX). Other otsepleniya groups can be introduced by replacement of the halogen group, using suitable reagents.

The compounds of formula (I)in which R5means the radical-CqH2q-Y-CpH2p-L, these compounds are represented by formula (I-e)can also be obtained by the interaction of the intermediate compound (X-a), where W1means suitable tsepliaeva group, such as, for example, halogen atom, e.g. chlorine, bromine, reagent HY-CpH2p-L. the Compound (I-e) can also be obtained by the interaction of the intermediate compound (X-b) with a reagent W1-CpH2p-L.

The compounds of formula (I-e), which are compounds of formula (I-d), in which Y represents NH, can also be obtained by the reaction of reductive amination of the intermediate (X-C) reagent

Intermediate compound (X-b) or (X-c) can be obtained by the interaction of the source material (X-a) with a suitable nucleophile such as ammonia, amine, metal hydroxide or sulfhydryl.

The compounds of formula (I)in which R5means the radical-Y-CpH2p-L, where Y represents-CH-N-O-mentioned compounds represented by formula (I-f)can be obtained by the interaction of the intermediate compound (VIII-a), where W1means suitable tsepliaeva group, preferably a halogen atom, for example, x is ora, bromine, with carbon monoxide in the presence of a suitable catalyst, such as dichlorobis(triphenylphosphine)palladium(II). The resulting aldehyde (VIII-c) interacts with the reagent W2-CpH2p-L, where W2is suitable tsepliaeva group, preferably a halogen atom, e.g. chlorine, chromium, with the formation of the desired compounds of formula (I-f).

The compounds of formula (I) can be obtained by transformation of compounds of formula (I) into each other in accordance with well-known in this field reactions of transformation groups.

The compounds of formula (I) can be converted into a form the corresponding N-oxides known methods of conversion of the tertiary nitrogen in the form of its N-oxide. This reaction N-oxidation may be carried out by the interaction of the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene acid or halogen-substituted benzonorbornadiene Ki the lot, for example, 3-chlorobenzotriazole acid, paracalanidae acid, for example, purakayastha acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

The compounds of formula (I)in which R2, R2a, R3or R4means2-6alkenyl, replaced by aminocarbonyl, can be converted into a compound of formula (I)in which R2, R2a, R3or R4means2-6alkenyl substituted by cyano by reaction with POCl3.

The compounds of formula (I)in which m is zero, can be converted into compounds of formula (I)in which m is different from zero and R4means a halogen atom, by reaction with a suitable agent, providing for the introduction of a halogen atom, such as, for example, N-chlorosuccinimide or N-barsocchini, or combinations thereof, in the presence of a suitable solvent, such as, for example, acetic acid.

The compounds of formula (I)in which R3means a halogen atom, can be converted into compounds of formula (I)in which R3means2-6alkenyl substituted by one or more substituents, it is gdy of which is independently selected from among such groups, as the halogen atom, cyano, NR9R10-C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7by reaction with the appropriate2-6the alkene, substituted by one or more substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10-C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7in the presence of a suitable base, such as, for example, N,N-diethylethanamine, a suitable catalyst, such as palladium acetate, in the presence of triphenylphosphine, and a suitable solvent, such as, for example, N,N-dimethylformamide.

The compounds of formula (I)in which R2Ameans a halogen atom, can be converted into compounds of formula (I)in which R2Ameans2-6alkenyl substituted by one or more substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10-C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7by reaction with the appropriate2-6the alkene, substituted by one or more substituents, each of which is independently selected from among such groups as halogen atom, cyano, NR9R10-C(=O)-NR9R10, -C(=O)-C1-6alkyl, or R7in the presence of a suitable base, such as, for example, N,N-diety is ethanamine, a suitable catalyst, such as palladium acetate, in the presence of triphenylphosphine, and a suitable solvent, such as, for example, N,N-dimethylformamide.

The compounds of formula (I)in which R1means1-6allyloxycarbonyl, can be converted into compounds of formula (I)in which R1means a hydrogen atom, by reaction with an appropriate base, such as, for example, the hydroxide or sodium methoxide. If R1means tert-butyloxycarbonyl corresponding compounds in which R1means a hydrogen atom, can be obtained by processing triperoxonane acid.

Some compounds of formula (I) and some intermediate compounds in the present invention may contain asymmetric carbon atoms. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using known methods. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic methods, for example, protivosokowoe distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures first transformation of these racemic mixtures using suitable agents permissions, such as, for example, Herald the e acid, in a mixture of diastereomeric salts or compounds; then physical separation of these mixtures of diastereomeric salts or compounds, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting these separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric form can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting materials, provided that the proceeding reactions occur stereospecific manner.

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

Some intermediate compounds and starting materials are known compounds and can be commercially available or can be obtained according to known methods.

Intermediate compounds of formula (II) can be obtained by the reaction of intermediate compounds of formula (XI), where W1has the values defined above, with an intermediate compound of formula (XII) in the presence of a suitable rest is ritala, such as, for example, tetrahydrofuran, and optionally in the presence of a suitable base, such as, for example, Na2CO3.

Intermediate compounds of formula (XI) can be obtained in accordance with known prior art methods.

Intermediate compounds of formula (III)in which R1means a hydrogen atom, the above intermediate compound represented by formula (III-a), or the intermediate compound (V-a-1), which are intermediate compounds (V-a)in which-X1H stands for-NH2can be obtained by the interaction of the intermediate compounds of formula (XIII) or (XIV) with a suitable reducing agent such as Fe, in the presence of NH4Cl and a suitable solvent, such as tetrahydrofuran, H2O or an alcohol, e.g. methanol and the like,

Intermediate compounds of formula (III-a) or (V-a-1)in which R2arelative to R3is2-6alkyl substituted by cyano, these intermediate compounds represented by formula (III-a-1) and (V-a-2)can be obtained by the interaction of the intermediate compounds of formula (XIII-a) respectively (XIV-a) with Pd/C in the presence of a suitable solvent, such as, for example, an alcohol, e.g. ethanol and the like,

Intermediate compounds of formula (III), (V-a) or (V1I), in which R2arelative to R3represents a halogen atom, these intermediate compounds represented by formula (III-b), (V-b) and (VII-b), can be converted into an intermediate compound of formula (III), respectively, (V) or (VII)where R2aaccordingly, R3is2-6alkenyl, substituted C(=O)NR9R10specified intermediate compound represented by formula (III-c), (V-c) and (VII-b), the interaction with an intermediate compound of formula (XIII) in the presence of Pd(OAc)2P(o-Tol)3suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, CH3-CN.

Intermediate compounds of formula (III-c), (V-c) and (VII-b) can also be obtained by the interaction of the intermediate compounds of formula (III-f), (V-f) and (VII-c) H-NR9R10in the presence of oxalicacid and in the presence of a suitable solvent, such as, for example, N,N-dimethylformamide, CH2Cl2and tetrahydrofuran.

Intermediate compounds of formula (III-d), (V-d) and (VII-c) can be obtained by the interaction of the intermediate compounds of formula (II-b), (V-b) and (VII-a) H-C2-6alkenyl-C(=O)-OH in the presence of Pd(OAc)2P(o-Tol)3suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, CH3CN.

Intermediate compounds of formula (III-b), (V-b) and (VII-a) can also be converted into intermediate compounds of formula (III), respectively, (V) or (VII)where R2arelative to R3means C2-6alkenyl, substituted CN, these intermediate compounds represented by formula (III-e), (V-c) and (VII-d), the interaction with the N-C2-6alkenyl-CN in the presence of Pd(OAc)2P(o-Tol)3suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, CH3-CN.

Intermediate compounds of formula (XV) can be obtained by the interaction of the intermediate compounds of formula (XVI), in which W3means suitable tsepliaeva group, such as, for example, halogen atom, e.g. chlorine, with H-NR9R10(XVII) in the presence of a suitable solvent, such as, for example, a simple diethyl ether and tetrahydrofuran.

The intermediate four the uly (XIII) or (XIV), in which R2arelative to R3means cyanovinyl, these intermediate compounds represented by formula (XIII-b) and (XIV-b), can be obtained by the interaction of the intermediate compounds of formula (XVIII) and (XIX) with citizen.metropolitan in the presence of a suitable base, such as, for example, NaOCH3and a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (XIII) or (XIV)in which R2arelative to R3means-C(CH3)=CH-CN, these intermediate compounds represented by formula (XIII-c) and (XIV-c), can be obtained by the interaction of the intermediate compounds of formula (XX) and (XXI) with citizen.metropolitan in the presence of a suitable base, such as, for example, NaOCH3and a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (XVIII) and (XIX) can be obtained by the interaction of the intermediate compounds of formula (XXII) and (XXIII) with a suitable oxidant, such as, for example, MnO2in the presence of a suitable solvent, such as, for example, acetone.

Intermediate compounds of formula (XXII) and (XXIII) can be obtained by the interaction of the intermediate compounds of formula (XXIV) and (XXV) with NaBH4in the presence of ethylchloride, a suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as tetrahydrofuran.

Intermediate compounds of formula (XIII) and (XIV)in which R2arelative to R3means a hydroxy-group, these intermediate compounds represented by formula (XIII-d) and (XIV-d), can be converted into an intermediate compound of formula (XIII) and (XIV)in which R2arelative to R3means1-6alkyloxy, where C1-6alkyl optionally may be substituted by cyano, specified R2arelative to R3denoted by R and the specified intermediate compounds of formula (XIII-e) and, respectively, (XIV-e)interaction with an intermediate compound of formula (XXV)in which W4is suitable tsepliaeva group, such as, for example, halogen atom, e.g. chlorine, etc. in the presence of NaI, a suitable base, such as, for example, K2CO3,and a suitable solvent, such as, for example, acetone.

Prom is mediate the compounds of formula (XIII) and (XIV) can be obtained by the interaction of the intermediate compounds of formula (XXVI) or (XXVII) with NaNO 3in the presence of CH3SO3H.

Intermediate compounds of formula (IV-d) can be obtained as follows:

Intermediate compounds of formula (XXX) can be transformed into intermediate compounds of formula (IV-e), which are intermediate compounds of formula (IV-d), in which R5represents a bromine atom, interaction with Br2in the presence of a suitable base, such as, for example, N,N-diethylethanamine, and a suitable solvent, such as, for example, dimethyl sulfoxide.

Intermediate compounds of formula (IV-e) can be transformed into intermediate compounds of formula (VI)in which R5and W2represent chlorine atoms specified intermediate compound represented by formula (VI-a), interaction with POCl3.

The compounds of formula (I) show antiviral properties (inhibiting reverse transcriptase properties), in particular against human immunodeficiency virus (HIV)is the etiological agent of acquired immunodeficiency syndrome (AIDS) in humans. The HIV virus primarily infects human T-4 cells and destroys them or change their normal functioning, especially coordination is the situation of the immune system. As a result, the infected patient has an increasing number of T-4 cells, which increasingly operate abnormally. Therefore, protective immune system becomes unable to fight off infections and neoplasma, and HIV-infected subject usually die from opportunistic infections, such as pneumonia or cancer. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma and infection of the Central nervous system characterized by progressive demyelination, leading to dementia and symptoms, such as progressive dysarthria, ataxia and disorientation. HIV infection is additionally associated with peripheral neuropathy, progressive widespread lymphadenopathy (PGL) and AIDS-related complex (ARC).

Compounds of the present invention has also demonstrated activity against resistant (multi)drug resistant HIV strains, in particular, against strains of HIV-1-resistant (multi)drugs, more specifically, the compounds of the present invention have demonstrated activity against HIV strains, especially strains of HIV-1 that have acquired resistance to one or more known in the field of non-nucleoside reverse transcriptase inhibitor. Known level of nucleoside inhibitors back the transcriptase inhibitors are those non-nucleoside reverse transcriptase inhibitor, which differ from the compounds of the present invention and well-known experts in this field, in particular, commercial non-nucleoside reverse transcriptase inhibitor. Compounds of the present invention have little or no affinity to the human glycoprotein α-1 acid; human glycoprotein α-1 acid has no effect or little effect on anti-HIV activity of the compounds of the present invention.

Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1 properties, the compounds of formula (I), their N-oxides, pharmaceutically acceptable additive salts, Quaternary amines and their stereochemical isomeric forms, can be used in the treatment of patients infected with HIV, and to prevent such contamination. In General, the compounds of the present invention can be used in the treatment of warm-blooded animals infected with viruses whose existence or indirect depends on the enzyme reverse transcriptase. Conditions that can be prevented or treated by the compounds of the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive disseminated lymphadenopathy (PGL), as well as chronic diseases of the Central nervous system, the th of the nervous system, caused by retroviruses, such as HIV induced dementia and multiple sclerosis.

Therefore, compounds of the present invention or any subgroup can be used as drugs against these conditions. Such use as a medicine or method of treatment includes the introduction of HIV-infected subjects amount, effective for the treatment of a condition associated with HIV and other pathogenic retroviruses, particularly HIV-1. In particular, the compounds of formula (I) can be used in the manufacture of a medicinal product for the treatment or prevention of HIV infections.

Given the possibility of using compounds of formula (I), the proposed method of treatment of warm-blooded animals, including humans, suffering from viral infections or prevention of viral infections in warm-blooded animals, including humans, especially HIV infections. This method includes the introduction, preferably oral method of administration, the effective amount of the compounds of formula (I), its N-oxide, pharmaceutically acceptable additive salt, Quaternary amine or a possible stereoisomeric form of warm-blooded animals, including humans.

The present invention also relates to compositions for the treatment of viral infections comprising a therapeutically effectiveagainst the compounds of formula (I) and pharmaceutical acceptable carrier or diluent.

Compounds of the present invention or any subgroup can be represented in various pharmaceutical forms for administration. As appropriate compositions can specify all compositions usually employed for the systematic introduction of medicines. To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound, optionally in the form of its salt additive, as activitiesthese ingredient together in the form of a homogeneous mixture with a pharmaceutically acceptable carrier, and the carrier may take a wide variety of forms depending on the form of preparation desired for administration. Data pharmaceutical compositions are desirable in standard doses, is suitable, in particular, for oral administration, rectal, percutaneous or parenteral injection. For example, upon receipt of the songs in standard dosage forms for oral injection may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, solvents, softeners, binders, release agents, etc. in the case of powders, pills, capsules and the of Ableton. Due to ease their introduction of tablets and capsules represent the most preferred standard doses for oral administration, in this case, use solid pharmaceutical carriers. For parenteral compositions, the carrier will typically contain sterile water, at least part, although the composition may include other ingredients, for example, increase the solubility. Can be obtained, for example, solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose. Can also be obtained suspension for injection, in this case, can be used appropriate liquid carriers, suspendresume agents, etc. also included are solid form preparations that are supposed to turn, shortly before use, to liquid form of the drug. In the compositions suitable for percutaneous administration, the carrier optionally includes an agent that increases the permeability and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small quantities, and supplements do not have significant negative effects on the skin. These supplements can expedite the introduction of the skin and/or can provide the desired compositions. Song data can be entered according to CNAME ways, for example, in the form of skin stickers for use on site, in the form of ointments. Compounds of the present invention can also be entered by inhalation or insufflation using the methods and compositions used in this area for the introduction of this way. Thus, in General, the compounds of the present invention can be introduced into the lungs in the form of a solution, suspension or dry powder. Any system designed for the delivery of solutions, suspensions or dry powders oral or nasal inhalation or insufflation suitable for administration of the compounds of the present invention.

To increase the solubility of the compounds of formula (I)in the composition can be included suitable ingredients, such as cyclodextrins. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers in which one or more hydroxy groups of links anhydroglucose substituted by such groups as1-6alkyl, especially methyl, ethyl or isopropyl, e.g. statistically methylated β-CD; hydraxis1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyl1-6alkyl, in particular, carboxymethyl or carboxyethyl; C1-6alkylsulphonyl, in particular acetyl. Special attention as complexing agents and/or solubilizing the s deserve β-CD, statistically methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD and, in particular 2-hydroxypropyl-β-CD (2-GP-β-CD).

The term "simple mixed ether" means derivative of cyclodextrin in which at least two of the hydroxy-group of the cyclodextrin tarifitsirovana different groups, such as hydroxypropyl and hydroxyethyl.

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

Other suitable compositions for oral or rectal injection include particles consisting of a solid dispersion comprising the compounds of formula (I) and one or more respective pharmaceutical acceptable water is Astoriya polymers.

The term "solid dispersion"used in the present description, refers to a system in a solid state (as opposed to liquid or gaseous state), containing at least two components, namely, a compound of formula (I) and water-soluble polymer, and one component is dispersed more or less evenly among the other component or components (in case of additional pharmaceutically acceptable agent composition, usually known in this field, such as plasticizers, preservatives and the like). When the specified variance of the components is such that the system is chemically and physically uniform or homogenous, or there is one phase that is determined by thermodynamics, this solid dispersion will be called "solid solution". Solid solutions preferably are physical systems, because their components are usually readily bioavailable to organisms in which they are inserted. Advantage can be explained by the case, when these solid solutions can form a liquid solution by contact with a liquid medium, such as gastro-intestinal juices. The phenomenon of dissolution may be due, at least partially, by the fact that the energy required for dissolution of the components of the solid solutions, less than required for dissolution of the components of Chris is aricescu or microcrystalline solid phase.

The term "solid dispersion" also covers dispersion, which are less homogeneous than solid solutions. Data dispersion are not chemically and physically homogeneous or contain more than one phase. For example, the term "solid dispersion" also refers to the system that contains domains or small areas in which amorphous, microcrystalline or crystalline compound of formula (I) or amorphous, microcrystalline or crystalline water-soluble polymer, or both are dispersed more or less evenly 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. These domains represent the area inside the solid dispersion, distinctly marked by some physical feature, small in size and evenly and statistically distributed according to a specified volume variance.

There are various methods for producing solid dispersions, comprising the extrusion of the melt, spray drying and evaporation of the solution.

The process of evaporation of a solution includes the following stages:

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

(b) the heat received under item(a) races the thief, optional under vacuum to evaporate the solvent. The solution can also be applied to a large surface to form a thin film, which will evaporate the solvent.

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

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

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

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

(C) heating and mixing the thus obtained mixture before formation of a homogeneous melt,

d) punching thus obtained melt through one or more holes, and

e) cooling the melt until it is cured.

The terms "melt" and "melting" should be interpreted widely. These terms do not only mean the transition from a solid state to a liquid state, but also relate to the transition to the glassy state or kauchukopodobnoe state in which it is possible for one component of the mixture to be distributed in another to mponent more or less evenly. In specific cases, one component will melt, and the other(s) component(s) will dissolve in the melt, thus forming a solution, which on cooling may form a solid solution having preferential solvent properties.

After obtaining a solid dispersion as described above, the obtained products can be optional crushed and sifted.

The product in the form of a solid dispersion can be pulverized or crushed to particles having a size less than 600 microns, preferably less than 400 microns and more preferably less than 125 microns.

Particles obtained as described above, can then be used to prepare conventional pharmaceutical standard doses, such as tablets and capsules.

It will be clear that the person skilled in the art will be able to optimize the parameters of the methods of obtaining this dispersion, described above, to use the most appropriate solvent, operating temperature, type of equipment used, the speed of spray drying, extrusion speed of the melt.

Water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20°C in aqueous solution containing 2% (wt./about.) from 1 to 5000 mPa.s, more preferably from 1 to 700 mPa.s, and most preferably from 1 to 100 MP is s For example, suitable water-soluble polymers include alkylaryl, hydroxyethylcellulose, hydroxyethylmethylcellulose, karboksimetsiltsellyulozy, alkali metal salts of carboxymethylcellulose, carboxylmethylcellulose, esters of carboxymethylcellulose, starches, pectines, chitin derivatives, di-, oligo - and polysaccharides such as trehalose, Aleynikova acid or its alkali metal salts and ammonium salts, carragenan, galactomannan, tragakant, agar-agar, Arabic gum, guar gum and xanthan gum, polyacrylic acids and their salts, polymethacrylic acids and their salts, copolymers of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, the combination of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylimide and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are hydroxypropylmethylcellulose.

In addition, there may be used one or more cyclodextrins as a water-soluble polymer when receiving the above-mentioned particles, as disclosed in WO 97/18839. These cyclodextrins include pharmaceutically acceptable unsubstituted and substituted cyclodextrins, known in this area, in particular, α-, β - or γ-cyclodextrins or their pharmaceutically acceptable the e derivatives.

Substituted cyclodextrins that can be used to obtain the above-described particles include polyethers described in U.S. patent 3459731. Additional substituted cyclodextrins are ethers, in which the hydrogen atom of one or more hydroxyl groups of the cyclodextrin substituted by such a group, as With1-6alkyl, hydroxys1-6alkyl, carboxy1-6alkyl or C1-6allyloxycarbonyl1-6alkyl or mixed ethers. In particular, the data of substituted cyclodextrins are ethers, in which the hydrogen atom of one or more hydroxyl groups of the cyclodextrin substituted by such a group, as With1-3alkyl, hydroxys2-4alkyl or carboxy1-2alkyl or, more specifically, methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

Of particular importance for use are ethers of β-cyclodextrin, for example, dimethyl-β-cyclodextrin, as described in the publication Drugs of the Future, Vol.9, No. 8, p.577-578 M. Nogradi (1984), and polyethers, for example, hydroxypropyl-β-cyclodextrin, and hydroxyethyl-β-cyclodextrin, which are presented as examples. Simple data alkalemia esters may consist of a simple methyl ether with a degree of substitution of from about 0.125 to 3, for example, p is IMEMO from 0.3 to 2. This hydroxypropylcellulose can be formed, for example, as a result of interaction between β-cyclodextrin and propylene oxide and can have a value of MS from about 0.125 to 10, for example, from about 0.3 to 3.

Another type of the substituted cyclodextrin is sulfosalicylate.

The ratio of the compounds of formula (I) to a water-soluble polymer may vary within wide limits. For example, can be applied to relationships from 1/100 to 100/1. The preferred values of the ratios of the compounds of formula (I) to the cyclodextrin are in the range from about 1/10 to 10/1. More preferred values of the relations are in the range from about 1/5 to 5/1.

Also it may be convenient to prepare the compounds of formula (I) in the form of nanoparticles, which contain a surface modifier adsorbed on their surface in a quantity sufficient to maintain an effective average particle size less than 1000 nm. Suppose that the surface modifiers include those that are physically adsorbed on the surface of the compounds of formula (I), but not chemically associated with the specified connection.

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

Another preferred method of making compounds of formula (I) includes a pharmaceutical composition, with the compounds of formula (I) is introduced into the hydrophilic polymer, and the mixture is applied as a coating film for many small balls, resulting in a gain composition, which can be easily obtained and which are suitable for preparing pharmaceutical standard doses for oral administration.

These balls include a Central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and optionally sealing the top layer.

Materials suitable for use as the core beads are comb, provided that these materials are pharmaceutically acceptable and have the appropriate size and hardness. Examples of these materials are polymers, inorganic substances, organic substances and sugars and their derivatives.

Especially, it is preferable to make the above pharmaceutical composition in the form of standard doses for easy administration and uniformity of dosage. Standard dosage forms,according to the present description, refer to physically discrete dosage forms, suitable standard doses, each dose contains a predetermined quantity activitiesthese ingredient, designed to achieve the desired therapeutic effect in combination with the desired pharmaceutical carrier. Examples data standard dosage forms are tablets (including read or coated tablets), capsules, pills, packaged powders, embossed plates, suppositories, solutions or suspensions for injection and the like, and combinations thereof.

Experts in the field of HIV treatment can determine the effective daily amount according to the results of the samples presented in this description. In General, it is accepted that an effective daily amount will 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. It may be appropriate to enter the desired dose in two, three, four or more doses at specific intervals during the day. These doses for receptions can be prepared in a standard dosage form, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of the active ingredient on the standard dose for admission.

The exact dose and frequency of administration depend on the particular used the compounds of formula (I), a specific state, ogliastro treatment, the severity of the condition to be treated, age, weight and General physical condition of the particular patient, and other medical treatment that the patient can take, which is well known to specialists in this field. Moreover, it is clear that the effective daily amount may be reduced or increased depending on the response of the patient and/or depending on the evaluation of the doctor who ordered the compounds of the present invention. The effective ranges of the daily quantities mentioned above are therefore only indicative and in no way are intended to limit the scope of the claims of the present invention.

Compounds of the present invention (I) can be used individually or in combination with other therapeutic agents such as antiviral agents, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They can also be used alone or in combination with other prophylactic agents for the prevention of viral infections. Compounds of the present invention can be used in the vaccines and methods for protecting people against viral infections over a long period of time. The compounds may be used in these vaccines either alone or together with other compounds present from the retene or together with other anti-viral agents so it is consistent with the adopted use of reverse transcriptase inhibitors in vaccines. Thus, the compounds of the present invention can be combined with pharmaceutically acceptable additives traditionally used in vaccines and entered in preventive effective amounts to protect individuals from HIV infection over a long period of time.

In addition, as medication may be used in combination of one or more additional antiviral compounds and the compounds of formula (I). Thus, the present invention also relates to a product containing (a) compound of formula (I) and (b) one or more additional antiretroviral compounds in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of HIV. Various medications can be combined in a single preparation together with pharmaceutically acceptable carriers. These other antiretroviral compounds may be any known antiretroviral compounds such as suramin, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trinatriumfosfaat); nucleoside reverse transcriptase inhibitors (NRTIs)such as zidovudine (AZT), didanosine (ddI), zalcitabine (dC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™), alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ACH-126443), and the like, non-nucleoside reverse transcriptase inhibitors (NNRTIS), such as delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine (CPV), calanoid AND TMS, etravirine (TMC), DMS, BMS-561390, DPC-083 and the like; nucleotide reverse transcriptase inhibitors (NtRTI), for example, tenofovir (TDF) and tenofovir disoproxil fumarate and the like; compounds of the type TIBO (tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-he tion), for example, (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)tion; connection type α-ARA (α-anilinoquinazoline), for example, α-[(2-nitrophenyl)amino]-2,6-dichlorosalicylic and the like; inhibitors of TRANS-activating proteins, such as TAT-inhibitors, for example, RO-5-3335; REV-inhibitors; protease inhibitors, such as ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), APV (VX-478), TMC-126, BMS-232632, VX-175, DMP-323, DMP-450 (Mozenavir), nelfinavir (AQ-1343), atazanavir (BMS 232632), palinavir, TMC-114, RO033-4649, fosamprenavir (GW433908 or VX-175), P-1946, BMS 186318, SC-55389a, L-756423, tipranavir (PNU-140690), ILA 1096 BS, U-140690, and the like; inhibitors of access, which include fusion inhibitors (e.g., T-20, T-1249), attachment inhibitors and inhibitors of the receptor, the latter include CCR5 antagonists and CXR4 antagonists (e.g., AMD-3100); what reamers inhibitors of access are enfuvirtide (ENF), GSK-873,140, PRO-542, SCH-417,690, TNX-355, maraviroc (UK-426857), an inhibitor of meiosis is, for example, PA-457 (Panacos Pharmaceuticals); integrase inhibitors virus; inhibitors ribonucleotidic reductase (cellular inhibitors), for example, hydroxyurea, etc.

Introduction compounds of the present invention with other anti-viral agents that act on different stages of the life cycle of the virus contributes to the enhancement of therapeutic effect of these compounds. Combination therapy as described above, have a synergistic effect on the inhibition of HIV replication, because each component of the combination acts in different places HIV replication. The use of such combinations may reduce the dosage of this traditional antiretroviral agent that may be required to achieve the desired therapeutic or prophylactic effect in comparison with the case where the agent is introduced in monotherapy. These combinations can reduce or eliminate side effects from traditional single antiretroviral therapy without affecting the antiviral activity of the agents. These combinations reduce the propensity for the emergence of resistance during treatment with one agent, while minimizing any associated toxicity. These combinations can also increase the efficiency of ordinary agent without increasing the knit with this toxicity.

Compounds of the present invention can also be introduced in combination with immunomodulatory agents, such as levamisole, bropirimine, antibodies human anti-interferon-alpha, interferon-alpha, interleukin-2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, such as pentamidine, isethionate etc.; cholinergic agents, for example, tacrine, rivastigmine, donepezil, galantamine and the like; blockers of NMDA channels, for example, memantine, to prevent or combat infection and disease or symptoms of disease associated with HIV infections such as AIDS and ARC, for example, dementia. The compound of formula (I) can also be combined with another compound of the formula (I).

Although the present invention is directed to the use of compounds of the present invention for the prevention or treatment of HIV infections, the compounds of the present invention can also be used as inhibiting agents for other viruses that depend on similar reverse transcriptase inhibitors for the mandatory stages in their life cycles.

The following examples are given to illustrate the present invention.

EXAMPLES

Further, "DMSO" is defined as dimethylsulfoxide, "TFA" is defined as tetracarboxylate acid, "DMF" is defined as N,N-di is malformed and "THF" is defined as tetrahydrofuran.

A. Obtaining intermediates

Example A1: obtain the intermediate compound 2

N-bromosuccinimide (0,0393 mol) by portions at room temperature was added to the intermediate connection 1, receipt of which is described in WO-03/016306 (0,0327 mol) in CH3CN (100 ml). The mixture was stirred at room temperature for 4 hours. The precipitation was filtered, washed with CH3CN and dried, resulting in a received 10,08 g of the desired final product. The filtrate is evaporated and was purified column chromatography (eluent: CH2Cl2100; 35-70 μm). The pure fraction was collected, the solvent evaporated and the residue was recrystallized from CH3CN. Yield: 2.4 g of intermediate compound 2. Collected two factions. Output: 12,48 g of intermediate compound 2 (86%, melting point >250°C).

Example A2: obtain the intermediate compound 3

N-bromosuccinimide (0,000327 mol) by portions at room temperature was added to the intermediate compound 1 (0,000273 mol) in CH3CN (5 ml). The mixture was stirred at room temperature for 4 hours. The precipitation was filtered, washed with CH3CN and dried. Output: 0,065 g (50%, melting point: >250°C).

Example A3: obtain the intermediate compound 4

/p>

Used the same technique as described in example A1, using as starting compound 2-fluoro-6-chloro analogue of intermediate compound 1 (0,000128 mol) and N-bromosuccinimide (0,000154 mol) in CH3CN (5 ml), output: 0,037 g of intermediate compound 4 (62%, melting point: 236°C).

Example A4: intermediate compounds 5, 6, 7

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0516 mol) and 4-(2-cyanoethyl)-2,6-dimethylphenylamine (0,0516 mol) was stirred at 140°C in an oil bath for 45 minutes, then poured into a mixture of water and K2CO310%. The precipitate was filtered and the filtrate was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, was filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2100; 35-70 μm). Pure fractions were collected and the solvent evaporated, yield: 6.0 g of intermediate compound 5 (35%, melting point: >250°C).

Obtaining an intermediate compound 6

A mixture of intermediate compound 5 (0,0182 mol) and 4-cyanoaniline (0,0182 mol) was heated at melting for 5 minutes, then poured into a mixture of water and K2CO310%. Added CH2Cl2and a small amount of the Meon, the residue was filtered and dried. Output: 7,4 g of the intermediate joint is 6 (95%, melting point: >250°C).

Obtaining an intermediate compound 7

A mixture of intermediate compound 6 (0,0180 mol) and chloride dihydrate tin(II) (0.125 mol) in ethanol (100 ml) was stirred at 70°C. overnight, then poured into a mixture of water and K2CO310%. The precipitate was filtered through celite. The filtrate was removed and the residue was washed CH2CL2and THF. The solvent is evaporated. Yield: 6.0 g of intermediate compound 7 (87%), melting point: >250°C).

Example A5

Getting 2-fluoro-6-chlorophenyl analogues of intermediate compounds 5, 6 and 7

A mixture of 2,4-dichloro-5-nitropyrimidine (0,0153 mol) and 4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine (0,0153 mol) was heated at melting for 5 minutes, then poured into a mixture of water and K2CO310% and was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified column chromatography over silica gel (eluent: CH2Cl2100; 35-70 μm). Pure fractions were collected and the solvent evaporated. Yield: 1.9 g of 2-chloro-4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidine, intermediate compound 8 (35%, melting point: 217°C).

A mixture of intermediate compound 8 (0,000424 mol) and 4-cyanoaniline (0,000424 mol) was heated at melting for 5 minutes, then poured into a mixture of water and K2CO310%. We use the and CH 2Cl2and a small amount of the Meon, the residue was filtered and dried. Output: of 1.34 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-nitropyrimidin]amino]benzonitrile, intermediate compound 9 (73%, melting point: >250°C).

A mixture of intermediate compound 9 (0,00306 mol) and chloride dihydrate tin(II) (0,0214 mol) in ethanol (20 ml) was stirred at 70°C. overnight, then poured into a mixture of water and K2CO310%. The precipitate was filtered through celite. The filtrate was removed and the residue was washed CH2Cl2and THF. The solvent is evaporated. Yield: 1.1 g of 4-[4-[4-(2-cyanoethyl)-2-fluoro-6-chlorpheniramine]-5-aminopyrimidine]amino]benzonitrile, intermediate compound 10 (89%, melting point: >250°C).

Example A6: obtain the intermediate compound (11)

A mixture of intermediate compound 2 (0,0112 mol), dichlorobis(triphenylphosphine)palladium (II) (0,00228 mol), sodium formate (0,0336 mol) and magnesium sulfate (1 g) in DMF (50 ml) was stirred for 20 hours under pressure of carbon monoxide 8 bar. The mixture was filtered through celite and poured into water. The residue was filtered, washed with water and Et2O and dried. Yield: 2.9 g of intermediate compound 11 (65%, melting point: >250°C).

Example A7: obtain the intermediate compound 12

Sodium borohydride parts, at 0°C until alali to the intermediate compound 11 (0,000254 mol) in THF (5 ml) and EtOH (3 ml). The mixture was stirred at room temperature for 15 minutes the Mixture was poured into water and was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was led from acetone, filtered and dried. Output: 0,045 g (45%, melting point >250°C) intermediate compound 12.

Example A8: obtain the intermediate compound 13

A mixture of intermediate 11 (0,000254 mol) and hydrochloride hydroxyamine (0,000380 mol) in pyridine (3 ml) was stirred at room temperature for 20 hours, then poured into water. The precipitation was filtered, washed with water and Et2O and dried. Output: 0,048 g of intermediate compound 13 (39%, melting point: >250°C).

Example B1: Getting connection 2

A few drops of acetic acid at room temperature was added to a mixture of cyanoborohydride on solid media (0,00042 mol), intermediate 7 (0,00021 mol) and 3-pyridinecarboxamide (0,000315 mol) in acetonitrile (5 ml). The mixture was stirred at room temperature for 40 hours and then was filtered. The mixture was poured into water and K2CO310% and was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, was filtered and the solvent is perivale. The residue was purified column chromatography over silica gel (eluent: CH2Cl2/MeOH/NH4HE 97/3/0,1; 10 μm). Pure fractions were collected and the solvent evaporated. Output: 0,041, This faction was led from diisopropyl - simple ethyl ester. The residue was filtered, and dried. Output: 0,034 g of compound 2 (34%, melting point: 140°C).

The second method is:

In this way used 3 equivalent cyanoborohydride sodium instead of cyanoborohydride on a solid medium and the mixture was stirred at room temperature overnight.

Example B2: Getting connection 64

Two drops of acetic acid at room temperature was added to a mixture of cyanoborohydride sodium (0,00114 mol), intermediate 11 (0,000380 mol) and 3-(aminomethyl)pyridine (0,000570 mol) in THF (5 ml). The mixture was stirred at room temperature for 20 hours. The mixture was poured into water and K2CO310% and was extracted with CH2Cl2. The organic layer was dried over magnesium sulfate, was filtered and the solvent evaporated. The residue was purified column chromatography over silica gel (eluent: CH2Cl2100; Cromasil 5 μm). Pure fractions were collected and the solvent evaporated. Output: of 0.066 g of compound 64 (36%, melting point: 236°C).

Example B3: Getting connection 72

A mixture of intermediate 11 (0,000254 mol) and hydrochloride of o-benzylhydroxylamine (0,000380 mol) in pyridine (3 ml) was stirred at room temperature for 20 hours and then poured into water. The precipitate was filtered, washed with water and Et2O and dried. Output: 0,082 g of compound 72 (65%, melting point: 99°C).

Example B4: Getting connection 75

A mixture of intermediate compound 13 (0,000244 mol), hydrochloride 4-chloromethylthiazole (0,000269 mol) and potassium carbonate (0,000488 mol) in DMF (3 ml) was stirred at room temperature for 20 hours and then poured into water. The precipitate was filtered, washed with water and Et2O and dried. The residue was purified column chromatography on silica gel (eluent: CH2Cl2100 to CH2Cl2/MeOH 98/2; Cromasil 5 μm). Pure fractions were collected and the solvent evaporated. Output: 0,051 g of compound 75 (41%, melting point: >250°C).

Example B5: Receive connection 82

Cyanoborohydride sodium (0,00050 mol) at room temperature was added to a mixture of compound 1 (0,000167 mol) and paraformaldehyde (0,000500 mol) in acetonitrile (10 ml). Added a few drops of acetic acid and the mixture was stirred at room temperature overnight. The mixture was poured into water and K2CO310% and was extracted with CH2 Cl2. The organic layer was dried over magnesium sulfate, was filtered and the solvent evaporated. The residue was purified column chromatography over silica gel (eluent: CH2Cl2100 to CH2Cl2/MeOH 95/5; Cromasil 5 μm). Pure fractions were collected and the solvent evaporated. Output: 0,028 g of compound 82 (34%, melting point: 216°C).

Example B6: Getting connection 84

A few drops of acetic acid at room temperature was added to a mixture of cyanoborohydride sodium (0,00119 mol), intermediate 7 (0,000393 mol) and 2-methoxycinnamaldehyde (0,000413 mol) in acetonitrile (8 ml). The mixture was stirred at room temperature for 40 hours. The mixture was poured into water and K2CO310% and was extracted with CH2Cl2, the organic layer was dried over magnesium sulfate, was filtered and the solvent evaporated. The residue was purified column chromatography over silica gel (eluent: CH2Cl2/OEt/NH4HE 95/5; Cromasil 5 μm). Pure fractions were collected and the solvent evaporated. Output: 0,010 g of compound 84 (5%, melting point: 118°C).

In tables 1-6 lists the compounds that can be obtained in accordance with the above examples (Ex. No.).

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Examples obtain the final 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 and vinyl acetate (PVP-VA) or hypromellose (HPMC), usually 5 mPa.s, dissolved in organic solvents, such as ethanol, methanol or methylene chloride. In an appropriate case, the polymer is dissolved in ethanol. The polymer solutions and compounds are mixed and then subjected to spray drying. The ratio of compound/polymer selected from a range from 1/1 to 1/6. Intermediate intervals can be 1/1,5 and 1/3. A suitable ratio may be 1/6. The powder formed by spray drying, the solid is the second dispersion, then placed in a capsule for introduction. The content of the drug in a capsule of 50 to 100 mg, depending on the size of the used capsules.

Tablets film coated

Obtain core tablets

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

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured alcohol add 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 add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye and the entire mixture is homogenized. The core tablets cover the thus obtained mixture in a device for coating.

Range antiviruse what about actions

Due to the increasing emergence of resistant to drug-resistant HIV compounds of the present invention were tested for their activity against clinically isolated strains of HIV that have undergone multiple mutations. These mutations are associated with resistance to reverse transcriptase inhibitors and the emergence of viruses that show different degrees of phenotypic cross-resistance to existing currently commercially available drugs, such as AZT and delavirdine.

Antiviral activity of the compounds of the present invention was evaluated in the presence of wide-type HIV and HIV mutants carrying mutations in the gene for reverse transcriptase. The activity of the compounds is evaluated using the cell sample, and the residual activity is expressed by the magnitude of Rees50. In columns IIIB and A-G in the table lists the values RES50against different strains IIIB, A-G.

Strain IIIB represents the wild type strain HIV-LAI.

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

The strain contains the K103N mutation in the reverse transcriptase of HIV.

The strain contains a mutation L1001 in the reverse transcriptase of HIV.

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

Strain E contains mutations L1001 and K103N in the reverse transcriptase of HIV.

Strain F contains mutations K103N and Y11C in the reverse transcriptase of HIV.

Strain G contains mutations L1001, K103N, Y181C, V179I, Y181C, E138G, V179I, L2214F, V278V/I and A327A/V in the reverse transcriptase of HIV.

Connection # IIIBABCDEFG
18,98,398,78,18,28,66,8
37,888,18,17,97,57,45

1. The compound of the formula

in the form of E-isomer or pharmaceutically acceptable additive salt, in which
-al=a2-a3=a4represents a bivalent radical of the formula
-CH=CH-CH=CH- (a-1);
-b1=b2-b3-b4represents a divalent radical of the formula is

n is 0;
m is 2;
each of the radicals R1independently from each other mean a hydrogen atom, a C1-6alkyl;
R2ameans cyano;
X1means-NR1-;
R3represents a C2-6alkenyl substituted by cyano;
R4means C1-6alkyl;
R5represents a radical of the formula-Y-Alk-L, -Alk'-Y-L or-Alk'-Y-Alk-L;
each of the radicals Alk or Alk' independently represents a divalent C1-6alkyl or C2-6alkenylphenol group;
L is aryl or Het;
Y represents NR1; -CH=N-O-;
Het denotes a 5 - or 6-membered fully unsaturated ring system in which one, two or three ring element are heteroatoms, each of which is independently selected from the group comprising nitrogen, oxygen and sulfur, and in which the remaining ring elements are carbon atoms; and, if possible, any nitrogen ring member may be optionally substituted C1-6the alkyl, where the ring system may not necessarily be linked with the benzene ring; and in which any carbon atom of the ring, including any optional carbon atom attached to the benzene ring, each independently may be substituted by the Deputy selected from such groups as halogen atom, a C1-6alkyl,hydroxys 1-4alkyl, carboxy1-4alkyl, C1-4alkylcarboxylic1-4alkyl, di(C1-4alkyl)amino1-4alkyl, aryloxy, morpholinyl, aryl, Het1;
Het1means thienyl, isoxazolyl, thiadiazolyl, each of which may be optionally substituted by one or two1-4alkyl radicals;
Q means a hydrogen atom;
each aryl represents phenyl or phenyl substituted one or two substituents, each of which is independently selected from among such groups as halogen atom, a C1-6alkyl, C2-6quinil, cyano, polyhalogen1-6alkyl or Het1.

2. The compound according to claim 1 in which Het denotes a heterocycle selected from among these heterocycles, as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyridyl, benzofuranyl, benzothiazolyl, and said heterocycle optionally substituted on carbon atoms by one, two or three substituents, each of which is independently selected from among such groups as halogen atom, a C1-6alkyl, hydroxys1-4alkyl, carboxy1-4alkyl, di(C1-4alkyl)amino1-4alkyl, aryloxy, morpholinyl, aryl, Het1.

3. The connection of claim 1, wherein the compound has the formula

where R1, R2aX1, R3, R4, R5/sup> n, m and Q have the values specified above.

4. The connection of claim 1, wherein the compound has the formula

where R1, R2aX1, R3, R4, R5and Q have the values specified above.

5. Pharmaceutical composition having any abscopal HIV replication properties containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 4.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline, represented by formula , where R1 represents (1-6C)alkyl; R2 represents halogen, (1-4C)alcoxy; R3 represents OH, NO2, CN, fluoridated with (1-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy. hydroxy(2-4C)alkoxy, (1-4C)alkoxycarbonyl, R7, R8-amino, R9, R10-amino, R9, R10-aminocarbonyl, R9, R10-aminosulfonyl or phenyl(1-4C)alkoxy, where phenyl ring in composition phenyl(1-4C)alkoxy is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R4 represents R11-phenyl or R11-(4-5C)heteroaryl, which represents heteroaromatic group, containing 4-5 carbon atoms and at least one heteroatom, selected from N and S, where phenyl or heteroaryl group is optionally additionally substituted with one or several substituents, selected from nitro, (1-4C)alkyl, (1-4C)alkoxy; R7 represents H, (1-4C)alkyl; R8 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (1-4C)alkoxy(1-4C)alkylcarbonyl, furylcarbonyl; phenyl(1-4C)alkylcarbonyl, where phenyl ring is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R9 and R10 are not necessarily selected from H, (1-6C)alkyl and (1-4C)alkoxy(2-4C)alkyl; or R9 and R10 can be bound together with formation of morpholinyl ring; R11 represents H, R12, R13-amino, R14, R15-aminocarbonyl or R14, R15-aminosulfonyl; R12 represents H; R13 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyperazinyl(1-4C)alkylcarbonyl; R14 and R15 are independently selected from H, (1-6C)alkyl, (1-4C)alkoxy(2-4C)alkyl and imidazolyl(1-4C)alkyl; X represents O or R16-N; Y represents CH2 or C(O);Z represents CN; R16 represents H, (1-4C)alkyl, (1-4C)alkylcarbonyl; or their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition, as well as to application of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline derivatives by any of i.i. 1-10.

EFFECT: obtaining novel biologically active compounds, which possess agonistic activity with respect to FSH receptor.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-(2-thiazolyl)amide of 2-(2-oxo-3-indolinylidene)hydrazine-4-oxo-4-phenyl-2-butenoic acid of formula: .

EFFECT: obtaining a compound having antibacterial and analgesic activity.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

FIELD: chemistry.

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

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts and esters. The disclosed compounds have inhibitory effect on cyclin-dependant kinase. In formula I R1 denotes , R3 is selected from a group consisting of H, CO2R6, C(O)R6, SO2R6 and SO2NR5R6, R5 and R6 are each independently selected from a group which includes H and (lower)alkyl, R2 is phenyl which contains one, two or three substitutes independently selected from a group which includes halogen or -O-(lower)alkyl.

EFFECT: preparation of a pharmaceutical composition which contains an effective amount of a formula I compound as an active ingredient.

6 cl, 1 tbl, 22 ex

FIELD: chemistry.

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

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

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention describes a phenothiazine derivative, specifically 2-(1-(2-(2-chloro-10H-phenothiazin-10-yl)-2-oxoethyl)-5-methyl-1H-1,2,4-triazol-3-yl)phenol of formula I: .

EFFECT: obtaining compounds with hypotensive and antiarrhythmic activity during intraperitoneal administration.

3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic compounds of formula (1) , where ring Q represented by is , (where is NH-CH2-, -N-CH-, -CH2-NH- or -CH=N-; and the carbon-carbon bond between the 3rd position and the 4th position of the heterocyclic skeleton which contains Z and Y, is a single or double bond); ring Q can have at least one substitute selected from a group consisting of a lower alkyl group, lower alkenyl group, lower alkynyl group, hydroxy group, lower alkoxy group, halogenated lower alkyl group, aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylcarbonyl group, lower alkenyloxy group, lower alkanoyl group, lower alkanoyloxy group, cycloalkyl group, cycloalkyl lower alkyl group, halogen atom, carbamoyl group which can have a lower alkyl group, carboxy group, lower alkoxycarbonyl group, amino group which can have a lower alkanoyl group, nitro group, hydroxy lower alkyl group, amino lower alkyl group which can have a lower alkyl group, thienyl group, lower alkyl group substituted with a saturated 3-8-member monoheterocyclic group containing 1-2 nitrogen atoms, and an oxo group; R2 is a hydrogen atom or a lower alkyl group; and A is -O-A1- (where A1 is an alkylene group which can be substituted with a hydroxy group (where the alkylene group may contain one oxygen atom) or a lower alkenylene group or a lower alkylene group; provided that if A is a lower alkylene group, Q is a bicyclic group selected from a group consisting of: (where the carbon-carbon bond is a single or double bond)] or salts thereof. The invention also relates to a pharmaceutical composition, to a method of preparing the pharmaceutical composition, to use of the formula (1) heterocyclic compound, as well as a method for synthesis of the heterocyclic compound.

EFFECT: obtaining novel biologically active compounds which have activity as a dopamine D2 receptor partial agonist and a serotonin receptor 5-HT2A antagonist, and an adrenaline receptor α1 antagonist, and serotonin uptake inhibitor or serotonin reuptake inhibitor.

15 cl, 197 ex, 24 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline or quinazoline derivatives of general formula

Ib, where R1 is C1-6-alkyl or C1-6-alkoxy; X is N or CH; R3 and R4 independently denote hydrogen, C1-6-alkyl, C1-6-alkylsulphonyl or a group of formula (IIa), where A is oxygen or sulphur; D is -(CH2)t, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur, (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or a group of formula (IIb), where A is oxygen or sulphur; D is -(CH2)t-, -(CH2)tO- or -O(CH2)t, where t equals 0, 1, 2, 3 or 4; and E is C1-6-alkyl, C3-7-cycloalkyl, or a 3-7-member monocyclic aromatic ring or a 6-10-member bicyclic aromatic ring in which 1-3 carbon atoms in the ring(s) are optionally substituted with a heteroatom which is independently selected from nitrogen, oxygen and sulphur (optionally substituted with 1 or 2 substitutes independently selected from halogen, C1-6-alkyl, CF3, cyano, hydroxy and C1-6-alkoxy); or R3 and R4 together with the nitrogen atom with which they are bonded form a 3-7-member ring or a 6-10-member bicyclic ring which can be saturated, partially saturated or unsaturated and contain 1, 2 or 3 heteroatoms selected from nitrogen, sulphur and oxygen, where each group is optionally substituted with 1 or 2 substitutes selected from oxo, C1-6-alkyl, C1-6-alkoxy, aryl and aryl-C1-6-alkyl (where aryl and aryl-C1-6-alkyl are also optionally substituted with 1 or 2 with C1-6-alkyls or C1-6-alkoxy). The invention also relates to use of formula Ib compounds in preparing a medicinal agent, to a pharmaceutical composition based on formula Ib compound and preparation method thereof.

EFFECT: obtaining novel quinoline and quinazoline derivatives having high affinity to 5-HT1-receptors.

12 cl, 171 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medication, reducing desire for alcohol, which represents substituted 1H-benzimidazoles of general formula 1 or their pharmaceutically acceptable salts and/or hydrates, pharmaceutical composition, and medication on their basis. Compounds can be applied in treatment of alcohol abuse with application of ethanol-containing products, if necessary, together with antidepressants. In compounds of general formula 1 , where: W represents sulfur atom or group S=O; R1 represents one or more substituents, selected from hydrogen, halogen, C1-C4alkyl, C1-C4alkyloxy, optionally substituted 5-6-member azaheterocyclyl with 1-2 atoms of nitrogen and/or oxygen in cycle; R2 represents atom of hydrogen or optionally substituted C1-C4alkyl; R3 and R4 independently on each other represent optionally similar substituents, selected from hydrogen, optionally substituted C1-C4alkyl, C3-C6cycloalkyl; R5 represents alkyl substituent, selected from hydrogen or optionally substituted C1-C7alkyl, C1-C7alkenyl, C1-C4alkynyl, optionally substituted phenyl, optionally substituted 5-6-member heterocyclyl with 1-3 heteroatoms, selected from nitrogen, oxygen and sulfur, possibly condensed with benzene ring; C1-C4-alkoxycarbonyl, optionally substituted amino carbonyl, or group CR3R4R together stands for group , where Alk stands for C1-C4alkyl.

EFFECT: medication allows to reduce symptoms of alcohol abuse considerably as compared with earlier known compounds and does not produce unfavorable effect on liver function.

12 cl, 3 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: in formula (1) A is a nitrogen atom or CH; when A is a nitrogen atom, B is NR9 (where R9 is a C1-10alkyl group), when A is CH, B is a sulphur atom, R1 is a phenyl group (where the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10alkyl group and C1-10alkoxy groups (where C1-10alkyl groups and C1-10alkoxy groups are not substituted of substituted with one or more halogen atoms)); L1 is a bond; X is OH; R2 is a C1-6alkyl group; L2 is a bond; L3 is NH; L4 is a bond or NH; Y is an oxygen atom or sulphur atom; R3 is a thienyl group (where the thienyl group is substituted with CONR29R30 (where R29 is hydrogen or a C1-10alkyl group, and R30 is an amino group (where the amino group is not substituted or substituted with a pyridyl group), mono- or di-C1-10alkylamino group, N-methylpiperzinyl group, piperidine group, morpholine group or C1-10alkyl group (C1-10alkyl group is substituted with one or more substitutes selected from a group consisting of a carboxyl group, carbamoyl groups, pyrroldinyl groups, tetrahydrofuryl groups or morpholine groups) or R29 and R30 together denote -(CH2)m3-G-(CH2)m4- (where G is CR31R32 (where R31 is a hydrogen atom and R32 is a C1-10alkylcarbonylamino group or pyrrolidinyl group) and each of m3 and m4 is independently equal to an integer from 0 to 5 provided that m3+m4 equals 3, 4 or 5), or NR29R30 as a whole denotes a piperidine group or pyrrolidinyl group (where the piperidine group or pyrrolidinyl group is substituted with two substitutes independently selected from a group consisting of: hydroxyl groups and C1-10alkoxy groups) or 2-(4-oxopyrridin-1(4H)-yl)acetyl group), phenyl group (where the phenyl group is substituted with one substitute selected from a group consisting of C1-10alkyl groups, C1-10alkylcarbonyl groups and C1-10alkylaminocarbonyl groups, (where C1-10alkyl group, C1-10alkylcarbonyl group and C1-10alkylaminocarbonyl group are substituted with one or two substitutes selected from a group consisting of hydroxyl groups, carboxyl groups and carbamoyl groups)), phenyl group (where the phenyl group is substituted with one C1-10alkylaminocarbonyl group or one halogen atom), dihydrobenzo[1,4]dioxine group or benzo[1,4]oxazine group. The invention also relates to a medicinal agent containing the disclosed compound as an active ingredient and to a thromopoeitin receptor activator which is a formula (1) compound.

EFFECT: disclosed compounds have thrombopoietin receptor agonist properties.

8 cl, 11 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts which involves the use as a parent compound, (phenylthio)acetic acid derivative or its salts presented by general formula: where X1 represents halogen atom, and is applicable as a safe method of volume production of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts effective as an agent in disorders of the central nervous system and peripheral nervous system.

EFFECT: there is provided high yield, safety for human body, low environment loads.

36 cl, 1 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (II) and to their pharmaceutically acceptable salts. In formula R1 means phenyl optionally substituted on one or more carbon atoms with one or more R9; where R9 is specified of halogen, amino, C1-6alkyl and C1-6alkoxy, one of R2 and R3 represents -C(=O)NR6R7, and the other represents -NHC(=O)NHR4; R4 and R6 represent N, and R7 represents piperidine-3-yl. Besides the invention refers to a pharmaceutical composition containing the compound of the invention, to application of the compound for preparing a drug, and also to an intermediate compound of formula (XI) or its salts, where A represents thienyl ring.

EFFECT: preparation of new compounds exhibiting inhibitory properties with respect to SNK1 kinase.

7 cl, 263 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

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

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

32 cl, 43 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline, represented by formula , where R1 represents (1-6C)alkyl; R2 represents halogen, (1-4C)alcoxy; R3 represents OH, NO2, CN, fluoridated with (1-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy. hydroxy(2-4C)alkoxy, (1-4C)alkoxycarbonyl, R7, R8-amino, R9, R10-amino, R9, R10-aminocarbonyl, R9, R10-aminosulfonyl or phenyl(1-4C)alkoxy, where phenyl ring in composition phenyl(1-4C)alkoxy is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R4 represents R11-phenyl or R11-(4-5C)heteroaryl, which represents heteroaromatic group, containing 4-5 carbon atoms and at least one heteroatom, selected from N and S, where phenyl or heteroaryl group is optionally additionally substituted with one or several substituents, selected from nitro, (1-4C)alkyl, (1-4C)alkoxy; R7 represents H, (1-4C)alkyl; R8 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (1-4C)alkoxy(1-4C)alkylcarbonyl, furylcarbonyl; phenyl(1-4C)alkylcarbonyl, where phenyl ring is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R9 and R10 are not necessarily selected from H, (1-6C)alkyl and (1-4C)alkoxy(2-4C)alkyl; or R9 and R10 can be bound together with formation of morpholinyl ring; R11 represents H, R12, R13-amino, R14, R15-aminocarbonyl or R14, R15-aminosulfonyl; R12 represents H; R13 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyperazinyl(1-4C)alkylcarbonyl; R14 and R15 are independently selected from H, (1-6C)alkyl, (1-4C)alkoxy(2-4C)alkyl and imidazolyl(1-4C)alkyl; X represents O or R16-N; Y represents CH2 or C(O);Z represents CN; R16 represents H, (1-4C)alkyl, (1-4C)alkylcarbonyl; or their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition, as well as to application of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline derivatives by any of i.i. 1-10.

EFFECT: obtaining novel biologically active compounds, which possess agonistic activity with respect to FSH receptor.

13 cl, 43 ex

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