Novel derivatives of benzimidazole and their using as medicaments

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

 

The object of the present invention is new derivatives of benzimidazole (amino - and thiobenzamide). These products are GnRH agonists (the hormone that stimulates gonadotropin or gonadotropin releasing hormone). This invention also relates to pharmaceutical compositions containing said products, and to their use for obtaining a medicinal product.

GnRH (gonadotropin releasing hormone), also called LHRH (luliberin)is a hypothalamic Decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), which regulates the reproductive system of vertebrates. It is released into the capillaries of the hypothalamic-hypophyseal portal system of the medial Eminence and funnel hypothalamus. Through this network, it reaches the anterior pituitary and secondary capillary network reaches its target cells. GnRH acts on the membrane level of target cells through receptors with seven transmembrane segments associated with phospholipase C via G proteins leads to increased release of intracellular calcium. Its action leads to the biosynthesis and release of gonadotropic hormones FSH (folliculo-stimulating hormone) and LH (luteinizing hormone). It is proved that the agonists and antagonists of GnRH is effective for the treatment of endometriosis, fibroids, polycystic ovary syndrome, breast cancer, ovary and endometrium, g is nagatani pituitary desensitization with medication ovarian stimulation for the treatment of infertility in women; in the treatment of benign prostatic hyperplasia and prostate cancer; and in the treatment of premature puberty.

Currently used by GnRH antagonists are peptide compounds which, as a rule, must be given intravenously or by subcutaneous due to its weak oral bioavailability. Ones GnRH antagonists, with the advantage of oral administration, are the goal of many research works. For example, ones connection, GnRH antagonists, have been described in theJ. Med. Chem, 41, 4190-4195 (1998) andBioorg. Med. Chem. Lett, 11, 2597-2602 (2001).

The present invention relates to a new class of strong ones GnRH antagonists.

Thus, the object of the invention is a compound of General formula (I)

in racemic, enantiomeric form or any combinations of these forms, where:

A represents-CH2- or-C(O)-;

Y represents-S - or-NH-;

R1and R2represent, independently, a hydrogen atom, (C1-C8)alkyl, (C5-C9)bicycloalkyl, optionally substituted by one or more identical or different (C1-C6)alkyl radicals, or a radical of the formula -(CH2)n-X, where X represents amino, (C1-C6)alkylamino, di((C1-C 6)alkyl)amino, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl, arylcarbamoyl or heteroaryl, or a radical of the formula

where (C3-C7)cycloalkenyl, heterologously, aryl and heteroaryl radicals are optionally substituted by one or more identical or different substituents selected from: -(CH2)n'-X'-Y', halogen, oxo, nitro, cyano, amino, (C1-C6)alkylamino and di((C1-C8)alkyl)amino, hydroxy, N3;

X' represents-O-, -S-, -C(O)-, -C(O)-O-, -NH-C(O)-, -NH-SO2- or a covalent bond;

Y' represents a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals; heteroaryl or aryl or heteroseksualci, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halogen, nitro, cyano, amino, CF3, OCF3, hydroxy, N3, (C1-C6)alkylamino and di((C1-C6)alkyl)amino;

n is an integer from 0 to 6 and n'is an integer from 0 to 2;

or R1and R2together with the nitrogen atom to which they are attached, form heteroseksualci, heterobicyclic is l or a radical of the formula:

where the radical formed together R1and R2, optionally substituted by one or more identical or different substituents chosen from:

-(CH2)n″X″-Y″, oxo, hydroxy, halogen, nitro, cyano;

X″ represents-O-, -C(O)-, -C(O)-O - or a covalent bond;

Y″ is a (C1-C6)alkyl, amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, (C3-C7)cycloalkyl, heteroseksualci, arylalkyl radical or an aryl or heteroaryl radical, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulphonyl, halogen, hydroxy, nitro, cyano, CF3, OCF3, amino, (C1-C6)alkylamino and di((C1-C6)alkyl)amino); or a radical of the formula

n″ is an integer from 0 to 4;

R3represents -(CH2)p-W3-(CH2)p'-Z3.

W3is a covalent bond, -CH(OH)- or-C(O)-;

Z3is a (C1-C6)alkyl, substituted, aryl radical, heteroaryl or a radical of the formula

where is Riley radical optionally substituted by one or more identical or different substituents, selected from: -(CH2)p″-V3-Y3, halogen, nitro, cyano, N3, hydroxy;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond;

Y3is a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals, amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenylcarbonylamino, geterotsiklicheskie or aryl radicals;

p, p' and p" represent, independently, an integer from 0 to 4;

R4represents a radical of the formula-(CH2)s-R4.

R4is heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W'4.

W4represents a hydrogen atom, (C1-C8)alkyl or (C3-C7)cycloalkyl;

W'4represents a radical of the formula -(CH2)S'-Q4-Z4;

Q4is a covalent bond, -CH2-CH(OH)-(CH2]t-[O]t'[CH2]t″or-C(O)-O-;

t, t'and t" represent, independently, 0 or 1;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)acidity and hydroxy; (C2-C6)alkenyl; (C2-C6)quinil; (C3-C7)cycloalkyl, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkyl, (C1-C6)alkoxycarbonyl and (C1-C6)hydroxyalkyl; cyclohexene; substituted; heteroaryl; aryl, optionally substituted by one or more identical or different radicals selected from the formula -(CH2)q-V4-Y4, hydroxy, halogen, nitro, cyano;

V4represents-O-, -S-, -NH-C(O)- or a covalent bond;

Y4is a (C1-C6)alkyl radical, optionally substituted di((C1-C6)alkyl)amino or by one or more identical or different halogen radicals; amino; (C1-C6)alkylamino; di((C1-C6)alkyl)amino; aralkyl; heteroseksualci radicals;

q" is an integer from 0 to 4;

or Z4represents a radical of the formula

s and s', not only is jut a, independently, an integer from 0 to 6;

or pharmaceutically acceptable salt of the latter.

In the definitions above, the expression halogen represents fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine radical. The expression alkyl (unless otherwise stated) preferably represents a straight or branched alkyl radical containing from 1 to 6 carbon atoms, such as radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, 2,2-dimethylpropyl, hexyl, isohexyl or 1,2,2-trimethylpropyl. The term (C1-C8)alkyl denotes a straight or branched alkyl radical containing from 1 to 8 carbon atoms, such as radicals containing from 1 to 6 carbon atoms, as stated above, but also heptyl, octyl, 1,1,2,2-TETRAMETHYLBUTYL, 1,1,3,3-TETRAMETHYLBUTYL. The term alkylaryl preferably designates the radicals, where the alkyl radical is as described above, such as, for example, methylcarbamyl and ethylcarboxyl. The term hydroxyalkyl denotes radicals, where the alkyl radical is as described above, such as, for example, hydroxymethyl, hydroxyethyl.

Under alkenyl, if not stated otherwise, understand straight or branched alkyl radical containing from 1 to 6 carbon atoms and containing at least the e, one unsaturated (double bond, such as, for example, vinyl, allyl, propenyl, butenyl or pentenyl. Under quinil, if not stated otherwise, understand straight or branched alkyl radical containing from 1 to 6 carbon atoms and containing at least one unsaturated double (triple) bond, such as, for example, radical ethinyl, propargyl, butynyl or pentenyl.

The term alkoxy refers to radicals, where the alkyl radical such as described above, such as, for example, the radicals methoxy, ethoxy, propyloxy or isopropoxy and direct, secondary, or tertiary, butoxy, pentyloxy. The term alkoxy-carbonyl, preferably designates the radicals where the alkoxy radical as mentioned above, such as, for example, methoxycarbonyl, etoxycarbonyl. The term alkylthio denotes radicals, where the alkyl radical such as described above, such as, for example, methylthio, ethylthio. The term acidity preferably designates the radicals, where the alkyl radical such as described above, such as, for example, matildico (CH3-S-S-), acidity or propylaia.

The term (C3-C7)cycloalkyl denotes a saturated carbon monocyclic system which contains from 3 to 7 carbon atoms, and preferably represents cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo or cyclohepta is inoe rings. Expression heteroseksualci denotes condensed monocyclic or bicyclic saturated system containing from 2 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably the heteroatoms are selected from oxygen, sulfur or nitrogen. As an example of geterotsiklicheskie can be mentioned ring containing at least one nitrogen atom, such as pyrrolidine, imidazolidine, pyrazolidine, isothiazolin, thiazolidin, isoxazolidine, oxazolidine, piperidine, piperazine, ASEAN, diazepan, morpholine, decahydroquinoline, and rings that do not contain a nitrogen atom, such as tetrahydrofuran or tetrahydrothiophene.

The term (C5-C9)bicycloalkyl denotes unfused saturated hydrocarbon bicyclic system containing from 5 to 9 carbon atoms, such as bicycloheptane, such as, for example, bicyclo[2,2,1]heptane or bicicletta, such as, for example, bicyclo[2,2,2]octane or bicyclo[3,2,1]octane. The term heterobinuclear denotes unfused saturated hydrocarbon bicyclic system containing from 5 to 8 carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur. As an example of heterobinuclear can be mentioned azabicycloalkanes, sabicic Oakton, such as 7-azabicyclo[2,2,1]heptane, 2-azabicyclo[2,2,2]octane or 6-azabicyclo[3,2,1]octane.

The expression aryl represents an aromatic radical consisting of a condensed ring or rings, such as, for example, phenyl, nattily or fluorenyl radical. Expression heteroaryl denotes an aromatic radical consisting of a condensed ring or rings, where at least one ring contains one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example, the heteroaryl radical may be mentioned radicals containing at least one nitrogen atom, such as pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, hinely, ethanolic, honokalani, indolyl, benzoxadiazole, carbazolyl, as well as radicals that do not contain a nitrogen atom, such as thienyl, benzothiazyl, furyl, benzofuran or pyranyl.

The term aralkyl (arylalkyl) preferably designates the radicals in which the aryl and alkyl radical as mentioned above; as example can be mentioned arylalkyl, benzyl, phenethyl, phenylpropyl and phenylbutyl. The term aryl-carbonyl, preferably designates the radicals in which the aryl radical such as described above, such as, for example, phenyl which arbonyl.

The terms alkylamino, dialkylamino preferably represent radicals in which the alkyl radicals such as described above, such as, for example, methylamino, ethylamino, dimethylamino, diethylamino or (methyl)(ethyl)amino.

Also in this application (CH2)ithe radical (i is an integer, which may be n, n', n″, p, p', p″, s, s', s" and q″, as defined above) is a straight or branched hydrocarbon chain of carbon atoms.

The object of this invention is a compound of General formula (I')

in racemic, enantiomeric form or all combinations of these forms and where:

Aarepresents-CH2- or-C(O)-;

Yarepresents-S - or-NH-;

R'1and R'2independently represent a hydrogen atom, (C1-C8)alkyl, (C5-C9)bicycloalkyl radical, optionally substituted by one or more identical or different (C1-C6)alkyl radicals, or a radical of the formula -(CH2)n-X, in which

X represents amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl, arylcarbamoyl or heteroaryl, or a radical of the formula

/p>

(C3-C7)cycloalkyl, heterocytolysine, aryl and heteroaryl radicals, optionally substituted by one or more identical or different substituents selected from: -(CH2)n'-X'-Y', halogen, oxo, nitro, cyano, amino, (C1-C6)alkylamino and di((C1-C8)alkyl)amino, hydroxy, N3;

X' represents-O-, -S-, -C(O)-, -C(O)-O-, -NH-C(O)-, -NH-SO2- or a covalent bond;

Y' represents a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen; heteroaryl, or aryl, or heterologously radicals, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halogen, nitro, cyano, amino, CF3, OCF3, hydroxy, N3, (C1-C6)alkylamino and di((C1-C8)alkyl)amino;

n is an integer from 0 to 6, and n' is an integer from 0 to 2;

or R'1and R'2together with the nitrogen atom to which they are attached, form heteroseksualci, heterobicyclic or a radical of the formula:

the radical, which together form the R'1and R'2, optionally substituted by one or a few is Kimi identical or different substituents, chosen from:

-(CH2)n″X″-Y″, oxo, hydroxy, halogen, nitro, cyano;

X″ represents-O-, -C(O)-, -C(O)-O - or a covalent bond;

Y″ is a (C1-C6)alkyl, amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, (C3-C7)cycloalkenyl, heterologously, arylalkyl, or aryl or heteroaryl radical, optionally substituted by one or more identical or different substituents selected from: (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulphonyl, halogen, hydroxy, nitro, cyano, CF3, OCF3, amino, (C1-C6)alkylamino and di((C1-C6)alkyl)amino); or a radical of the formula

n″ is an integer from 0 to 4;

R'3represents -(CH2)p-W3-(CH2)p'-Z3.

W3is a covalent bond, -CH(OH)- or-C(O)-;

Z3is a (C1-C6)alkyl, adamantly, aryl, heteroaryl radical or a radical of the formula

aryl radical, optionally substituted by one or more identical or different substituents selected from: -(CH2)p″-V3-Y3halog is on, nitro, cyano, N3, hydroxy;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond;

Y3is a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals, amino, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenylcarbonylamino, heteroseksualnymi or aryl radicals;

p, p' and p″ independently represent an integer from 0 to 4;

R'4represents a radical of the formula-(CH2)s-R″4.

R4is heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W'4.

W4represents a hydrogen atom, (C1-C8)alkyl or (C3-C7)cycloalkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond, -CH2-CH(OH)-(CH2]r[O]t'- (CH2]t″- or-C(O)-O-;

t, t' and t″ independently 0 or 1;

Z4represents a hydrogen atom, (C1-C8)and the keel, (C3-C7)cycloalkyl; heteroaryl; aryl, optionally substituted by one or more identical or different radicals selected from the formula -(CH2)q″-V4-Y4, hydroxy, halogen, nitro, cyano;

V4represents-O-, -S-, -NH-C(O)- or a covalent bond;

Y4is a (C1-C6)alkyl radical, optionally substituted di((C1-C6)alkyl)amino or by one or more identical or different halogen; amino; (C1-C6)alkylamino; di((C1-C6)alkyl)amino; Aracely; heterologously radicals;

q″ is an integer from 0 to 4;

or Z4represents a radical of the formula

s and s' independently represent an integer from 0 to 6;

or pharmaceutically acceptable salt of the latter.

A more specific object of the present invention is a compound of formula I or I'as defined above, or pharmaceutically acceptable salt of the latter, where a represents-C(O)-.

A more specific object of the present invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where

cycloalkyl represented by X is a cyclohexyl or cycloheptyl,

heteroseksualci, Pres the set X, selected from: piperidine, pyrrolidine, thiazolidine, research and tetrahydrothiophene;

the aryl represented by X represents a phenyl, nattily or fluorenyl radical;

aryl arylcarboxylic radical represented by X represents a phenyl radical;

heteroaryl represented by X is selected from pyridine, imidazole, thiophene, indole, carbazole and isoquinoline;

heteroaryl represented by Y'is selected from oxazole and imidazole;

the aryl represented by Y'represents a phenyl radical;

heteroseksualci represented by Y'represents a piperazine;

heteroseksualci, which together with the nitrogen atom to which they are attached, form an R1and R2selected from: piperidine, piperazine, diazepan, thiazolidine and research;

cycloalkyl, presents Y″, is cyclopentyl or cyclohexyl;

heteroseksualci, presents Y″, selected from: piperidine, pyrrolidine and research;

arylalkyl and aryl, presents Y″, represent, respectively, the benzyl radical and the phenyl radical;

heteroaryl, presents Y″, is selected from pyridine, pyrazine, furan and thiophene.

A more specific object of the present invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where

the aryl represented by Z3represents phenyl or nattily radical;

heteroaryl, presents Z3selected from benzo[b]thiophene and benzo[b]furan;

heteroseksualci and aryl represented by Y3represent, respectively, pyrolidine and phenyl radicals.

A more specific object of the present invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where

heteroseksualci represented by R4selected from piperazine, piperidine, research and pyrrolidine;

aralkyl, optionally substituted heterocyclization represented by R"4represents a benzyl radical;

heteroaryl, presents R″4, is an imidazole;

(C3-C7)cycloalkyl, presents Z4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

heteroaryl, presents Z4selected from pyridine, thiophene, indole and furan;

the aryl represented by Z4represents phenyl or naphthyl;

aralkyl represented by Y4represents benzyl;

heteroseksualci, which is Y4is pyrrolidin;

aralkyl, substituted on heteroseksualci that together the way the Ute W 4and W'4represents a benzyl radical.

Preferably the object of this invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where a represents-C(O)- and R1and R2independently represent a hydrogen atom, ((C1-C8)alkyl radical or a radical of the formula -(CH2)n-X, where

X represents amino, di(alkyl)amino, adamantyl, cyclohexyl, cycloheptyl, piperidine, morpholine, pyrrolidine, phenyl, pyridine, imidazole, thiophene, indole, carbazole, optionally substituted (C1-C6)alkyl, or a radical of the formula

piperidine, pyrolidine and phenyl radicals, optionally substituted by one or more identical or different substituents selected from: -(CH2)n'-X'-Y', halogen, oxo, amino and di((C1-C8)alkyl)amino;

X' represents-O-, -S-, -C(O)-O-, -NH-C(O)-, -NH-SO2- or a covalent bond;

Y' represents a (C1-C6)alkyl, oxazol, phenyl radical, optionally substituted (C1-C4)alkyl, or piperazine, optionally substituted (C1-C4)alkyl;

or R1and R2together with the nitrogen atom to which they are attached, form a piperidine, piperazine, diazepan, thiazolidin, orfelin or a cyclic radical of the formula:

the radical, which together form an R1and R2, optionally substituted by one or more identical or different substituents chosen from:

-(CH2)n″X″-Y″;

X″ represents-C(O)-, -C(O)-O - or a covalent bond;

Y″ is a (C1-C6)alkyl; di(alkyl)amino, cyclopentenyl, tsiklogeksilnogo, piperidinyl, pyrolidine, morpholinyl, benzyl, pyridine, pyrazinoic, furan, titanovyi or phenyl radical, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylcarboxylic and halogen; or Y″ is a radical of the formula

Preferably the object of this invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where a represents-C(O)- and R3represents -(CH2)p-W3-(CH2)p'-Z3.

W3is a covalent bond, -CH(OH)- or

-C(O)-;

Z3is a (C1-C6)alkyl, phenyl, nattily, benzo[b]titanovyi, benzo[b]farnily radical or a radical of the formula

the phenyl radical, optionally substituted by one or more identical or different substituents selected from: -(CH2)p″-V3-Y3, halogen, nitro, cyano;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond;

Y3is a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen; amino; di((C1-C6)alkyl)amino; phenylcarbonylamino; pyrolidine or phenyl radicals;

p, p' and p″ independently is an integer from 0 to 2.

Preferably the object of this invention is a compound of formula I'as defined above, or pharmaceutically acceptable salt of the latter, where Aarepresents-C(O) -, and the radicals R'1, R'2, R'3and R'4defined as the radicals R1, R2, R3and R4respectively, as defined above.

Preferably the object of this invention is a compound of formula I, as defined above, or pharmaceutically acceptable salt of the latter, where a represents-C(O)-, and R4represents a radical of the formula-(CH2)s-R4

R4represents piperidino ring, optionally substituted benzyl, piperazine, it is certainly substituted benzyl, or a radical of the formula-NW4W'4.

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)S'-Q4-Z4;

Q4is a covalent bond, -CH2-CH(OH)-,-CH2-CH(OH)-CH2-O-, -CH2-CH(OH)-CH2-, -CH2-CH(OH)-CH2-O-CH2- or-C(O)-O-;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)acidity or one or two hydroxy; (C2-C6)alkenyl; (C2-C6)quinil; cyclopropyl radicals, optionally substituted by alkoxycarbonyl; cyclobutyl, cyclopentyl, optionally substituted hydroxyalkyl; cyclohexyl, optionally substituted by one or more alkilani; cycloheptyl, cyclohexen, substituted, pyridine, thiophene, indole, furan, naphthyl; phenyl radicals optionally substituted by one or more identical or different radicals selected from: -(CH2)q″-X4-Y4, hydroxy, halogen and cyano;

X4represents-O - or a covalent bond;

Y4is a (C1-C6)alkyl, di((C1-C6)alkyl)amino or pyrolidine radical.

Very preferably, about what the target of the present invention is a compound of formula I, as defined above, where a represents-C(O)-, Y is-NH - and

R1and R2independently represent a (C1-C8)alkyl radical;

R3represents -(CH2)p-W3-(CH2)p'-Z3.

W3is a covalent bond; Z3represents a phenyl radical substituted by one or more identical or different substituents selected from: -(CH2)P″-V3-Y3and halogen; V3represents-O - or-S-; and Y3is a (C1-C6)alkyl radical; p, p' and p″ 0;

R4represents a radical of the formula -(CH2)s-R″4

R4represents a radical of the formula-NW4W'4.

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)S'-Q4-Z4;

Q4is a covalent bond;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted hydroxy, (C3-C7)cycloalkyl, heteroaryl, aryl, optionally substituted by one or more identical or different radicals selected from -(CH2)q″-V4-Y4;

V4represents-O - or Cova is entou communication;

Y4is a (C1-C6)alkyl or di((C1-C6)alkyl)amino radical;

q″ is 0; s is an integer from 2 to 4, and s' is an integer from 1 to 2.

And very preferably (C3-C7)cycloalkyl selected from cyclopentyl and cyclohexyl, heteroaryl represents pyridine and aryl represents phenyl; or a pharmaceutically acceptable salt of the latter.

Preferably the object of this invention is a compound of formula I', as described above, or pharmaceutically acceptable salt of the latter, where Aarepresents-C(O)-, Ya, -NH-, the radicals R'1, R'2and R'3defined as the radicals R1, R2and R3respectively, as defined above, and R'4represents a radical of the formula -(CH2)s-R″4.

R"4represents a radical of the formula-NW4W'4.

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond;

Z4represents a hydrogen atom, (C1-C8)alkyl, (C3-C7)cycloalkyl, heteroaryl, aryl, optionally substituted by one or more identical or different radicals of the mi, selected from the formula -(CH2)q-V4-Y4;

V4represents-O - or a covalent bond;

Y4is a (C1-C6)alkyl or di((C1-C6)alkyl)amino radical;

q″ is 0; s is an integer from 2 to 4, and s' is an integer from 1 to 2.

And very preferably (C3-C7)cycloalkyl selected from cyclopentyl and cyclohexyl, heteroaryl represents pyridine and arylvinyl; or a pharmaceutically acceptable salt of the latter.

Very preferably the object of this invention is the compound of formula I, as defined above, where a represents-C(O)-, Y represents a sulfur atom, and

R1and R2independently represent a (C1-C8)alkyl radical;

R3represents -(CH2)p-W3-(CH2)p'-Z3.

W3is a covalent bond or-C(O)-; Z3represents a phenyl radical substituted by one or more identical or different substituents selected from: -(CH2)p″-V3-Y3and halogen; V3represents-O - or a covalent bond; and Y3is a (C1-C6)alkyl or di((C1-C6)alkyl)amino radical; p is 1, and p' and p″ 0;

R4represents the t is a radical of the formula-(CH 2)s-R″4.

R″4represents a radical of the formula-NW4W'4.

W4represents a hydrogen atom or a (C1-C8)alkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond;

Z4represents a hydrogen atom, (C1-C8)alkyl, heteroaryl, aryl;

s is an integer from 2 to 4, and s' is an integer from 1 to 2.

And very preferably heteroaryl represents pyridine and arylvinyl; or a pharmaceutically acceptable salt of the latter.

Preferably the object of the invention is a compound of formula I'as defined above, or pharmaceutically acceptable salt of the latter, where Aarepresents-C(O)-, Yarepresents a sulfur atom, the radicals R'1, R'2, R'3and R'4defined as, the radicals R1, R2, R3and R4respectively, as defined above, if a represents-C(O)- and Y represents a sulfur atom.

Preferably the object of this invention is the compound of formula I, as defined above, where a represents a-CH2-, Y represents-NH-, and R1and R2independently represent a ((C1-C6)alkyl radical; R3present is employed, a phenyl, substituted by one or more identical or different (C1-C6)alkoxy substituents; R4represents a radical of the formula -(CH2)s-R″4; R4represents a radical of the formula-NW4W'4; W4is a (C1-C8)alkyl; W4represents a radical of the formula -(CH2)S'-Q4-Z4; Q4is a covalent bond and Z4represents pyridine; or a pharmaceutically acceptable salt of the latter.

Preferably the object of this invention is a compound of formula I'as defined above, or pharmaceutically acceptable salt of the latter, where Aarepresents-CH2-, Yarepresents-NH-, and the radicals R'1, R'2, R'3and R'4defined as the radicals R1, R2, R3and R4respectively, as defined above, if a represents-CH2-, and Y is-NH-.

In this application, the symbol -> * corresponds to the place of attachment of the radical. If the place of attachment of the radical is not specified, it means that the attachment is at any available place of this radical.

In accordance with the definitions of the various groups A, Y, R1, R2, R3and R4compounds according to this invention MoE the ut can be obtained in the liquid phase in accordance with the various methods a-H, described below.

A.Receive under co by the reaction scheme A:

The compounds of formula I according to this invention where Y is-NH-, and a represents-C(O)-, can be obtained in accordance with the following scheme A:

As shown in scheme A, 4-fluoro-3-nitrobenzoic acid (1) can be connected with primary or secondary amine in the presence of a binding agent, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide, in the presence or in the absence of 1-hydroxybenzotriazole (HOBt), in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at room temperature for 3-24 hours to obtain the corresponding amide (2). Handling fluorinated derivative (2) the primary amine in the presence of an inorganic base such as cesium carbonate or potassium, in an inert organic solvent such as dimethylformamide or acetonitrile, at a temperature of 20-70°C for 2-16 hours leads to the formation of a derivative (3). The nitro-group of the compound (3) was reduced by treatment with chloride dihydrate tin in an inert solvent, such as ethyl acetate or dimethylformamide, at a temperature of 60-80° C for 3-5 hours, or by using a catalytic reduction in the presence of 10%palladium on ug is erode in an inert solvent, such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25°C for 2-8 hours with obtaining dianiline (4). Then the derivative (4) was treated with isothiocyanates in the presence of a binding agent with the substrate from the resin with or without, such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, or N-methylcyclohexylamine N-methylpredisolone resin, in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, at a temperature of 20-70°C within 2-72 hours with derivatization (5). Alternative derivative (4) can be processed by isothiocyanates in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, and the resulting thiourea can be processed by methyliodide in a polar solvent such as ethanol, for 3-24 hours at a temperature of 20-70°C obtain (5).

Example A1: hydrochloride of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

Stage 1: 4-fluoro-N,N-Diisobutyl-3-nitrobenzamide

Diisopropylcarbodiimide (13,8 ml, 1.2 EQ.) was added to 4-fluoro-3-nitrobenzoic acid (15 g, 1 EQ.) in THF solution (150 ml). The mixture was stirred for 3 hours at a temperature of approximately 20° C, then added disobe the ylamine (12.9 ml, 1 EQ.). After stirring for 15 hours at a temperature of approximately 20°C, the reaction mixture was evaporated under reduced pressure at 40°C. the Residue was treated with dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with aqueous salt solution, then dried over Na2SO4, then was evaporated under reduced pressure at a temperature of 40°C. Purification of compounds using flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2) gave the desired compound as a yellow solid (13.8 g; 63%yield).

MS/LC: calculated MW = 296,3; m/z = 297,2 (MH+) melting point equal to 47°C.

Stage 2: N,N-Diisobutyl-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)-3-nitrobenzamide

A mixture of 4-fluoro-N,N-Diisobutyl-3-nitrobenzamide (2,07 g, 1 EQ.), N-(2-pyridin-2-retil)propane-1,3-diamine (1.6 g, 1.2 EQ.) and cesium carbonate (4.5 g, 2 EQ.) in acetonitrile (70 ml) was boiled under reflux for 3 hours, then concentrated under reduced pressure at 40°C. the Precipitate was placed in dichloromethane (100 ml) and water (40 ml). After decantation and extraction, the combined organic phases are washed with aqueous saline solution, dried over Na2SO4, then was evaporated under reduced pressure at 40°C. Purification sludge flash chromatography on silica gel (eluent : dihormati is 100 to dichloromethane/methanol 8:2) gave the expected compound as a yellow oil (3.1 g; 92%yield).

MS/LC: calculated MW = 496,6; m/z = 470,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 0.79(m, N), a 1.75(m, 2H), 1,90(m, 2H), of 2.23 (s, 3H), 2,48 (t, 3H),3J=6 Hz), a 2.71(t, 2H,3J=7 Hz), 2,87(t, 2H,3J=7 Hz), 3,19(d, 4H,3J=7 Hz), 3.33 and(m, 2H), 7,01(d, 1H), 7,10(m, 1H), 7.23 percent(d, 1H), 7,50(m, 1H), 7,60(m, 1H), to 7.99(s, 1H), to 8.41(m, 1H), 8,59(t, 1H,3J=5 Hz).

Stage 3: 3-amino-N,N-Diisobutyl-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)benzamide

N,N-Diisobutyl-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)-3-nitrobenzamide (2.9 g) in solution in a mixture of ethyl acetate/ethanol (100 ml) and 10% palladium on coal (290 mg) was added in the autoclave. After stirring for 7 hours in an atmosphere of hydrogen (3 bar), the catalyst was removed by filtration on celite and the filtrate was concentrated under reduced pressure at 40°C to obtain the expected compound in the form of an oil (2.5 g, 92%yield).

MS/LC: calculated MW = 439,6; m/z = 440,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 0.77(m, N), 1,71(m, 2H), 1,90(m, 2H), 2,22(s, 3H), 2,47(m, 3H), 2,70(t, 2H,3J=7 Hz), 2,87(m, 2H,3J=7 Hz), 3.0 a(m, 2H), 3,17(d, 4H,3J=7.5 Hz), to 4.62(s, 2H), 4,71(s, 1H), 6,33(d, 1H), 6,50(d, 1H), to 6.57(s, 1H), 7,15(m, 1H), 7,25(d, 1H), 7,63(m, 1H), 8,45(m, 1H).

Stage 4: hydrochloride of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazo the-5-carboxamide

3,4,5-trimethoxyphenethylamine (27 mg, 1.2 EQ.) and N-methylcyclohexylamine-N-methyl polystyrene resin (acquired from Novabiochem; loading was 1.69 mmol/g, 236 mg, 4 equiv.) successively added to a solution of 3-amino-N,N-Diisobutyl-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)benzamide (48 mg, 1 EQ.) in tetrahydrofuran (2 ml). The mixture was boiled under reflux for 18 hours, then cooled to room temperature and added aminomethyl-polystyrene resin (acquired from Novabiochem, 2 EQ.). After stirring for 4 hours at room temperature, the mixture was filtered on a Frit, and the filtrate was concentrated under reduced pressure at 40°C. the precipitate was dissolved in ethyl ether and was added dropwise a solution of 1H. HCl in ethyl ether to obtain the expected compound in the form of cleaners containing hydrochloride salt (80 mg, 89%yield).

MS/LC: calculated MW = 630,8; m/z = 631,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,66(m, 6N), of 0.91(m, 6N), 1,71-2,03(m, 2H), 2.49 USD(m, 2H), 2,86 (s, 3H), 3,01-and 3.72(m, 10H), 3,81 (s, 3H), 3,88(C, 6N), 4,58(t, 2H,3J=7 Hz), 6,93(s, 2H), 7,30(m, 2H), 7,60(m, 1H), of 7.70(m, 1H), 7,82(d, 1H), 8,12(m, 1H), 8,67(d, 1H), and 11.2(s, 1H), 11,7(s, 1H), 13,0(s, 1H).

Example A2: hydrochloride of 1-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-acid)amino]-N,N-Diisobutyl-1H-benzimidazole-5-carboxamide

Stage 1: Besame is 3-amino-4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-Diisobutyl

To a solution of 4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-Diisobutyl-3-nitrobenzamide (1.44 g, obtained in accordance with the method described for example A1) in ethyl acetate (40 ml) was added chloride dihydrate tin (3.58 g, 5 EQ.). The mixture was boiled under reflux for 7 hours, then cooled to a temperature of approximately 20°C and was poured into a saturated solution of NaHCO3. After decantation and extraction with ethyl acetate the organic phase was combined, washed with aqueous saline solution, dried over sodium sulfate and concentrated under reduced pressure at 40°C. Purification using flash chromatography on silica gel (eluent dichloromethane/methanol 95:5) gave the compound as a foam (1.06 g, 78%yield).

MS/LC: calculated MW = 424,3; m/z = 425,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 0.77(m, N), of 1.78(m, 2H), 1,90(m, 2H), 2,12 (s, 3H), 2.49 USD(m, 3H), 3,06(t, 2H,3J=7 Hz), 3,17(d, 4H,3J=7.5 Hz), of 3.48(s, 2H), br4.61(s, 2H), 4.72 in(s, 1H), 6,38(d, 1H), 6,51(m, 1H), 6,59(s, 1H), 7,19-7,30(m, 5H).

Stage 2: hydrochloride of 1-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-acid)amino]-N,N-Diisobutyl-1H-benzimidazole-5-carboxamide

3,4-Dimethoxyphenylethylamine (35 mg, 1.2 EQ.) and N-methylcyclohexylamine-N-methylpredisolone resin (acquired from Novabiochem; loading was 1.69 mmol/g, 355 mg, 4 equiv.) successively added to a solution of 3-amino-4-({3-[benzyl(IU who yl)amino]propyl}amino)-N,N-diisobutylamine (65 mg, 1 EQ.) in tetrahydrofuran (2 ml). The mixture was boiled under reflux for 18 hours, then cooled to room temperature and dabwali aminomethyl-polystyrene resin (acquired from Novabiochem, 2 EQ.). After stirring for 4 hours at room temperature the mixture was filtered on a Frit and the filtrate was concentrated under reduced pressure at 40°C. the precipitate was dissolved in ethyl ether and was added dropwise 1N. a solution of HCl in ethyl ether to obtain the expected compound in the form of cleaners containing hydrochloride salt (81 mg, 92%yield).

MS/LC: calculated MW = 585,3; m/z = 586,5 (MH+).

NMR(1H, 400 MHz, DMSO-d6):of 0.85(m, 6N), to 0.92(m, 6N), of 1.85(m, 1H), 2.05 is(m, 1H), 2,28(m, 2H), 2,86(s, 3H), is 3.08-3,3(m, 6N), of 3.78(s, 6N), 4,20-and 4.40(m, 2H), 4,50(m, 2H), 6.42 per(s, 1H), 6.90 to(m, 2H), 7,22(m, 1H), 7,22-to 7.64(m, 8H), 10,98(m, 1H).

The following compounds were obtained according co the reaction scheme And the same method described for the synthesis of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide or 1-{3-[benzyl(methyl)amino]propyl}-2-[(3,5-acid)amino]-N,N-Diisobutyl-1H-benzimidazole-5-carboxamide:

In the above formula, R1,R2N are one of the following radicals:

R3is one of h is deprivating radical

and R4is one of the following radicals (if R4represents a radical containing at the end of the secondary amine, such as propylaminoethyl, the compound was obtained by catalytic hydrogenation in the presence of palladium on coal corresponding N-benzyl derivative; and if R4represents a radical containing at the end of primary amine, for example, ethylamino, the compound was obtained by treatment of the corresponding derivative, protected tertbutoxycarbonyl group, acid).

B.Receive under co by the reaction scheme B:

The compounds of formula I according to this invention, where Y represents-S-, and a represents-C(O)-, can be obtained in accordance with the following scheme B:

As shown in scheme B, Danilin (4) can be processed by thiocarbonyldiimidazole (TCD) or thiophosgene in an inert organic solvent, such as tetrahydrofuran, methylene chloride or chloroform, at room temperature for 2-17 hours with derivatization (6). Then the compound (6) alkilirovanie interaction halogen derivatives, such as alkyl or benzyl iodide, bromide or chloride or bromoketones in risotti tertiary base, such as triethylamine or diisopropylethylamine, or in the presence of tertiary bases on a polymeric substrate, such as morpholinomethyl polystyrene resin, in an inert organic solvent, such as tetrahydrofuran, chloroform or methylene chloride, at a temperature of 20-70°C for 3-24 hours. The resulting thiobenzamide (7) can be selected either by using flash chromatography on silica gel or by adding to the reaction mixture nucleophilic agent to the polymeric substrate, such as, for example, aminomethylpyrimidine resin, and an electrophilic agent in a polymeric substrate, such as, for example, 4-promotingdecentralization resin, followed by filtration and evaporation of the filtrate.

Example B1: N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide

Stage 1: N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamide

A mixture of 3-amino-N,N-Diisobutyl-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)benzamide (1.52 g, 1 EQ.) and thiocarbonyldiimidazole (0.74 g, 1.2 EQ.) in THF (30 ml) was stirred at approximately 20°C for 15 hours. After concentration under reduced pressure at 40°C the precipitate was placed in dichloro is an (80 ml) and water (30 ml). After desantirovaniya and extraction combined organic phases are washed with aqueous saline solution, dried over Na2SO4, then was evaporated under reduced pressure at 40°C. Purification sludge using flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) gave the expected compound in the form of light beige foam (1.2 g; 72%yield).

MS/LC: calculated MW = 481,7; m/z = 482,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 0.64(m, 6N), of 0.91(m, 6N), 1,79-2,03(m, 4H), to 2.18 (s, 3H), 2,37(t, 3H),3J=6.5 Hz), to 2.66(t, 2H,3J=7 Hz), and 2.83(t, 2H,3J=7 Hz), 3,19(m, 2H), 3,24(m, 2H), 4.16 the(t, 2H,3J=7 Hz), 7,05-the 7.65(m, 6N), 8,43(d, 1H), 12,79(s, 1H).

Stage 2: N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide

To a solution of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxamide in tetrahydrofuran was sequentially added morpholinobutyrophenone resin (acquired from Novabiochem, 2 EQ.) and 2-bromo-1-(3,4,5-trimethoxyphenyl)Etalon. The mixture was stirred for 15 hours at approximately 20°C, then added tetrahydrofuran, aminomethylpropanol resin (2 EQ. purchased from Novabiochem) and 4-promotingdecentralization resin (3 EQ. purchased from Novabiochm). After stirring for 6 hours, the mixture was filtered on the Frith. The filtrate is then concentrated to dryness under reduced pressure at 40°C to obtain the expected compound.

MS/LC: calculated MW = 689,9; m/z = 690,5 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,61(m, 6N), of 0.91(m, 6N), 1,71-2,03(m, 4H), are 2.19(s, 3H), 2,35(t, 3H),3J=6.5 Hz), to 2.67(t, 2H,3J=7 Hz), 2,85(t, 2H,3J=7 Hz), is 3.08-3,30(m, 4H), of 3.75(s, 3H), of 3.84(s, 6N), is 4.15(t, 2H,3J=7 Hz), 5,09(s, 2H), 7,11-to 7.67(m, 8H), to 8.45(d, 1H).

The following compounds were obtained according co the reaction scheme in the same way described for the synthesis of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide:

In the above formula, R1,R2N is one of the following radicals:

R3is one of the following radicals

and R4is one of the following radicals

C.Receive under co by the reaction scheme C:

The compounds of formula I of the present invention, where Y represents-NH-, and a represents-C(O)-, can be obtained in accordance with the following what hemou C:

As shown in scheme C, 4-fluoro-3-nitrobenzoic acid can be converted to methyl ester (8) through the formation of carboxylate salts using inorganic base, such as the dihydrate lithium hydroxide, or cesium carbonate, at room temperature for from 30 minutes to 2 hours, in an inert organic solvent, such as tetrahydrofuran, followed by the addition of dimethylsulfate at room temperature and stirring while boiling under reflux for 5-15 hours. Fluorinated derivative (8) can be treated with a primary amine in the presence of an inorganic base such as cesium carbonate or potassium, in an inert organic solvent such as dimethylformamide or acetonitrile, at a temperature of 20-70°C for 2-16 hours with derivatization (9). The nitro-group of compound (9) was reduced by treatment with chloride dihydrate tin in an inert solvent, such as ethyl acetate or dimethylformamide, at a temperature of 60-80°C for 3-15 hours, or by using a catalytic reduction in the presence of 10%palladium on carbon in an inert solvent, such as methanol, ethanol, ethyl acetate or a mixture of these solvents, at a temperature of 18-25°C for 2-8 hours with obtaining dianiline (10). Then the derivative (10) is probatively isothiocyanates in the presence of a binding agent, such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, at a temperature of 20-70°C within 2-72 hours with derivatization (11). Alternative derivative (10) can be processed by isothiocyanates in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, and the resulting thiourea may be treated with methyl iodide in a polar solvent such as ethanol, for 3-24 hours at a temperature of 20-70°C obtain (11). Methyl ether (11) can then be zapolirovan in the presence of inorganic bases, such as the dihydrate lithium hydroxide, in a mixture of polar solvents such as water and tetrahydrofuran, at a temperature of 20-70°C for 3-17 hours. The resulting acid (12) can be connected with primary or secondary amine in the presence of a binding agent, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or carbonyldiimidazole, with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at room temperature for 3-24 hours. The corresponding amide (13) can be selected either by using flash chromatography on silica gel or by adding to the reaction mixture nucleophile what about the reagent on a polymer substrate, such as, for example, aminomethylpyrimidine resin, and an electrophilic agent in a polymeric substrate, such as, for example, Methylisothiazolinone resin, followed by filtration and evaporation of the filtrate.

Example C1: propane-1-it 1-(2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-yl)-3-Tien-2-yl

Stage 1: methyl 4-fluoro-3-nitrobenzoate

The monohydrate of lithium hydroxide (4.5 g, 1 EQ.) small portions were added to a solution of 4-fluoro-3-nitrobenzoic acid (20 g, 1 EQ.) in tetrahydrofuran (100 ml). After stirring for 1 hour at approximately 20°C yellow precipitate was added dropwise dimethylsulfate (10,2 ml). The reaction mixture is then boiled under reflux for 8 hours, then concentrated under reduced pressure at 40°C. the Residue was dissolved in dichloromethane and water, saturated Na2CO3. After desantirovaniya and extraction, the combined organic phases are washed with aqueous saline solution, dried over sodium sulfate and concentrated under reduced pressure at 40°C. the yellow solid product was recrystallized with a mixture of diethyl ether/petroleum ether to obtain the expected compound in the form of a light yellow powder (16.7 g, 78%yield). Melting point = 59°C./p>

NMR(1H, 400 MHz, DMSO-d6):to 3.99(s, 3H), 7,39(m, 1H), with 8.33(s, 1H), total of 8.74(s, 1H).

Stage 2: methyl 4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)-3-nitro Bezout

A mixture of methyl 4-fluoro-3-nitrobenzoate (5,08 g, 1 EQ.), N-(2-pyridin-2-retil)propane-1,3-diamine (5,4 g, 1.2 EQ.) and potassium carbonate (7.0 g, 2 EQ.) in acetonitrile (180 ml) was boiled under reflux for 3 hours, then concentrated under reduced pressure at 40°C. the precipitate is placed in dichloromethane (150 ml) and water (60 ml). After desantirovaniya and extraction, the combined organic phases are washed with aqueous saline solution, dried over Na2SO4, then was evaporated under reduced pressure at 40°C. Purification of compounds using flash chromatography on silica gel (eluent: dichloromethane to dichloromethane/methanol 9:1) gave the expected compound in the form of an orange oil (9,2 g; 97%yield).

MS/LC: calculated MW = 372,4; m/z = 373,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 1.75(m, 2H), of 2.23(s, 3H), 2,48(t, 3H),3J=6 Hz), a 2.71(t, 2H,3J=7,8 Hz), of 2.86(t, 2H,3J=7,8 Hz)to 3.35(m, 2H), 3,81(s, 3H), 7,05(d, 1H), 7,10(m, 1H), 7.23 percent(d, 1H), to 7.59(m, 1H), to 7.93(m, 1H), 8,40(d, 1H), 8,59(s, 1H), 8,87(t, 1H,3J=5 Hz).

Stage 3: methyl 3-amino-4-({3-[methyl(2-pyridin-2-ylmethyl)amino]propyl}amino) Bezout

Methyl 4-({3-[methyl(2-pyridin-2-retil)amino]propyl}and the eno)-3-nitrobenzoate (9,1 g) in solution in a mixture of ethyl acetate/methanol and 10% palladium on coal (910 mg) was added in the autoclave. After stirring for 4 hours in an atmosphere of hydrogen (3 bar), the catalyst was removed by filtration on silica gel and the filtrate was concentrated under reduced pressure at 40°C to obtain the expected compound in the form of oil (8.2 g, 98%yield).

MS/LC: calculated MW = 342,4; m/z = 343,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):1,71(m, 2H), of 2.21(s, 3H), 2,46(t, 3H),3J=6,8 Hz), 2,68(t, 2H,3J=7 Hz), of 2.86(t, 2H,3J=7 Hz), 3,05(m, 2H), 3,71(s, 3H), 4,70(s, 2H), 5,23(t, 1H,3J=7 Hz), 6,37(d, 1H), 7,14-7,26(m, 4H), to 7.64(m, 1H), 8,45(m, 1H).

Stage 4: methyl-2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylate

3,5-dimethoxyphenylethylamine (571 mg, 1 EQ.) and diisopropylcarbodiimide (1.35 ml, 4 EQ.) successively added to a solution of methyl 3-amino-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)batata (1.0 g, 1 EQ.) in tetrahydrofuran (10 ml). the mixture is refluxed for 18 hours, then cooled to room temperature and concentrated under reduced pressure at 40°C, the precipitate was placed in ethyl acetate (100 ml) and water (40 ml). After desantirovaniya and extraction, the combined organic phases are washed with aqueous saline solution, dried over Na2SO4, then was evaporated under reduced pressure at 40°C. Purification of the residue using flash chromatogr is the philosophy on silica gel (eluent: dichloromethane/methanol 99:1 to 98:2) gave the expected compound in the form of a beige foam (1.12 g; 76%yield).

MS/LC: calculated MW = 503,6; m/z = 504,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 2.08(m, 2H), 2.40 a(t, 2H,3J=7 Hz), a 2.45(s, 3H), 2,99(t, 2H,3J=7 Hz), to 3.09(t, 2H,3J=7 Hz), 3,82(C, 6N), 3,93(s, 3H), 4,01(t, 2H,3J=6 Hz), x 6.15(m, 1H), 6,92-rate of 7.54(m, 6N), 7,87(m, 1H), of 8.25(s, 1H), 8,51(m, 1H), 9,37(s, 1H).

Stage 5: 2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylic acid

The lithium hydroxide (0,350 g, 4 EQ.) was added to a solution of methyl 2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylate (1,05 g, 1 EQ.) in a mixture of tetrahydrofuran (10 ml) and water (5 ml). The mixture was stirred at 65°C for 18 hours, then cooled to room temperature and concentrated under reduced pressure at 40° C. To the precipitate was added ethyl acetate and water. The mixture was acidified by adding acetic acid to pH 5. After desantirovaniya and extraction, the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Purification using flash chromatography on silica gel (eluent: dichloromethane/ethanol 95/5-70/30) to give the expected compound as a white foam (0,93 g, 91%yield).

MS/LC: calculated MW = 489,6; m/z = 490,1 (MH+)

NMR(1H, 400 MHz, DMSO-d6):of 1.88(m, 2H), of 2.23(s, 3H), 2,31(t, 2H,3Ja 6.5 Hz), to 2.74(t, 2H,3J=7 Hz), 2.91 in(t, 2H,3J=7 Hz), and 3.72(s, 6N), 4,14(t, 2H,3J=6.5 Hz), 6,14(m, 1H), 7,09-7,72(m, 8H), to 7.93(s, 1H), 8,44(m, 1H), of 9.21(s, 1H).

Stage 6: 1-(2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-yl)-3-Tien-2-improper-1-he

To a solution of 2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylic acid (24 mg, 1 EQ.) in a mixture of dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml) was added carbonyldiimidazole (10.5 mg, 1.3 EQ.) in the solution with chloroform (0.2 ml). The mixture was stirred for 15 hours at approximately 20°C, then was added thiophene-2-ethylamine (13 mg, 2 EQ.) in the solution with tetrahydrofuran (0.1 ml). After stirring for 15 hours at approximately 20°C to the mixture dissolved in dichloromethane, was added aminomethyl polystyrene resin (2 EQ.), TBD-methyl polystyrene resin (2 EQ.) and methylisothiocyanate polystyrene resin (4 EQ.). After stirring for 6 hours at approximately 20 ° C and the mixture was filtered and the filtrate was concentrated under reduced pressure at 40°C to obtain the expected compound in the form of an oil (27 mg, 90%yield).

MS/LC: calculated MW = 598,8; m/z = 599,2 (MH+)

NMR(1H, 400 MHz, DMSO-d6):to 1.87(m, 2H), and 2.26(s, 3H), 2,48(t, 2H,3J=6.5 Hz), 2,78(m, 2H), with 2.93(t, 2H,3J=7 Hz), is 3.08(t, 2H,3 J=7 Hz), 3,50(m, 2H), and 3.72(s, 6N), 4,14(t, 2H,3J=6.5 Hz), 6,14(m, 1H), 6,92-to 7.93(m, N), to 8.45(m, 1H), 9,16(s, 1H).

The following compounds were obtained according co the reaction scheme With the same method described for the synthesis of 1-(2-[(3,5-acid)amino]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-yl)-3-Tien-2-improper-1-it:

In the above formula, R1,R2N represents one of the following radicals:

R3is one of the following radicals:

and R4is one of the following radicals:

D.Receive under co by the reaction scheme D:

The compounds of formula I in accordance with this invention, where Y represents-S-, and a represents-C(O)-, can be obtained in accordance with the following scheme D:

As shown in scheme D, Danilin (10) can be processed by thiocarbonyldiimidazole (TCD) or thiophosgene in an inert organic solvent, such as tetrahydrofuran, at room temperature for 2-17 hours with derivatization (14). The compound (14) then alkilirovanie by interacting with halogenated PR is iswalnum, such as alkyl or benzyl iodide, bromide or chloride or bracton, in the presence of a tertiary base such as triethylamine or diisopropylethylamine, in an inert organic solvent, such as tetrahydrofuran, chloroform or methylene chloride, at a temperature of 20-70°C for 3-24 hours with obtaining dibenzylidene derivative (15). Then methyl ester (15) can be zapolirovan in the presence of inorganic bases, such as the monohydrate of lithium hydroxide, in a mixture of polar solvents such as water and tetrahydrofuran, at a temperature of 20-70°C for 3-17 hours. The resulting acid (16) can be connected with primary or secondary amine in the presence of a binding agent, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or carbonyldiimidazole, with or without 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide, at room temperature for 3-24 hours. The corresponding amide (17) can be selected either by using flash chromatography on silica gel or by adding to the reaction mixture nucleophilic agent to the polymeric substrate, such as, for example, aminomethylpyrimidine resin, and an electrophilic agent in a polymeric substrate, such as, for example, Methylisothiazolinone resins is, subsequent filtration and evaporation of the filtrate.

Example D1: 3-(2-[(3-bromobenzyl)sulfanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazole-l-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine

Stage 1: methyl 1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxylate

A mixture of methyl 3-amino-4-({3-[methyl(2-pyridin-2-retil)amino]propyl}amino)batata (4.09 g, 1 EQ.) and thiocarbonyldiimidazole (2,77 g, 1.3 EQ.) in tetrahydrofuran (100 ml) was stirred at approximately 20°C for 15 hours. After concentration under reduced pressure at 40°C, the precipitate was placed in dichloromethane (150 ml) and water (50 ml). After desantirovaniya and extraction, the combined organic phases are washed with aqueous saline solution, dried over Na2SO4, then was evaporated under reduced pressure at 40°C. Purification using flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) gave the expected compound in the form of foam (3.94 g; 85%yield).

MS/LC: calculated MW = 384,5; m/z = 385,2 (MH+)

NMR(1H, 400 MHz, DMSO-d6):to 1.86(m, 2H), 2,18(s, 3H), is 2.37(t, 2H,3J=6,8 Hz)to 2.65(t, 2H,3J=7 Hz), 2,84(t, 2H,3J=7 Hz), 3,85(s, 3H), of 4.16(t, 2H,3J=7 Hz), 7,16-7,81(m, 6N), 8,44(m, 1H), 12,95(s, 1H).

Stadia : methyl 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylate

The triethylamine (of 0.82 ml, 1.6 EQ.) and 3-bromobenzylamine (0.97 g, 1 EQ.) successively added to a solution of methyl 1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-thioxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (1.5 g) in tetrahydrofuran (30 ml). The mixture was stirred for 15 hours at approximately 20°C, then concentrated under reduced pressure at 40°C. the precipitate was dissolved in ethyl acetate and water. After desantirovaniya and extraction of the organic phase is washed with aqueous saline solution, dried over sodium sulfate and concentrated under reduced pressure at 40°C. Purification using flash chromatography on silica gel (eluent: dichloromethane/methanol from 95/5 to 90/10) to give the expected compound as a colourless oil (1.5 g, 70%yield).

MS/LC: calculated MW = 553,5; m/z = 553,3 (MH+)

NMR(1H, 400 MHz, DMSO-d6):to 1.76(m, 2H), and 2.14(s, 3H), and 2.27(t, 3H),3J=6.5 Hz), 2,62(t, 2H,3J=7 Hz), of 2.81(t, 2H,3J=7 Hz), 3,86(s, 3H), 4,06(t, 2H,3J=7 Hz), br4.61(s, 2H), 7,15-of 7.82(m, N), 8,13(s, 1H), 8,43(d, 1H).

Stage 3: 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylic acid

The lithium hydroxide (0,315 g, 3 EQ.) was added to a solution of methyl 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-p is ridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylate (1,03 g, 1 EQ.) in a mixture of tetrahydrofuran (10 ml) and water (5 ml). The mixture was boiled under reflux for 18 hours, then cooled to room temperature and concentrated under reduced pressure at 40° C. To the precipitate was added ethyl acetate and water. The mixture was acidified by adding acetic acid to pH 5. After desantirovaniya and extraction, the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Purification using flash chromatography on silica gel (eluent: dichloromethane/methanol from 95/5 to 80/20) to give the expected compound in the form of a foam of 0.85 g, 85%yield).

MS/LC: calculated MW = 539,5; m/z = 539,2 (MH+)

NMR(1H, 400 MHz, DMSO-d6):to 1.76(m, 2H), and 2.14(s, 3H), 2,29(t, 3H),3J=6.5 Hz), 2,62(t, 2H,3J=7 Hz), 2,82(t, 2H,3J=7 Hz), Android 4.04(t, 2H,3J=7 Hz), br4.61(s, 2H), 7,15-of 7.82(m, N), 8,10(s, 1H), 8,43(d, 1H).

Stage 4: 3-(2-[(3-bromobenzyl)sulfanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazole-1-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine

To a solution of 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxylic acid (27 mg, 1 EQ.) in a mixture of dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml) was added carbonyldiimidazole (10.5 mg, 1.3 EQ.) in the solution with chloroform (0.2 ml). The mixture was stirred for 15 hours at approximately 20�B0; C, and then were added 4-(1-pyrrolidinyl)piperidine (15 mg, 2 EQ.). After stirring for 15 hours at approximately 20°C to the mixture diluted in dichloromethane, was added aminomethyl polystyrene resin (2 EQ. purchased from Novabiochem), TBD-methyl polystyrene resin (2 EQ. purchased from Novabiochem) and methylisothiocyanate polystyrene resin (4 equiv. purchased from Novabiochem). After stirring for 6 hours at approximately 20°C the mixture was filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain the expected compound in the form of an oil (28 mg, 84%yield).

MS/LC: calculated MW = 675,7; m/z = 674,2 (MH+)

NMR(1H, 400 MHz, CDCl3):1,4-of 1.98(m, 10H), and 2.26(s, 3H), 2,32(m, 5H), 2,60 is 3.15(m, 8H), 3,81(m, 1H), 4,01(t, 2H,3J=7 Hz), 4,50(m, 1H), 4,57(s, 2H), 7,08-7,72(m, 10H), 8,51(d, 1H).

The following compounds were obtained according co the reaction scheme D and the same method described for the synthesis of 3-(2-[(3-bromobenzyl)sulfanyl]-5-{[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl}-1H-benzimidazole-1-yl)-N-methyl-N-[2-(2-pyridinyl)ethyl]-1-propanamine:

In the above formula, R1,R2N represents one of the following radicals:

R3is one of the following radicals:

and R4is one of the following radicals:

E.Receive under co by reaction scheme E:

The compounds of formula I according to this invention, where a represents -(CH2)-can be obtained from compounds where a represents-C(O)-, in accordance with the following scheme E:

As shown in scheme E, amide (18)obtained in accordance with reaction schemes a or B, can be restored to the corresponding amine (19)using borane or alumoweld lithium in an aprotic solvent such as tetrahydrofuran or diethyl ether, at temperatures from 0 to 70°C for 1-6 hours.

Example E1: 5-[(diisobutylamine)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethyl]amino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine

Molar solution of lithium aluminum hydride in tetrahydrofuran (0,83 ml, 5 EQ.) was added dropwise to a solution of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (105 mg, 1 EQ., obtained in accordance with example A1), cooled to 0°in tetrahydrofuran (3 ml). After stirring for 15 minutes at 0° C, the mixture was heated at 60°C for 3 hours, then was cooled to 0°C and hydrolyzed. After adding ethyl acetate, desantirovaniya and extraction, the combined organic phases are washed with aqueous salt solution, then dried over sodium sulfate and concentrated under reduced pressure. Purification using flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) gave the expected compound in the form of foam (63 mg, 62%yield).

MS/LC: calculated MW = 616,8; m/z = 617,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,81(d, N), or 1.77(m, 2H), to 1.86(m, 2H), 2.06 to(d, 4H), 2,24(s, 3H), 2.49 USD(t, 2H,3J=6 Hz), is 2.74(t, 2H,3J=7 Hz), 2.91 in(t, 2H,3J=7 Hz), of 3.48(s, 2H), 3,62(s, 3H), of 3.78(s, 6N), of 4.05(m, 2H), 6,97(d, 1H), 7,13-of 7.24(m, 5H), 7,63(m, 1H), 8,43(d, 1H), to 8.94(s, 1H).

F.Receive under co by reaction scheme F:

The compounds of formula I according to this invention where Y is-S - and-NH-, and a represents a-CH2-can be obtained in accordance with the following scheme F:

As shown in scheme F, the derivative (3) can be restored to a connection (20)using borane in an aprotic solvent such as tetrahydrofuran or diethyl ether, at temperatures from 0 to 70°C for 18-24 hours. Then dianiline (20) can be processed by isothiocyanates in risotti a bonding agent without or on a polymer substrate, such as diisopropylcarbodiimide or dicyclohexylcarbodiimide, or N-methylcyclohexylamine N-methyl polystyrene resin, in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, at a temperature of 20-70°C within 2-72 hours of obtaining the derivative (21). Alternative derivative (4) can be processed by isothiocyanates in an inert solvent, such as tetrahydrofuran, methylene chloride or chloroform, and the resulting thiourea can be processed by methyliodide in a polar solvent such as ethanol, for 3-24 hours at a temperature of 20-70°C) to obtain compound (21).

As also shown in the reaction scheme B in example B1, Danilin (20) can be processed by thiocarbonyldiimidazole (TCD) or thiophosgene in an inert organic solvent, such as tetrahydrofuran, methylene chloride or chloroform, at room temperature for 2-17 hours with derivatization (22). Compound (22) then alkilirovanie by interacting with halogenated derivatives, such as alkyl - or benzylated, bromide, or chloride, or bracton, in the presence of a tertiary base such as triethylamine or diisopropylethylamine, or in the presence of a tertiary base polymer substrates, such as morpholinobutyrophenone resin, in an inert organic rest retele, such as tetrahydrofuran, chloroform or methylene chloride, at a temperature of 20-70°C for 3-24 hours. Received dibenzylidene derivative (23) can be allocated either on silica gel or by adding to the reaction mixture nucleophilic agent to the polymeric substrate, such as, for example, aminomethylpyrimidine resin, and an electrophilic agent in a polymeric substrate, such as, for example, 4-promotingdecentralization resin, followed by filtration and evaporation of the filtrate.

Example F1: 5-[(diisobutylamine)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethylamino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine

Stage 1: 4-[(diisobutylamine)methyl]-N-(3-{methyl[2-(4-pyridinyl)ethyl]amino}propyl)-1,2-benzydamine

Molar solution of a complex of boron-tetrahydrofuran (6.25 ml, 15 EQ.) was added dropwise to a solution of N,N-Diisobutyl-4-({3-[methyl(2-pyridin-4-retil)amino]propyl}amino)-3-nitrobenzamide (200 mg, 1 EQ.) in tetrahydrofuran (3 ml), cooled to 0°C. the Mixture was boiled under reflux for 20 hours, then was cooled to 0°C and hydrolyzed in 6N. aqueous solution of hydrochloric acid (12 ml). After 1 hour 30 minutes, the mixture was cooled to 0°With a reflux condenser and using 6 N. aqueous solution of soda brought to alkaline pH. After adding utilized the TA desantirovaniya and extraction of the organic phase was combined, and then washed with aqueous saline solution, dried over sodium sulfate and evaporated under reduced pressure. Purification using flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 8:2) gave the expected compound in the form of oil (92 mg, 51%yield).

MS/LC: calculated MW = 425,6; m/z = 426,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,83(d, N), 1,72(m, 4H), 2,03(d, 4H,3J=7 Hz), of 2.23(s, 3H), 2,48(t, 2H,3J=7 Hz), 2,60(t, 2H,3J=7 Hz), a 2.75(t, 2H,3J=7 Hz), 2,96(m, 2H), 3,38(s, 2H), 4,30(m, 3H), 6,30(d, 1H), 6.42 per(d, 1H), 6,51(s, 1H), 7,25(d, 1H), 7,45(m, 1H), to 8.41(m, 2H).

Stage 2: 5-[(diisobutylamine)methyl]-1-(3-{methyl[2-(2-pyridinyl)ethyl]amino}propyl)-N-(3,4,5-trimethoxyphenyl)-1H-benzimidazole-2-amine

To a solution of 4-[(diisobutylamine)methyl]-N-(3-{methyl[2-(4-pyridinyl)ethyl]amino}propyl)-l,2-benzydamine (90 mg, 1 EQ.) in tetrahydrofuran (2 ml), was added 3,4,5-trimethoxyphenethylamine (57 mg, 1.2 EQ.) and N-methylcyclohexylamine-N-methyl polystyrene resin (acquired from Novabiochem; loading was 1.69 mmol/g, 501 mg, 4 EQ.). The mixture was boiled under reflux for 18 hours, then cooled to room temperature and added aminomethylpropanol resin (acquired from Novabiochem, 2 EQ.). After stirring for 4 hours at room temperature, the mixture was filtered on a Frit and Phi is Trat concentrated under reduced pressure at 40° C. Purification using flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) gave the expected compound in the form of a beige foam (92 mg, 83%yield).

MS/LC: calculated MW = 616,8; m/z = 617,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,81(d, N), or 1.77(m, 2H), to 1.86(m, 2H), 2.06 to(d, 4H), 2,22(s, 3H), 2,31(t, 2H,3J=6 Hz), to 2.55(t, 2H,3J=7 Hz), a 2.71(t, 2H,3J=7 Hz), 3,49(s, 2H), 3,68(s, 3H), of 3.77(s, 6N), 4,11(m, 2H), 6,99(d, 1H), 7,13-7,25(m, 6N), 8,39(d, 2H), of 8.90(s, 1H).

G.Receive under co by reaction scheme G:

The compounds of formula I according to this invention, where a represents-C(O)- and R4is a NW4W'4can be obtained in accordance with the following scheme G:

As shown in scheme G, benzimidazole derivative (24), obtained in accordance with reaction schemes A, B, C or D, may be treated with an organic or inorganic acid, such as triperoxonane acid or hydrogen chloride (aqueous or gaseous form), in an aprotic solvent such as dichloromethane or ethyl acetate, at a temperature of 0-20°C for 0.5-5 hours to obtain an amine (25). Amin (25) can then be treated with an epoxide in the proton or an aprotic polar solvent such as methanol, ethanol or acetonitrile, in prisutstvie and or in the absence of lithium perchlorate or triflate ytterbium at a temperature of 20-80° C for 4-48 hours to obtain compound (26). Amin (25) may also interact with the aldehyde in a proton or an aprotic solvent such as dichloromethane, tetrahydrofuran or methanol, for 1-15 hours at a temperature of 0-50°C. the resulting Imin then restoredin situusing a reducing agent without or on a polymeric substrate, preferably using sodium triacetoxyborohydride on a polymer substrate, sodium cyanoborohydride or borohydride, in the presence or in the absence of acid, such as acetic acid, at a temperature of from 20 to 50°C for 0.2 to 5 hours to obtain compound (27).

Compounds 27, where s = 3, can also be obtained in accordance with the following scheme G':

As shown in the diagram G'derived (30)obtained in accordance with reaction schemes A, B, C or D, may be processed or organic acid, such as pyridine, toilet or paratoluenesulfonyl acid, in an aprotic solvent, such as acetone, in the presence of water at a temperature of 20-70°C for 2-12 hours or inorganic acid, such as aqueous hydrogen chloride in an aprotic solvent such as tetrahydrofuran. at a temperature of 0-20°C for 6-18 hours to obtain the compound (31). Then the aldehyde (31) can be processed amino is a proton or an aprotic solvent, such as dichloromethane, tetrahydrofuran or methanol, for 1-18 hours at a temperature of 20°C. the resulting Imin then restoredin situusing a reducing agent, preferably using sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or in the absence of acid, such as acetic acid, at a temperature of 20-50°C for 0.2 to 6 hours to obtain compound (27').

Example G1: 1-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

Stage 1: hydrochloride 1-(2-amino-ethyl)-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

A stream of dry HCl was passed through a solution of tert-butyl 2-{5-[(diisobutylamine)carbonyl]-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-1-yl}ethylcarbamate (2,56 g, obtained in accordance with the method described in example A1, the reaction scheme (A) in ethyl acetate (100 ml) (100 % ethyl acetate) was cooled to 0°C until complete disappearance of the original product, as determined by TLC. The mixture then was evaporated under reduced pressure. The obtained solid product was ground into powder with titilation and filtered to obtain the expected compound in the form of white crystals (2.25 g, 97%yield).

MS/LC: calculated MW = 497,6; m/z = 498,3 (MH+)

NMR(1H,400 MHz, DMSO-d6):of 0.67(m, 6N), to 0.92(m, 6N), 1,84-2,03(m, 2H), 3,10-3,17(m, 4H), to 3.38(m, 2H), 3,71(s, 3H), 3,81(C, 6N), was 4.76(m, 2H), 6,93(s, 2H), 7,30(m, 2H), 7,81(d, 1H), 8,56(m, 3H).

Stage 2: 1-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

A solution of 1-(2-amino-ethyl)-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (30 mg, 1 EQ.) and cyclohexanecarboxaldehyde (5 mg, 0.8 EQ.) in methanol (0.7 ml) was stirred at a temperature of approximately 20°C for 4 hours. Added borhydride polymer (48 mg, 2.5 mmol/g, Amberlite ®IRA-400), and the mixture was stirred for 18 hours, then was added dichloromethane (0.5 ml) and benzyloxybenzaldehyde polymer Wang (37 mg, up 3.22 mmol/g, Novabiochem). After stirring overnight the mixture was filtered and the filtrate was evaporated under reduced pressure to obtain the expected compound in the form of a beige foam (18 mg, 65%).

MS/LC: calculated MW = of 593.8; m/z = 594,4 (MH+)

NMR(1H, 400 MHz, CDCl3):0,65 and 1.80(m, N), 2,60(d, 2H), 3,13(m, 2H), 3,82(s, 3H), 3,90(C, 6N), 4,10(m, 2H), 6,91(s, 2H), 7,07; 7,16(AB, 2H), 7,53(s, 1H), 10,1(s, 1H).

The following compounds were obtained according co the reaction scheme G, and in the same way described for the synthesis of 1-{2-[(cyclohexylmethyl)amino]ethyl}-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (also held OK Natalino purification using flash chromatography on silica gel):

In the above formula, R4represents one of the following radicals:

Example G2:1-{2-[(1-hydroxy-2-phenylethyl)amino]ethyl}- N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide

To a solution of 2,3-epoxypropanol (7 mg, 1 EQ.) in acetonitrile (0.5 ml) was added perchloric lithium (16 mg, 3 EQ.), and after 5 minutes, 1-(2-amino-ethyl)-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (25 mg, 1 EQ.) at a temperature of approximately 20 C. the Mixture is boiled under reflux for 24 hours, then was cooled to ambient temperature and added water, saturated bicarbonate and dichloromethane. After desantirovaniya and extraction of the organic phase were combined and washed with aqueous salt solution, and then dried over magnesium sulfate and evaporated under reduced pressure at 40 C. Purification of the resulting oil by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) gave the expected compound in the form of oil (31 mg, 55% yield).

MS/LC: calculated MW = 631,8; m/z = 632,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,83(m, 6N), of 0.91(m, 6N), 1,81 is 2.10(m, 2H), 2.57 m-to 2.65(m, 3H), 2.91 in(m, 2H), 3,21(m, N), 3,62(s, 3H), of 3.75(m, 7H), 4,22(m, 2H), 4,74(d, 1H), 6,97-7,33(m, 10H).

The following compounds were obtained according co the reaction scheme G, and in the same way described for the synthesis of 1-{2-[(1-hydroxy-2-phenylethyl)amino]ethyl}-N,N-Diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide:

in the above formula, R4represents one of the following radicals:

H.Receive under co by reaction scheme H:

The compounds of formula I according to this invention, where a represents-C(O)-, Y represents-S-, and R3represents -(CH2)p-CH(OH)-(CH2)p-Z3can be obtained in accordance with the following scheme H:

As shown in scheme H, dibenzylidene derivative (28)obtained in accordance with reaction schemes a, B, or D, may be treated regenerating agent such as sodium borohydride, in proton solvent such as methanol, at a temperature of 0-20°C for 0.2 hour to 1 hour to obtain the corresponding alcohol (29).

Example H1: 2-{[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-1H-benzimidazole-5-carboxamide

Sodium borohydride (8 is g, 2 EQ.) was added at 0°C to a solution of N,N-Diisobutyl-1-{3-[methyl(2-pyridin-2-retil)amino]propyl}-2-{[2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl]thio}-1H-benzimidazole-5-carboxamide (69 mg, 1 EQ.) in methanol (2 ml). After stirring for 10 minutes at 0°C the mixture is brought up to a temperature of about 20°C and stirred at this temperature for 30 minutes. The mixture is then concentrated under reduced pressure at 40°C, then added water, saturated ammonium chloride and dichloromethane. After desantirovaniya and extraction of the organic phase were combined and washed with aqueous saline solution, dried over sodium sulfate and evaporated under reduced pressure at 40 C. Purification of the resulting oil by flash chromatography on silica gel (100% dichloromethane to dichloromethane/methanol 80:20) gave the expected compound in the form of oil (61 mg, 88%yield).

MS/LC: calculated MW = 691,9; m/z = 692,4 (MH+)

NMR(1H, 400 MHz, DMSO-d6):0,61(m, 6N), of 0.91(m, 6N), 1,71-2,03(m, 4H), 2,17(s, 3H), 2,31(t, 3H),3J=6.5 Hz), to 2.65(t, 2H,3J=7 Hz), 2,85(t, 2H,3J=7 Hz), is 3.08-3,30(m, 4H), of 3.56(m, 1H), 3,60(s, 3H), 3,71(m, 1H), 3.75 to(C, 6N), of 4.05(t, 2H,3J=7 Hz), a 4.86(m, 1H), by 5.87(d, 1H), 6.75 in(s, 2H), 7,11-the 7.65(m, 6N), 8,43(d, 1H).

Receiving agents synthesis

N-(2-pyridin-2-yl ethyl)propane-1,3-diamine

To the solution was cooled to approximately 4°C, 2-[2-(meth the laminitis)ethyl]pyridine (19,5 ml, 1 EQ.) in methanol (200 ml) was slowly added Acrylonitrile (10.1 ml, 1.1 EQ.). The reaction medium was then stirred for 3 hours at approximately 20°C, then concentrated under reduced pressure at 40°C with 3-[(2-pyridin-2-retil)amino]propanenitrile in the form of a yellow oil (25.6 g, 96%yield).

The solution of this oil (15.3 g) in methanol saturated with ammonia, (250 ml) then was first made in the presence of Raney Nickel (1.5 g) at about 20°C for 15 hours. The reaction mixture was then filtered through celite. The filtrate was concentrated under reduced pressure at about 40°C to obtain the expected compound in the form of a greenish oil (15.5 g, 97%yield).

The following compounds were obtained by the same method described for the synthesis of N-(2-pyridin-2-retil)propane-1,3-diamine:

2-bromo-1-(3,4,5-trimethoxyphenyl)alanon

The hydrobromide of perbromide pyridine on a polymer substrate (23, g, 1 EQ.) was added to a solution of 3,4,5-trimetoksi-acetophenone (10 g, 1 EQ.) in methanol (150 ml). After stirring for 3 hours at approximately 20°C the mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the resulting sludge using flash chromatography on silica gel (eluent: heptane/ethyl acetate 8/2, then 7/3) gave the expected compound in the form of a white p the Rosca (8,2 g, 60%yield). Melting point = 66°C.

3,4,5-trimethoxybenzoyl isothiocyanate

The potassium thiocyanate was added to a solution of 3,4,5-trimethoxybenzylamine (2.3 g) in acetonitrile (40 ml). After stirring for 15 minutes at approximately 20°C, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the expected compound in the form of a beige powder (2.4 g, 96%yield). Melting point = 101°C.

Compound I (or I') according to the present invention have an effective pharmacological properties. Thus, it was found that compound I (or I') according to the present invention have antagonism against GnRH (gonadotropin releasing hormone).

Thus, the compounds of the present invention may have broad therapeutic application. They can be effectively used in women to treat endometriosis, fibroids, polycystic ovary syndrome, breast cancer, ovary and endometrium, gonadotropic pituitary desensitization with medication ovarian stimulation for fertility treatment; men in the treatment of benign prostatic hyperplasia and prostate cancer; and in the treatment of premature puberty in men and women. Examples of pharmacological use of compounds according to this invention can be found below, in the experimental frequent is.

The object of the present invention are also products of the above formula I (or I')that are used as medicines, as well as salts of addition of pharmaceutically acceptable inorganic or organic acids specified products of formula I (or I'), as well as pharmaceutical compositions containing as active ingredient at least one drug, above, in combination with a pharmaceutically acceptable carrier.

The pharmaceutical composition may be in solid form, for example, in the form of powders, granules, tablets, gelatin capsules or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing a compound according to this invention, can also be in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions, in water with the addition of pharmaceutically acceptable oils or fats. Sterile liquid composition can be used for vnutrimy echnik, intraperitoneal or subcutaneous injection, and sterile compositions can also be administered intravenously.

The values of all special and scientific terms used herein are well understood by a person skilled in this field. Moreover, all patents (or patent applications), and other references listed in the reference.

Experimental part:

Compounds according to this invention obtained in accordance with the methods of examples A, B, C, D, E, F, G, and H, described previously, are listed in the table below.

Compounds described by their delay time (wresaling.) and their molecular peak, identified through mass spectrometry (MH+).

For mass spectrometry was used uniform quadrupole mass spectrometer (Micromass, Platform model), equipped with a source ofelektrorazpredeleniewith a resolution of 0.8 Yes with 50% of the valley. Calibration was carried out monthly in the mass region 80-1000 Yes, using a calibration mixture of sodium iodide and rubidium iodide in a solution of a mixture of isopropanol/water (1/1 vol./vol.).

For liquid chromatography used system Waters, including the line degasser, a Quaternary noses Waters 600, the applicator of the samples on the plate Gilson 233 and UV detector Waters 996 PDA.

Used the following elution conditions:

Eluent And water + 0,04% trithorax SNA acid

In acetonitrile

T (min)A%B%
1955
8,5595
10,5595
10,6955
14,9955
15,0955

Flow rate: 1 ml/min

Injection: 10 µl

Column 3 μm 75×4.6 mm e Uptisphere ODS

These examples are presented to illustrate the methods above, and not in any way intended to limit the scope of the present invention.

In each example, the radicals R1, R2, R3and R4the radicals X1X2X3and X4represent respectively the rest of the compounds of General formula (I).

Examples 1-253, 254-255 and 256-538 illustrate, respectively, of compound I, where a represents-C(O)-, and Y represents-S-, And a represents a-CH2-, and Y is-NH-, and a represents-C(O)- and Y represents-NH-.

Pharmacological study

Antagonizes activity of GnRH compounds of this invention were measured in sootvetstviis the following protocols:

Obtaining a stable line, transfected receptor LHRH person

cDNA LHRH receptor human cloned into the site expressing vector pCDNA3 mammalian,1 (InVitrogen Lie). This plasmid construct was transferrable using Effectene according to the manufacturer's recommendations (Qiagen), the cell line derived from embryonic human kidney, HEK-293 (ATCC) and were breeding in DMEM containing 0.5 mg/ml geneticin. Cells containing the expression vector of the LHRH receptor, and then cloned by limited dilution, then multiplicatively in culture. These cloned cells are then examined for the expression of LHRH receptor of the person by means of tests on competitive inhibition of communications and conducting measurement of Inositol phosphates.

Cell culture and obtaining membranes

Cells HEK-293 stably expressing the receptor LHRH person, as described above, was konturirovany in DMEM containing 10% fetal calf serum and supplemented with 0.4 mg/ml geneticin (G418, Sigma Chemical Company). Cells were separated from culture medium with 0.5 mm EDTA and centrifuged at 500 g for 10 minutes at 4°C. the Cell precipitate was washed with 50 mm Tris, pH 7.4 and centrifuged twice at 500 g for 10 minutes. In conclusion, the cells were literally ultrasound, and then was centrifuged at 39000 g for 10 minutes at 4°C is adok resuspendable in 50 mm Tris 50, pH 7.4 and centrifuged at 50000 g for 10 minutes at 4°C to obtain sediment membranes, which then was divided into several aliquot and stored at -80°C before use.

Study of the affinity towards the receptor LHRH person

The affinity of the compounds according to this invention in relation to the LHRH receptor of a person was determined by measuring inhibition of binding of [125I-Tyr5]-DTrp6-LHRH on human cells transfected with cDNA of the receptor LHRH person.

The study of competitive inhibition of binding of [125I-Tyr5]-DTrp6-LHRH was performed in 96-hole polypropylene dies, duplicating them. The cell membranes of HEK-293 stably expressing the receptor LHRH person (20 μg protein/well), incubated in the presence of [125I-Tyr5]-DTrp6-LHRH (0.2 nm) for 60 minutes at 4°C in a medium containing 50 mm Tris/HCl, pH 7,4, bacitracin 0.1 mg/ml BSA in 0.1% (1 mg/ml).

Related [125I-Tyr5]-DTrp6-LHRH was separated from free [125I-Tyr5]-DTrp6-LHRH by filtering through filtrowanie plates of glass fiber GF/C Unifilter, Packard), soaked in 0.1% polyethylenimine using FilterMate 96 (Packard). Then the filters were washed in 50 mm buffer Tris/HCl at 4°C for 4 seconds and using scintillation counter (Packard Topcount) was calculated radioactivity.

Specific binding was calculated after visit is of non-specific binding (determined in the presence of 0.1 μm DTrp 6-LHRH) from the total binding. Data related to the binding, were obtained using the analysis of nonlinear regression and determining values of the inhibition constants (Ki).

Determination of the parameters of agonism or antagonism of the compounds of the present invention was performed by the method described below.

Functional test: Inhibition of the production of intracellular Inositol phosphates

Cells HEK-293 stably expressing the GnRH receptor of man, he konturirovany in the amount of 200,000 cells per well in 24-hole plate coated with poly-D-lysine (Falcon Biocoat) in DMEM containing 10% fetal calf serum and 0.4 mg/ml geneticin, within 24 hours.

The medium was then replaced with DMEM without Inositol containing 10% fetal calf serum and 1 mccu/ml [3H]myoinositol (Amersham), for 16-18 hours at 37°C.

Cells were washed in DMEM without Inositol containing 10 mm lithium chloride, and incubated for 30 minutes at 37°C.

The production of Inositol phosphates stimulated by the addition of 0.5 nm DTrp6-LHRH for 45 minutes at 37°C.

The antagonistic effect of the compounds was measured by adding 0.5 nm DTrp6-LHRH, and the compounds with various increasing concentrations (example: from 10-10M to 10-5M).

Reaction medium was eliminated, was added 1 ml of 0.1 M formic is islote and incubated for 5 minutes at 4° C.

The plate was then frozen at -80°C, then thawed at room temperature.

Then on ion-exchange resin (Biorad) was separated Inositol phosphates from all intracellular Inositol, elwira 1 M ammonium formate and 0.1 M formic acid.

The amount of Inositol phosphates, left column, finally was measured in the presence stsintilliruyushchei liquid.

Results

Conducted in accordance with the above protocols, studies have shown that the products of General formula (I), as defined in this application, have good affinity against LHRH receptor, the inhibition constant Ki at this receptor below micromolar for specific examples of the compounds.

1. The compound of General formula

in racemic, enantiomeric form or any combinations of these forms,

where a represents a-CH2- or-C(O)-;

Y represents-S - or-NH-;

R1and R2represent, independently, a hydrogen atom, (C1-C8) alkyl, (C5-C9) bicycloalkyl, optionally substituted by one or more identical or different (C1-C6)alkyl radicals, or a radical of the formula -(CH2)n-X, where

X represents amino, di((C1-C6)alkylamino, (C3-C7)cycloalkyl, substituted, heteroseksualci, aryl, or heteroaryl, or a radical of the formula

where (C3-C7) cycloalkenyl, heterologously, aryl and heteroaryl radicals are optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-X'-Y', halogen, oxo, amino, (C1-C6)alkylamino and di((C1-C8)alkyl)amino;

X' represents-O-, -S-, -C(O)-O-, -NH-C(O)-, -NH-SO2- or a covalent bond;

Y' represents a (C1-C6)alkyl radical; heteroaryl, or aryl, or heteroseksualci, optionally substituted by one or more identical or different substituents selected from (C1-C6) alkyl, (C1-C6) alkoxy, halogen;

n is an integer from 0 to 6 and n' is an integer from 0 to 2;

or R1and R2together with the nitrogen atom to which they are attached, form heteroseksualci, heterobicyclic or a radical of the formula

where the radical formed together R1and R2not necessarily replaced by the ne or more identical or different substituents, selected from the

-(CH2)n"-X"-Y", oxo, hydroxy, halogen, nitro, cyano;

X represents-O-, -C(O)-, -C(O)-O - or a covalent bond;

Y" represents a (C1-C6)alkyl, di((C1-C6)alkyl)amino, (C3-C7)cycloalkyl, heteroseksualci, arylalkyl radical, or aryl or heteroaryl radical optionally substituted by one or more identical or different substituents selected from (C1-C6)alkyl, (C1-C6) alkoxy, (C1-C6)alkylsulphonyl, halogen; or a radical of the formula

n represents an integer from 0 to 4;

R3represents -(CH2)p-W3-(CH2)p'-Z3;

W3is a covalent bond, -CH(OH)- or-C(O)-;

Z3is a (C1-C6)alkyl, substituted, aryl radical, heteroaryl or a radical of the formula

where the aryl radical is optionally substituted by one or more identical or different substituents chosen from -(CH2)p"-V3-Y3, halogen, nitro,cyano, N3,hydroxy;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond;

Y3is a (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals, amino, di((C1-C6)alkyl)amino, phenylcarbonylamino, geterotsiklicheskie or aryl radicals;

R, R' and R" represent, independently, an integer from 0 to 4;

R4represents a radical of the formula -(CH2)s-R4;

R4is heteroseksualci containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen atom and optionally substituted (C1-C6)alkyl; or a radical of the formula-NW4W'4;

W4represents a hydrogen atom, (C1-C8) alkyl or (C3-C7) cycloalkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond, -CH2-CH(OH)-(CH2]t[O]t'[CH2]t- or-C(O)-O-;

t, t' and t" represent, independently, 0 or 1;

Z4represents a hydrogen atom, (C1-C8) alkyl, optionally substituted by one or more identical or different substituents selected is passed from (C 1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)acidity and hydroxy; and (C2-C6)alkenyl; and (C2-C6)quinil; and (C3-C7)cycloalkyl, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkyl, (C1-C6)alkoxycarbonyl and (C1-C6)hydroxyalkyl; cyclohexene; substituted; heteroaryl; aryl, optionally substituted by one or more identical or different radicals selected from the formula -(CH2)q-V4-Y4, hydroxy, halogen, nitro, cyano;

V4represents-O-, -NH-C(O)- or a covalent bond;

Y4is a (C1-C6)alkyl radical, optionally substituted di((C1-C6)alkyl)amino, a heterocyclic radical;

q" is an integer from 0 to 4;

or Z4represents a radical of the formula

s and s' represent, independently, an integer from 0 to 6,

or pharmaceutically acceptable salt of the latter.

2. The compound of formula I according to claim 1, characterized in that a represents-C(O)-; or a pharmaceutically acceptable salt of the latter.

3. The compound of formula I according to claims 1 and 2, characterized in that

p num="574"> cycloalkyl represented by X is a cyclohexyl or cycloheptyl,

heteroseksualci represented by X is selected from the

piperidine, pyrrolidine, thiazolidine, research and tetrahydrothiophene;

the aryl represented by X represents a phenyl, nattily or fluorenyl radical;

heteroaryl represented by X is selected from pyridine, imidazole, thiophene, indole, carbazole and isoquinoline;

heteroaryl represented by Y'is selected from oxazole and imidazole;

the aryl represented by Y'represents a phenyl radical;

heteroseksualci represented by Y'represents a piperazine;

heteroseksualci, which together with the nitrogen atom to which they are attached, form an R1and R2selected from piperidine, piperazine, diazepan, thiazolidine and research;

cycloalkyl represented by Y is cyclopentyl or cyclohexyl;

heteroseksualci represented by Y is selected from piperidine, pyrrolidine and research;

arylalkyl and aryl represented by Y are respectively the benzyl radical and the phenyl radical;

heteroaryl represented by Y is selected from pyridine, pyrazine, furan and thiophene; or a pharmaceutically acceptable salt of the latter.

4. The compound of formula I according to claim 1, great for the different themes, that

the aryl represented by Z3represents phenyl or nattily radical;

heteroaryl, presents Z3selected from benzo[b]thiophene and benzo[b]furan;

Y3are (C1-C6)alkyl radical, optionally substituted by one or more identical or different halogen radicals, amino, di((C1-C6)alkyl)amino, phenylcarbonylamino, heterocyclyl or aryl radicals.

5. The compound of formula I according to claim 1, characterized in that

heteroseksualci represented by R4selected from piperazine, piperidine, research and pyrrolidine;

heteroaryl represented by R4, is an imidazole;

(C3-C7)cycloalkyl, presents Z4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

heteroaryl, presents Z4selected from pyridine , thiophene, indole and furan;

the aryl represented by Z4represents phenyl or naphthyl;

Y4is a (C1-C6)alkyl radical, optionally substituted di((C1-C6)alkyl)amino

aralkyl, substituted on heteroseksualci, which together form W4and W'4represents a benzyl radical; or farmacevtichesky acceptable salt of the latter.

6. The compound of formula I according to claim 1, characterized in that a represents-C(O)- and R1and R2independently represent a hydrogen atom, ((C1-C8) alkyl radical or a radical of the formula -(CH2)n-X, where

X represents amino, di(alkyl)amino, adamantyl, cyclohexyl, cycloheptyl, piperidine, morpholine, pyrrolidine, phenyl, pyridine, imidazole, thiophene, indole, carbazole, optionally substituted (C1-C6)alkyl, or a radical of the formula

piperidine, pyrolidine and phenyl radicals optionally substituted by one or more identical or different substituents chosen from -(CH2)n'-X'-Y', halogen, oxo, amino and di((C1-C8)alkyl)amino;

X' represents-O-, -S-, -C(O)-O-, -NH-C(O)-, -NH-SO2- or a covalent bond;

Y' represents a (C1-C6)alkyl, oxazol, phenyl radical, optionally substituted (C1-C4)alkyl, or piperazine, optionally substituted (C1-C4)alkyl;

or R1and R2together with the nitrogen atom to which they are attached, form a piperidine, piperazine, diazepan, thiazolidine, morpholine or cyclic radical of the formula

the radical, which together form an R1and R2, optionally substituted by one or more identical or different substituents selected from

-(CH2)n-X"-Y"

X represents-C(O)-, -C(O)-O - or a covalent bond;

Y" represents a (C1-C6)alkyl; di(alkyl)amino, cyclopentenyl, tsiklogeksilnogo, piperidinyl, pyrolidine, morpholinyl, benzyl, pyridine, pyrazinoic, furan, titanovyi or phenyl radical, optionally substituted by one or more identical or different substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6) alkyl-carbonyl, and halogen; or Y is a radical of the formula

or pharmaceutically acceptable salt of the latter.

7. The compound of formula I according to claim 1, characterized in that a represents-C(O)- and R3represents -(CH2)p-W3-(CH2)p'-Z3;

W3is a covalent bond, -CH(OH)- or-C(O)-;

Z3is a (C1-C6)alkyl, phenyl, nattily, benzo[b]titanovyi, benzo[b]farnily radical or a radical of the formula

the phenyl radical, optionally substituted by one or more identical or different substituents chosen from -(CH2)R-V3-Y3, halogen, nitro, cyano;

V3represents-O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond;

Y3is a (C1-C6) alkyl radical, optionally substituted by one or more identical or different halogen; amino; di((C1-C6)alkyl) amino; phenylcarbonylamino; pyrolidine or phenyl radicals;

R, R' and R" independently is an integer from 0 to 2;

or pharmaceutically acceptable salt of the latter.

8. The compound of formula I according to claim 1, characterized in that a represents-C(O)-, and R4represents a radical of the formula -(CH2)s-R4;

R4represents piperidino ring, optionally substituted benzyl, piperazine, optionally substituted benzyl, or a radical of the formula-NW4W'4;

W4represents a hydrogen atom or a (C1-C8) alkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond, -CH2-CH(OH)-, -CH2-CH(OH)-CH2-O-, -CH2-CH(OH)-CH2,-CH 2-CH(OH)-CH2-O-CH2- or-C(O)-O-;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)acidity or one or two hydroxy; and (C2-C6)alkenyl; and (C2-C6)quinil; cyclopropyl radicals, optionally substituted by alkoxycarbonyl; cyclobutyl, cyclopentyl, optionally substituted hydroxyalkyl; cyclohexyl, optionally substituted by one or more alkilani; cycloheptyl, cyclohexen, substituted, pyridine, thiophene, indole, furan, naphthyl; phenyl radicals optionally substituted by one or more identical or different radicals selected from -(CH2)q-X4-Y4, hydroxy, halogen and cyano;

X4represents-O - or a covalent bond;

Y4is a (C1-C6)alkyl, di((C1-C6)alkyl)amino

or pharmaceutically acceptable salt of the latter.

9. The compound of formula I according to claim 1, characterized in that a represents-C(O)-, Y is-NH - and

R1and R2independently represent a (C1-C8)alkyl radical;

R3represents -(CH2)p-W3-(CH2)p'-Z ;

W3is a covalent bond;

Z3represents a phenyl radical substituted by one or more identical or different substituents chosen from -(CH2)R-V3-Y3and halogen;

V3represents-O - or-S-;

Y3is a (C1-C6)alkyl radical;

R, R' and R" 0;

R4represents a radical of the formula -(CH2)s-R4;

R4represents a radical of the formula-NW4W'4;

W4represents a hydrogen atom or a (C1-C8) alkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond;

Z4represents a hydrogen atom, (C1-C8)alkyl, optionally substituted hydroxy, (C3-C7)cycloalkyl, heteroaryl, aryl, optionally substituted by one or more identical or different radicals selected from the formula -(CH2)q-V4-Y4;

V4represents-O - or a covalent bond;

Y4is a (C1-C6) alkyl or di((C1-C6)alkyl)amino radical;

q is 0;

s R the VNO integer from 2 to 4;

s' is an integer from 1 to 2;

or pharmaceutically acceptable salt of the latter.

10. The compound of formula I according to claim 9, characterized in that (C3-C7)cycloalkyl selected from cyclopentyl and cyclohexyl, heteroaryl represents pyridine, and aryl represents phenyl; or a pharmaceutically acceptable salt of the latter.

11. The compound of formula I according to claim 1, characterized in that a represents-C(O)-, Y represents a sulfur atom, and

R1and R2independently represent a (C1-C8)alkyl radical;

R3represents -(CH2)p-W3-(CH2)p'-Z3;

W3is a covalent bond or-C(O)-;

Z3represents a phenyl radical substituted by one or more identical or different substituents chosen from -(CH2)R-V3-Y3and halogen;

V3represents-O - or a covalent bond;

and Y3is a (C1-C6)alkyl or di((C1-C6)alkyl)amino radical;

p is 1;

R' and R" 0;

R4represents a radical of the formula -(CH2)s-R4;

R4represents a radical of the formula-NW4W'4;

W4PR is dstanley a hydrogen atom or a (C 1-C8) alkyl;

W'4represents a radical of the formula -(CH2)s'-Q4-Z4;

Q4is a covalent bond;

Z4represents a hydrogen atom, (C1-C8)alkyl, heteroaryl, aryl;

s is an integer from 2 to 4, and s' is an integer from 1 to 2,

or pharmaceutically acceptable salt of the latter.

12. The compound of formula I according to claim 11, characterized in that heteroaryl represents pyridine and aryl represents phenyl or a pharmaceutically acceptable salt of the latter.

13. The compound of formula I according to claim 1, characterized in that a represents a-CH2-, Y is-NH - and R1and R2independently represent a (C1-C6)alkyl radical; R3represents phenyl substituted by one or more identical or different (C1-C6)alkoxy substituents; R4represents a radical of the formula -(CH2)s-R4; R4represents a radical of the formula-NW4W'4; W4represents a hydrogen atom or a (C1-C8) alkyl; W'4represents a radical of the formula -(CH2)s'-Q4-Z4; Q4is a covalent bond and Z4represents pyridine; or a pharmaceutically who ramlila salt last.

14. The compound of formula I according to claim 1 as a drug, which antagonists GnRH, as well as salts of addition of pharmaceutically acceptable inorganic or organic acids of the compounds of formula I.

15. Pharmaceutical composition, which is a GnRH antagonist containing as an active ingredient, at least one medicinal substance, as defined in 14, in combination with a pharmaceutically acceptable carrier.

16. The use of compounds according to any one of claims 1 to 13 when getting medicines for the treatment of endometriosis, fibroids, polycystic ovary syndrome, breast cancer, ovary and endometrium, gonadotropic pituitary desensitization with medication ovarian stimulation for the treatment of infertility in women.

17. The use of compounds according to any one of claims 1 to 13 when getting medicines for the treatment of benign prostatic hyperplasia and prostate cancer in men.

18. The use of compounds according to any one of claims 1 to 13 when getting medicines for the treatment of male and female premature puberty.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, chemical technology, pesticides.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein Q means nitrogen atom (N); Y means nitro-group (-NO2); Z means -NR3; R1 and R2 mean in common alkylene bridge that comprises two or three carbon atoms and, optionally, a heteroatom chosen from the group comprising -NR5 and oxygen atom (O); R3 means unsubstituted (C1-C12)-alkyl; R5 means hydrogen atom (H) or (C1-C12)-alkyl. Method involves the following steps: (a) interaction of compound of the formula (II): wherein X means a leaving group with a halogenated agent to yield compound of the formula (III): wherein W means halogen atom and wherein treatment of compound of the formula (III) involves extraction of compound of the formula (III) with hydrochloric acid taken in the concentration 10-50 wt.-%, and (b) interaction of the synthesized compound of the formula (III) with compound of the formula (IV): wherein R1, R2, Y, Z and Q have above given values. In the process for synthesis of compound of the formula (III) the stage (a) involves purification stage wherein formed crude product is treated with water at acid range of pH values.

EFFECT: improved method of synthesis.

3 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 47 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of mycophenolate mofetil. Method involves the direct esterification of mycophenolic acid and 2-morpholinoethanol. The esterification reaction is carried out by boiling in ethers medium as a solvent of the general formula R3OR4 wherein R3 and R4 mean independently alkyl. Method involves using from 1.01 to 3.0 mole equivalents of 2-morpholinoethanol. The initial temperature of reaction is in the range 130-138°C and the final temperature of reaction is in the range 140-145°C, and the reaction period is from 5 to 50 h. The ratio of mycophenolic acid to solvent is in the range from 1 g/2 ml to 1 g/5 ml. Invention avoids problems associated with coloring mycophenolate mofetil, low solubility of product in higher ethers.

EFFECT: improved method of synthesis.

8 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivative of phenylpiperazine mesylate of the formula: possessing preferable properties as compared with form of a free base of the same compound. Also, invention describes a pharmaceutical composition and a method for inhibition of activity of dopamine D2-receptors and site of serotonin reuptake.

EFFECT: valuable pharmacological properties of derivatives.

3 cl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

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