Imidazolidine-2,4-dione derivatives, possessing antiproliferative activity

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely, to novel heterocyclic compounds of the general formula or to their pharmaceutically acceptable salts, where R1 stands for cyano, nitro, amino, -NHCOOR4 or -NHCOR4; R2 stands for a halogen, C1-alkyl, halogenC1-alkyl or C1-alkoxy; R3 stands for C1-alkyl; or both radicals R3 form a cycloalkyl, containing 3 members, together with carbon atom, which they are bound to; X stands for either an alkylene chain of 4-7 carbon atoms, linear or branched, and the said chain can contain one or several similar or different additional units, selected from -O-, -N(R5)-; either a group where n1 and p1 stand for two integer numbers, the sum of which n1+p1 is an integer number, selected from 2; R6 and R7 together form a covalent bond or R6 and R7 together with carbon atoms, which they are bound to, form a cycle or a cycloalkyl, containing 3 members; R4 stands for C1-alkyl; R5 stands for C1-alkyl. The invention also relates to particular compounds, a pharmaceutical composition based on formula (I), application of the formula (I) compound.

EFFECT: obtained are the novel heterocyclic compounds, useful in treating cancer.

23 cl, 10 dwg, 23 ex

 

The scope to which the invention relates

The object of the present application are new derivatives imidazolidin-2,4-dione. These products possess antiproliferative activity. They are of particular interest for the treatment of pathological conditions and diseases associated with abnormal cell proliferation such as cancer. The invention also relates to pharmaceutical compositions comprising said products and their use to obtain the drug.

The level of technology

In these days cancer is one of the leading causes of death, despite the presence of many molecules in the pharmaceuticals market.

Therefore, a need exists for new and more powerful molecules that provides the best anti-tumor response due to the high inhibitory activity against the proliferation of tumor cell colonies.

Such molecules are of particular interest for the treatment of pathological conditions associated with abnormal cellular proliferation. They can therefore be used for the treatment of tumors and cancers, such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervical, endometrial, ovarian,

prostate, testis, bladder, kidney, liver, pancreas, �awn, connective tissue, skin, such as melanoma, eye, brain and Central nervous system, and thyroid cancer, leukaemia, Hodgkin's disease, lymphomas except Hodgkin lymphoma, multiple melanoma and other cancers.

Of particular interest is the creation of therapy of hormone-dependent cancers, tumors that Express the androgen receptor, and breast cancer and prostate cancer.

The use of antiandrogens in prostate cancer based on their ability to enter into rivalry with natural agonists of the androgen receptor. However, the effectiveness of these antiandrogens have limited time, because patients fail to respond to treatment. There have been several hypotheses for this phenomenon, which exhibit agonist activity is agonist activity of these molecules (Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E. Biochemistry 1992 Mar 3;31(8): 2393-9). For example, nilutamid able to stimulate the growth of human cancerous prostate cells in culture. In addition to these experimental data, clinical data also support that the detrimental role of antiandrogens (Akimoto S.; Antiandrogen withdrawal syndrome Nippon Rinsho. 1998 Aug; 56(8): 21135-9. Paul R, Breul J. Antiandrogen withdrawal syndrome associated with prostate cancer therapies: incidence and clinical significance Drug Saf 2000 Nov; 23 (5): 381-90).

In this case, the applicant identified compounds �monsterhouse antiproliferative activity against prostate tumor, who unexpectedly did not show agonist activity at concentrations at which nilutamid behaved as an agonist. This difference impacts on the proliferation of new compounds compared with nilutamid is confirmed by their ability to cause the extinction of androgen receptors in their protein form. Nilutamid has no impact on this indicator of the receptor.

The properties of these new molecules should contribute to more effective treatment of prostate cancer, eliminating resistance to modern antiandrogens.

In addition, the compounds of the present invention can also be used for the treatment of pathologies associated with the presence of androgen receptor, such as, for example, benign prostatic hyperplasia, prostatomegaly, acne, androgenic alopecia, hirsutism, etc.

Thus, the object of the invention are compounds of the General formula (I):

in which:

R1denotes a radical cyano, nitro, amino, -NHCOOR4or-NHCOR4;

R2denotes halogen, alkyl, allogeneically or alkoxy radical;

R3denotes an alkyl radical or a hydrogen atom; or both radicals R3form together with the carbon atom to which they are linked, cycloalkyl containing from 3 to 4 chains;

X oboznachaet�

either alkylenes chain of 3-7 carbon atoms, linear or branched, and this chain may contain one or more identical or different additional chains selected from-O-, -N(R5)-, -S-, -SO - or-SO2-;

any group,

where n1 and P1 denote two integers whose sum n1+P1 is an integer selected from 2, 3, 4 and 5;

R6and R7together form a covalent bond or R6and R7form together with the carbon atoms to which they are linked, a cycleor cycloalkyl containing from 3 to 6 chains;

R4denotes alkyl, aryl or heteroaryl;

R5denotes hydrogen, alkyl or aralkyl;

or its pharmaceutically acceptable salt.

Preferably X denotes alkylenes chain containing from 3 to 7 carbon atoms, linear or branched, and this chain may contain one or more identical or different additional chains selected from-O-, -N(R5)-, -S-, -SO - or-SO2-.

More preferably X denotes alkylenes chain, which may contain one chain chosen from-O-, -N(R5)-, -S-, -SO - or-SO2-.

In an embodiment, X denotes a group,

where n1 and P1 denote two integers whose sum n1+P1 is an integer of Chi�scrap, selected from 2, 3, 4 and 5;

R6and R7together form a covalent bond or R6and R7form together with the carbon atoms to which they are linked, a cycleor cycloalkyl containing from 3 to 6 chains;

Preferably, n1 and P1 are equal.

Preferably, the sum n1+P1 is equal to 2. Preferably, the sum n1+P1 is equal to 3. Preferably, the sum n1+P1 is equal to 4. Preferably, the sum n1+P1 is equal to 5.

In another embodiment, X denotes a groupand X' denotes a group-O-, -N(R5)- or-S-, -SO -, - SO2-, -CH2orand n2 and p2 denote two integers that sum to n2+P2 is either an integer selected from 3, 4, 5, 6 and 7, if X' represents a group-O-, -N(R5)-, -S-, -SO -, - SO2or an integer selected from 2, 3, 4 and 5, if X' represents a group-CH2or.

Preferably X' refers to a group of.

Preferably X' refers to a group of-O-, -N(R5)- or -(CH2)-.

Preferably n2 and p2 are equal.

Preferably the sum n2+p2 equal 2. Preferably the sum n2+p2 is equal to 3. Preferably the sum n2+p2 is equal to 4. Preferably the sum n2+p2 is equal to 5. Preferably the sum n2+p2 is equal to 6. Preferably the sum n2+p2 is equal to 7.

Preferably, R3denotes alkyl and�and both radical R 3form together with the carbon atom to which they are linked, cycloalkyl containing from 3 to 4 chains.

Preferably, R4denotes alkyl.

Preferably, R5denotes alkyl.

Preferably X denotes a linear alkylenes chain having 3-7 carbon atoms.

Preferably, R1is in the para-position.

Preferably, R2is in the meta-position.

Preferably, R2is file halogenated.

Preferably, R6and R7together form a covalent bond.

Preferably, R6and R7form together with the carbon atoms to which they are linked, a cycle.

Preferably, R6and R7form together with the carbon atoms to which they are linked, 3-6-membered cycloalkyl.

In accordance with another variation of R3denotes alkyl or hydrogen; and preferably alkyl.

Preferably, R4denotes alkyl and R5denotes alkyl.

Preferably

R1denotes a radical cyano, nitro, amino, -NHCOOR4or-NHCOR4;

R2denotes halogen, alkyl, halogenated, alkoxy;

R3denotes alkyl;

X denotes a linear or branched alkylenes chain having 3-7 carbon atoms, wherein the chain may contain additional W�eno-O - or-N(R 5)-;

R4denotes alkyl;

and R5denotes alkyl.

More preferably, R1denotes a radical cyano, nitro, or-NHCOOR4.

Also very preferably X denotes alkylenes chain with 4 to 7 carbon atoms, wherein the chain may contain additional link-O-.

Preferably the alkyl radical is a methyl group.

The compound of formula (I) is preferably selected from the following compounds:

- 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-hexane-1,6-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-heptane-1,7-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis{4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 1,1'-(3-methylpentan-1,5-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-(oxititan-2,1-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{3-[4-amino-3-(trifluoromethyl)phenyl]-5,5-dimethylimidazolidin-2,4-dione}

- N,N'-(pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)[2-(trifluoromethyl)-4,1-phenylene]})diacetamide

- 1,1'-pentane-1,5-diyl�IP[5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidin-2,4-dione]

- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis[3-(3-chloro-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

- 1,1'-pentane-1,5-diylbis[3-(3-methoxy-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

- dimethyl{pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)(2-methyl-4,1-phenylene)]}bicarbonic

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile)

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-chlorobenzonitrile)

- 1,1'-propane-1,3-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-dioxoimidazolidin-1-yl}-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-dioxoimidazolidin-1-yl}ethyl)-N-methylethanamine

- 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis(5,7-diokso-4,6-diazaspiro[2.4]heptane-4,6-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-[(2Z)-but-2-ene-1,4-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-{(2R,3S)oxirane-2,3-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-{(1R,2R)cyclopropane-1,2-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

�whether pharmaceutically acceptable salt of this compound.

More specifically, the compound of formula (I) selected from the following compounds:

- 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-hexane-1,6-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-heptane-1,7-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis{4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 1,1'-(3-methylpentan-1,5-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-(oxititan-2,1-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{3-[4-amino-3-(trifluoromethyl)phenyl]-5,5-dimethylimidazolidin-2,4-dione}

- N,N'-(pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)[2-(trifluoromethyl)-4,1-phenylene]})diacetamide

- 1,1'-pentane-1,5-diylbis[5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidin-2,4-dione]

- 1,1'-pentane-1,5-diylbis-{5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis[3-(3-chloro-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

- 1,1'-pentane-1,5-diylbis[3-(3-methoxy-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

- dimethyl{pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)(2-methyl-4.1 phenylene)]}bicarbonat

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile)

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-chlorobenzonitrile)

- 1,1'-propane-1,3-diylbis-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-dioxoimidazolidin-1-yl}-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-dioxoimidazolidin-1-yl}ethyl)-N-methylethanamine

- 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis(5,7-diokso-4,6-diazaspiro[2.4]heptane-4,6-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-[(2Z)-but-2-ene-1,4-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-{(2R,3S)oxirane-2,3-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

- 4,4'-{(1R,2R)cyclopropane-1,2-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

or pharmaceutically acceptable salts of this compound.

Preferably, the compound of formula (I) selected from the following compounds:

- 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-(oxititan-2,1-diyl)bis{5,5-dimethyl-3-[-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-chlorobenzonitrile)

- 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

or pharmaceutically acceptable salts of this compound.

Preferably, the compound of formula (I) selected from the following compounds:

- 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 1,1'-(hexadecan-2,1-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile)

- 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

or pharmaceutically acceptable salts of this compound.

Preferably the compound of formula (I) is 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione} or 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}.

Particularly preferably the compound of formula (I) is 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}.

The object of the invention is also a method for producing a compound of formula (I), including the stage, which concludes�I

(i) condensation of two equivalents of arylhydrazines of the General formula (II):

in which R2and R3such as defined above, and R1is nitro or a cyano group, a derivative of the General formula Gp1-X-Gp2and Gp1and Gp2are deleted groups and X, as defined above, in the presence of a strong base to obtain a compound of the General formula (I):

in which R2, R3and X are such as defined above, and R1is nitro - or cyano group.

Preferably the condensation is carried out by heating the reaction mixture to a temperature of from 20 to 100°C, preferably from 45 to 65°C.

Preferably the reaction is carried out in a polar aprotic solvent.

Preferably, the method further comprises a stage

(ii) the restoration of the nitro group to obtain the compound of formula (III):

Preferably, the method additionally includes the stage, which is

(iii) the interaction of a compound of formula (III) obtained in stage (ii) with the acid chloride of the General formula R4-COCl, in which R4such as defined above, to obtain compounds of formula (IV):

In an embodiment, the method comprises the further stage,which is

(iv) the interaction of the compounds obtained in stage (ii), with CHLOROFORMATES of the General formula R4-O-CO-Cl in which R4such as defined above, to obtain compounds of formula (V):

In another embodiment, if R6and R7together form a covalent bond, the method further comprises the stage of:

(v) oxidation of a compound of formula (I) in which R6and R7together form a covalent bond, double bond, thus formed a R6and R7to obtain a compound of formula (VI):

The invention also relates to a compound of formula (I) as a drug.

The invention also relates to pharmaceutical compositions containing as active substance at least one compound of formula (I) in Association with a pharmaceutically acceptable carrier.

The invention also relates to the use of a compound of formula (I) for obtaining a medicinal product intended for the treatment of cancer.

Preferably the drug is intended to treat hormone-dependent cancer.

Preferably the drug is intended for treatment of a cancer expressing the androgen receptor.

Preferably the drug is intended to treat cancer� breast cancer or prostate cancer, preferably prostate cancer.

Brief description of figures

Figure 1 depicts the effect of compounds of examples 2-19 on LNCaP cell proliferation, cultured in non-steroidal anti-environment.

In the figures 2-9 depicts the effect of compounds of the examples 2, 7, 10, 15, 16, 19, 21 and 22 on the reduction of protein expression of androgen receptor.

Figure 10 depicts the effect of nilutamide in reducing protein expression of androgen receptor.

Detailed description of the methods of the invention

The object of the invention are compounds of the General formula (I):

in which R1denotes a radical cyano, nitro, amino, -NHCOOR4or-NHCOR4.

R2denotes halogen, alkyl, halogenated or alkoxy. R3denotes an alkyl radical or hydrogen. In the embodiment, both of the radical R3form together with the carbon atom to which they are linked, 3-4-membered cycloalkyl;

X denotes alkylenes chain of 3-7 carbon atoms, linear or branched, and this chain may contain one or more identical or different additional chains of-O-, -N(R5)- or-S-, -SO - or-SO2-. In an embodiment, X denotes a group,where n1 and P1 denote two integers whose sum n1+P1 is 2 �about 5. For example, n1 and P1 are equal to each 1 or 2, preferably n1 and P1 is equal to 1.

R6and R7together form a covalent bond. In this case, X denotes a group (CH2)n1-CH=CH-(CH2)p1.

In an embodiment, R6and R7form together with the carbon atoms to which they are linked, a cycle.In accordance with another variation of R6and R7form together with the carbon atoms to which they are linked, 3-6-membered cycloalkyl, for example, cyclobutyl, cyclopentyl or cyclohexyl.

R4denotes alkyl, aryl or heteroaryl.

R5denotes hydrogen, alkyl or aralkyl.

Compounds of formula (I) can be in the form of pharmaceutically acceptable salts.

Under a pharmaceutically acceptable salt understand in particular salts of accession with inorganic acids such as hydrochloride, bromhidrato, sulfate, phosphate, diphosphate and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, benzolsulfonat, p-toluensulfonate, pamoate and stearate. To the field of the present invention also include, if they are suitable, salts derived from bases, such as sodium hydroxide or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to “Salt selection for basic drugs”, Int. J. Pharm, (1986), 33, 201-217.

In refurbished new descriptio�x above definitions, the term halogen means fluorine, chlorine, bromine or iodine, preferably chlorine, fluorine or bromine.

Unless otherwise indicated, the term alkyl in the context of the present invention means alkyl, linear or branched, containing from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl and tertbutyl, pentyl or amyl, isopentyl, neopentyl, hexyl or isohexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. Preferably represents an alkyl (C1-C6)alkyl, i.e., alkyl containing from 1 to 6 carbon atoms, such as defined above, or (C1-C4)alkyl meaning an alkyl containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl and tertbutyl. Also very preferably, the alkyl is methyl.

The term alkyl in expressions alkoxy (or alkyloxy) or halogenated denotes alkyl such as defined above.

More specifically, under halogenation understand the alkyl, at least one of hydrogen atoms of which (and possibly all) substituted by halogen atom as, for example, and preferably trifluoromethyl.

Under cycloalkyl, if not specified more specifically, understand a saturated cyclic hydrocarbon radical containing 3-4 chains, such as cyclopropyl or cyclobutyl.

In the context of the present invention, arily can� to be an aromatic mono or polycyclic. The monocyclic arily you can choose from fanilow, Tomilov, xelilov, musicrow, kumanov and preferably fanilow. The polycyclic arily you can choose from naftel, Anttila, financila, fluorenyl. They can choose to replace one or more radicals, identical or different, such as alkyl, halogenated, alkoxy, alkoxycarbonyl, alkylcarboxylic, halogen, cyano, nitro, aryl, aryloxy, aryloxyalkyl or arylcarboxylic.

In the context of the present invention, aralkyl denotes alkyl such as defined above, substituted aryl, as defined above.

In the context of the present invention, the term heteroaryl denotes an aromatic unsaturated cycle containing one or more heteroatoms, identical or different, selected from N, O and S, such as furyl, thienyl isoxazolyl, benzothiazolyl, pyridinyl, oxazolyl, pyrazolyl, pyrimidinyl or chinoxalin.

The object of the invention is also a method for producing a compound of formula (I) comprising a stage which consists in

(i) condensation of two equivalents of arylhydrazines of the General formula (II):

in which R2and R3such as defined above, and R1is nitro or a cyano group, a derivative of the General formula Gp1-X-Gp2and Gp1and Gp2are UDA�yamimi groups and X, as defined above, in the presence of a strong base to obtain a compound of formula (I):

in which R2, R3and X are such as defined above, and R1is nitro - or cyano group.

A) preparation of compounds in which R1is a nitro or cyano group.

Compounds of the General formula (I) according to the invention can be obtained by the synthesis shown below in Scheme 1. Compounds of the General formula (I) in which R1, R2, R3and X are such as defined above, can be obtained in a single stage by condensation of two equivalents of the intermediate arylhydrazines of the General formula (II) derivative of the General formula Gp1-X-Gp2and Gp1and Gp2are deleted groups, and X, as defined above, for example, a halogen atom or sulfonate group. This condensation is carried out in the presence of base, such as for example NaH. Preferably the condensation is carried out by heating the reaction mixture to a temperature of from 20 to 100°C, preferably from 45 to 65°C. Preferably, the condensation is carried out in a polar solvent, preferably a polar aprotic solvent, such as THF, DMF or DMSO. Mostly the reaction is conducted during the time period from 1 to 15 hours.

Scheme 1

A. 1) �Poluchenie compounds in which R1is an amino group.

In the particular case when R1is a nitro group, R2, R3and X are such as defined above, obtaining aniline derivatives of the General formula (I)A1depicted in scheme A1. The restoration of the nitro group is carried out using SnCl2That 2H2O (J. Heterocyclic Chem. 1987, 24, 927-930; Tetrahedron Letters, 1984, 25(8), 839-842) in an appropriate solvent, such as ethyl acetate.

Scheme A1

A. 2) preparation of compounds in which R1is acetamido group

Acetamide derivatives of the General formula (I)A2in which a, R2, R3, R4and X such as described above, the gain in one stage from aniline derivatives of the General formula (I)A1scheme A2. The acylation reaction can be performed using a large excess of acid chloride of the General formula R4-COCl, for example, acetyl chloride or anhydride type (R4-CO)2About, such as acetyloxy anhydride, and the use of excess of this reagent as a solvent.

Scheme A2

A3) Obtaining compounds in which R1is a carbamate group:

Carbamate derivatives of the General formula (I)A3in which R2, R3, R4and X such as described above, the gain in one stage of a�Ionovich derivatives of the General formula (I) A1, diagram A3. The formation of the carbamate is carried out using an excess amount of chloroformate of the General formula R4-O-CO-Cl in the presence of an anhydrous solvent, preferably an anhydrous polar aprotic solution. Preferably used anhydrous pyridine. The reaction is conducted mainly by heating to a temperature of from 60 to 100°C for 12-24 hours.

Scheme A3

A4) Obtaining compounds in which X contains the oxirane

In the particular case when X contains a double bond, R2, R3, R4such as described above, the compounds of the General formula (I)A4can be obtained by oxidation of compounds of the General formula (I) with an appropriate oxidizing agent, such as, for example, parmentola acid or peracetic acid in an aprotic solvent. The reaction is carried out mainly at room temperature and within 1-4 days.

Scheme A4

C) preparation of the intermediates of the General formula (II)

Synthesis of intermediate arylhydrazines of the General formula(II)in which R1, R2and R3such as described above can be carried out in accordance with the strategy described in the following schemes:

V. 1) Obtaining originating by condensation of:

Synthesis of arylhydrazines of the General formula (II),scheme B1 can about�westwith by nucleophilic substitution of fluorine atom, associated with the aromatic nucleus of the compounds of the General formula (II)1anion hydantoin of the General formula (II)2obtained in the presence of base, such as, for example, K2CO3. The reaction is carried out by heating to a temperature of from 65 to 140°C in a polar aprotic solvent, such as, for example, DMF or DMSO. The temperature and duration of reaction depend on nucleofugal the nature of the fluorine atom, which strongly depends on the nature of R1and R2. Nonprofit hydantoins of the General formula (II)2can be obtained by methods described in the literature (e.g., J. Med. Chem. 1984, 27(12), 1663-8).

Scheme B1

In the case that R1and R2are not sufficient electronicsstore in order to facilitate nucleophilic aromatic substitution as described in scheme B1, you can apply the binding between arylboronic acid and hydantoin of the General formula (II)2in the presence of cupric acetate (Synlett 2006, 14, 2290-2) to obtain compounds of the General formula (II).

V. 2) Obtaining originating by creating gigantinho cycle of arrizurieta

Receiving hydantoins of the General formula (II) in this case, in accordance with the Protocol described in Bioorg. Med. Chem. Lett. 2004, 14, 5285.

V. 3) Obtaining originating the cyclization of arylcarbamoyl

The synthesis of PR�of interstitial arylhydrazines of the General formula (II), scheme B3, in which R1, R2and R3such as defined above, can be carried out by cyclization of the intermediate compounds of the General formula (II)3obtained by the methods described in the literature (for example, Organic Process Reseaech &Development 2002, 6, 759-761). The cyclization reaction can be carried out by the intermediate receiving acyl-halide, followed by heating. The acyl-halide can be obtained using a halogenation agent, such as, for example, oxaliplatin or thionylchlorid in an aprotic solvent, such as, for example, 1,4-dioxane or tetrahydrofuran.

Scheme B3

V. 4) Receive originating by creating gigantinho cycle of isocyanates complex aminoethers:

As an alternative, originalton of the General formula (II) can be synthesized from isocyanates complex aminoethers, as described in Eur. J. Med. Chem. 1984, 19 (3), 261.

The formation of salts of compounds of formula (I) can be accomplished by any known specialist way. For example, scaling can be performed by introducing a base or acid, e.g., sodium hydroxide, potassium or hydrochloric acid.

Compounds of formula (I) of the present invention possess interesting pharmacological properties. Indeed, it has been found that the compounds of formula (I) of the present invention are enjoying�Ute antineoplastic (anti-cancer) activity and more specifically inhibitory activity against cell proliferation of cells expressing the androgen receptor, such as cells of the prostate type LnCAP. Thus, the compounds of the present invention can be used for various therapeutic applications. They mainly can be used for the treatment of cancer, particularly hormone-dependent cancer, a cancer expressing the androgen receptor and more specifically breast cancer and prostate cancer. Following experimental section illustrates the pharmacological properties of the compounds according to the invention.

Thus, an object of the present application are compounds of formula (I) such as defined above, as medicaments.

It is also an object of the present application are compounds of formula (I) such as defined above, as medicaments intended for the treatment of proliferative diseases, preferably cancer, very preferably hormone-dependent cancer or a cancer expressing the androgen receptor, or prostate cancer, and breast and very preferably prostate cancer.

The object of the present application are pharmaceutical compositions containing as active substance at least one compound of formula (I), such as defined above in Association with a pharmaceutically acceptable carrier.

Object� present application is also the use of a compound of formula (I) according to the present invention for receiving antineoplastic drugs.

The object of the present application is also the use of a compound of formula (I) according to the present invention for obtaining a medicinal product intended for the inhibition of cell proliferation.

The object of the present application is also the use of a compound of formula (I) according to the present invention for obtaining a medicinal product intended for the treatment of proliferative diseases, preferably cancer, very preferably hormone-dependent cancer or a cancer expressing the androgen receptor, or prostate cancer, and breast and very preferably prostate cancer.

The pharmaceutical composition may be in solid form, e.g., powders, granules, tablets, gelatin capsules. Appropriate solid carriers can, for example, be calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing a compound of the invention may also be in liquid form, e.g. solutions, emulsions, suspensions or syrups. Suitable liquid carriers can, for example, be water, organic solvents such as glycerol or glycols, and mixtures thereof in varying proportions, in water � the addition of pharmaceutically acceptable oils or fats. Sterile liquid compositions can be used for intramuscular, intraperitoneal or subcutaneous injections, and sterile compositions can also be administered intravenously.

All technical and scientific terms used in the present text have the meanings known to the specialist. In addition, all patents (or patent applications), as well as bibliographic information is given for reference.

Experimental part

In accordance with the changing definitions of the groups R1, R2, R3and X, the compounds according to the invention can be obtained in different ways, described above.

The NMR analyses of examples 1-23 were performed on a Bruker-Avance II 400 MHz.

The examples illustrate the ways specified above, and shall not in any case be considered as limiting the scope of the invention.

The terminology used for the nomenclature of the compounds listed below, and examples is the IUPAC terminology.

Example 1: 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

In the atmosphere of argon injected NaH (60%) (22 mg, 0.55 mmole) in a solution of 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione (158 mg, 0.5 mmole) in anhydrous DMF (8 ml). Gas evolution accompanies the color change of the reaction medium, which becomes orange. Stirring was maintained for 30 minutes at 23�With prior to the introduction of 1,4-dibromobutane (30 μl A 0.25 mmole). The reaction mixture was heated to 55°C for 1 hour, then poured into a saturated aqueous solution of NH4Cl (25 ml) and extracted using AcOEt (2 × 25 ml). The organic phase is collected and washed successively with water (25 ml) and brine (25 ml). After drying over Na2SO4the organic solution was filtered and concentrated in vacuo. The residue obtained by evaporation, is purified on a column of silica gel (eluent: heptane/AcOEt: from 4/6 to 1/9)

The target connection receive in the form of a solid of light yellow color with a yield of 45%. Melting point: 211-212°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,32 (d, 2H, Ph); 8,21 (d, 2H, Ph); 8,08 (DD, 2H, Ph); 3,39 (m, 4H, 2 × NCH2); 1,70 (m, 4H, 2 × CH2); 1,49 (s, 12H, 4 × CH3).

Example 2: 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of compounds of Example 1, 1,5-diiodopentane replaces 1,4-dibromobutane. The target connection receive in the form of a solid substance of white color with a yield of 40%. Melting point: 163-164°C.

1H NMR 400 MHz (DMSO-d6) δ: of 8.33 (d, 2H, Ph); 8,21 (d, 2H, Ph); 8,07 (d, 2H, Ph); to 3.34 (m, 4H, 2 × NCH2); To 1.69 (m, 4H, 2 × CH2); 1,50 (s, 12H, 4 × CH3); Of 1.41 (m, 2H, CH2).

Example 3: 1,1'-hexane-1,6-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as op�San for the synthesis of compounds of Example 1 thus 1,6-iodohexane replaces 1,4-dibromobutane. The target connection receive in the form of a solid of light yellow color with a yield of 27%. Melting point: 187-188°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,31 (d broad, 2H, Ph); 8,20 (broad, 2H, Ph); 8,07 (d broad, 2H, Ph); of 3.32 (m, 4H, 2 × NCH2); 1,64 (m, 4H, 2 × CH2); Of 1.46 (s, 12H, 4 × CH3); To 1.38 (m, 4H, 2 × CH2).

Example 4: 1,1'-heptane-1,7-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of compounds of Example 1, wherein 1,7-dibromsalan replaces 1,4-dibromobutane. The target connection receive in the form of a solid of light yellow color with a yield of 35%. Melting point: 137-138°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,31 (d, 2H, Ph); to 8.19 (d, 2H, Ph); 8,06 (DD, 2H, Ph); 3,30 (m, 4H, 2 × NCH2); 1,64 (m, 4H, 2 × CH2); Of 1.46 (s, 12H, 4 × CH3); Of 1.36 (m, 6H, 3× CH2).

Example 5: 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

5.1) 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

A mixture of 4-fluoro-(trifluoromethyl)benzonitrile (5,67 g, 30 mmol), 5,5-dimethylhydantoin (7,68 g, 60 mmol), K2CO3(Of 8.28 g, 60 mmol) in DMF (45 ml) is distributed in equal shares to the three tubes intended for the microwave. Under magnetic stirring each tube was irradiated at 140�C for 20 minutes. The reaction mass is then pooled, poured into water (200 ml) and extracted using AcOEt (2 × 75 ml). The organic phases were combined, washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized in Et2O (25 ml). After recrystallization in EtOH (75 ml) powder was filtered and dried in vacuum. The target connection receive in the form of a solid substance of white color with a yield of 46% (4.1 g). Melting point: 212-213°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,80 (s, 1H, NH); 8,29 (d, 1H, Ph); 8,18 (s, 1H, Ph); 8,02 (d, 1H, Ph); to 1.42 (s, 6H, 2 × CH3).

5.2) 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 5.1. replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target connection receive in the form of a solid substance of white color with a yield of 50% (330 mg). Melting point: 167-169°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,28 (d, 2H, Ph); 8,18 (s, 2H, Ph); 8,02 (d, 2H, Ph); 3,30 (m, 4H, 2 × NCH2); At 1.67 (m, 4H, 2 × CH2); Of 1.46 (s, 12H, 4 × CH3); Of 1.40 (m, 2H, CH2).

Example 6: 1,1'-(3-methylpentan-1,5-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of the compound from Example , moreover, 1,5-dibrom-3-methylpentan replaces 1,4-dibromobutane. The target connection receive in the form of foam light yellow color with a yield of 39%.

1H NMR 400 MHz (DMSO-d6) δ: 8,30 (d, 2H, Ph); 8,20 (d, 2H, Ph); 8,07 (DD, 2H, Ph); 3,38 (m, 4H, 2 × NCH2); 1,72 (m, 4H, 2 × CH2); 1,53 (m, 1H, CH); 1,49 (s, 12H, 4 × CH3); And 1.00 (d, 3H, CH3).

Example 7: 1,1'-(Occidental-2,1-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of compounds of Example 1, with simple bis(2-bromacil) ether replaces 1,4-dibromobutane. The target connection receive in the form of a solid substance of white color with a yield of 70%. Melting point: 186-188°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,28 (d, 2H, Ph); 8,16 (d, 2H, Ph); 8,03 (DD, 2H, Ph); to 3.67 (t, 4H, 2 × CH2); 3,52 (t, 4H, 2 × CH2); 1,47 (s, 12H, 4 × CH3).

PRemer 8: 1,1'-pentane-1,5-diylbis{3-[4-amino-3-(trifluoromethyl)phenyl]-5,5-dimethylimidazolidin-2,4-dione}

The joint compound from example 2 (410 mg, of 0.58 mmole) and SnCl2That 2H2O (1,32 g, 5.8 mmole) in AcOEt (10 ml) was heated to 80°C for 90 minutes. Then the reaction mixture was cooled to 0°C, then poured into a saturated aqueous solution of Na2CO3(40 ml). Thus obtained heterogeneous mixture was filtered through celite and rinsed AcOEt (2 × 50 ml). After settling, the organic phases were combined, dried over Na2SO4filter and dissolve�RER evaporated under reduced pressure. The obtained residue was treated with a mixture of heptane/AcOEt to obtain after filtration, the white solid substance with a yield of 78% (290 mg). Melting point: 108-109°C.

1H NMR 400 MHz (DMSO-d6) δ: 7,32 (d, 2H, Ph); 7.23 percent (DD, 2H, Ph); of 6.85 (d, 2H, Ph); 5,80 (s, 4H, 2 × NH2); 3,27 (m, 4H, 2 × NCH2); 1,64 (m, 4H, 2 × CH2); Of 1.40 (s, 12H, 4 × CH3); 1,31 (m, 2H, CH2).

Example 9: N,N'-(pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)[2-(trifluoromethyl)-4,1-phenylene]})diacetamide

In argon atmosphere, the compound of Example 8 (161 mg, 0.25 mmole) is mixed with acetylchloride (10 ml) and stirring was maintained for 15 minutes at 23°C. the Reaction mixture was then evaporated to dryness (distillation with toluene) and the residue obtained is purified on a column of silica gel (eluent: CH2Cl2/From EtOH 99/1 to 90/10). After evaporation of the target compound was obtained as a cream-colored foam with a yield of 52%.

1H NMR 400 MHz (DMSO-d6) δ: 9,63 (s, 2H, CONH); 7,81 (d, 2H, Ph); 7,69 (DD, 2H, Ph); 7,58 (d, 2H, Ph); 3,30 (m, 4H, 2 × NCH2); Of 2.06 (s, 6H, 2 × CH3); At 1.67 (m, 4H, 2 × CH2); Of 1.40 (s, 12H, 4 × CH3); Of 1.40 (m, 2H, CH2).

Example 10: 1,1'-pentane-1,5-diylbis[5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidin-2,4-dione]

10.1) 5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidin-2,4-dione

A mixture of 5-fluoro-2-nitrotoluene (1.55 g, 10 mmol), 5,5-dimethylhydantoin (1.28 g, 10 mmol), K2CO3(1,38 g, 10 mmol) in DMF (15 ml) is injected into the tube, p�rednaznachena for microwave oven and irradiated at 100°C for 70 minutes under conditions of magnetic stirring. The reaction mixture was then poured into water (200 ml) and extracted using AcOEt (2 × 75 ml). The organic phases were combined, washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on a column of silica gel (eluent: heptane/AcOEt: 7/3). The target connection receive in the form of a solid substance of white color with a yield of 25% (666 mg). Melting point: 177-178°C.

1H NMR 400 MHz (DMSO-d6) δ: to 8.70 (s, 1H, NH); 8,10 (d, 1H, Ph); 7,58 (s, 1H, Ph); 7,52 (DD, 1H, Ph); 2,54 (s, 3H, CH3); Of 1.41 (s, 6H, 2 × CH3).

10.2) 1,1'-pentane-1,5-diylbis[5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidin-2,4-dione]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 10.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target connection receive in the form of a solid substance of white color with a yield of 67% (495 mg). Melting point: 130-131°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,09 (d, 2H, Ph); 7,58 (s, 2H, Ph); 7,52 (DD, 2H, Ph); of 3.32 (s, 4H, 2 × NCH2); 2,53 (s, 6H, 2 × CH3); 1,68 (m, 4H, 2 × CH2); Of 1.46 (s, 12H, 4 × CH3); To 1.38 (m, 2H, CH2).

Example 11: 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

11.1) 5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)phenyl]imidazolidin-2,4-dione

The experimental Protocol is the same as that described glycinate intermediate 10.1, the 2-fluoro-5-nitrobenzotrifluoride replaces 5-fluoro-2-nitrotoluene. The target connection receive in the form of a solid substance of white color with a yield of 29%. Melting point: 175-176°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,76 (s, 1H, NH); 8,68 (DD, 1H, Ph); 8,58 (d, 1H, Ph); 8,04 (d, 1H, Ph); 1,47 (s, 3H, CH3); To 1.38 (s, 3H, CH3).

11.2) 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 11.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target compound was obtained as a light yellow foam color with a yield of 12%.

1H NMR 400 MHz (DMSO-d6) δ: 8,68 (m, 2H, Ph); 8,58 (d, 2H, Ph); 8,04 (d, 2H, Ph); of 3.33 (m, 4H, 2 × NCH2); Of 1.66 (m, 4H, 2 × CH2); 1,50 (m, 6H, 2 × CH3); To 1.42 (m, 6H, 2 × CH3); To 1.35 (m, 2H, CH2).

Example 12: 1,1'-pentane-1,5-diylbis[3-(3-chloro-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

12.1) 3-(3-chloro-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione

The experimental Protocol is the same as that described for the synthesis of intermediate 10.1, 2-chloro-4-ftorirovannom replaces 5-fluoro-2-nitrotoluene. The target compound was obtained as a solid pale yellow color with a yield of 28%. Melting point: 144-145°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,77 (s, 1H, NH); 8,21 (d, 1H, Ph); 7,92 (d, 1H, Ph); 7,71 (DD, 1H, Ph); Of 1.41 (s, 6H, 2 × CH3).

12.2) 1,1'-pentane-1,5-diylbis[3-(3-chloro-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 12.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target compound was obtained as a light yellow foam with a yield of 7%.

1H NMR 400 MHz (DMSO-J6) δ: 8,28 (d, 2H, Ph); 7,99 (d, 2H, Ph); 7,79 (DD, 2H, Ph); 3,37 (m, 4H, 2 × NCH2); 1,74 (m, 4H, 2 × CH2); 1,53 (m, 12H, 4 × CH3); Of 1.46 (m, 2H, CH2).

Example 13: 1,1'-pentane-1,5-diylbis[3-(3-methoxy-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

13.1) 3-(3-methoxy-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione

The experimental Protocol is the same as that described for the synthesis of intermediate compounds 10.1 5-fluoro-2-nitroanisole replaces 5-fluoro-2-nitrotoluene. The target connection receive in the form of a solid substance of white color with a yield of 20%.

1H NMR 400 MHz (DMSO-d6) δ: to 8.70 (s, 1H, NH); 7,99 (d, 1H, Ph); 7,47 (d, 1H, Ph); 7,20 (DD, 1H, Ph); of 3.91 (s, 3H, OCH3); To 1.42 (s, 6H, 2 × CH3).

13.2) 1,1'-pentane-1,5-diylbis[3-(3-methoxy-4-nitrophenyl)-5,5-dimethylimidazolidin-2,4-dione]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 13.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. Target Conn�kit was obtained as a white foam with a yield of 10%.

1H NMR 400 MHz (DMSO-d6) δ: 8,07 (d, 2H, Ph); 7,54 (d, 2H, Ph); 7,28 (DD, 2H, Ph); 3,97 (s, 6H, 2 × OCH3); 3,38 (m, 4H, 2 × NCH2); 1,74 (m, 4H, 2 × CH2); 1,53 (m, 12H, 4 × CH3); Of 1.46 (m, 2H, CH2).

Example 14: dimethyl{pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)(2-methyl-4,1-phenylene)]}bicarbonat

14.1) 1,1'-pentane-1,5-diylbis[3-(4-amino-3-methylphenyl)-5,5-dimethylimidazolidin-2,4-dione]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 8 from the compound of example 10, with the latter replaces the compound of example 2. The target compound was obtained as a white foam with a yield of 69%.

1H NMR 400 MHz (DMSO-d6) δ: of 6.79 (m, 4H, Ph); 6,60 (d, 2H, Ph); 5,02 (s, 4H, 2 × NH2); 3,26 (m, 4H, 2 × NCH2); 2,03 (s, 6H, 2 × CH3); 1,62 (m, 4H, 2 × CH2); Of 1.39 (s, 12H, 4 × CH3); 1,31 (m, 2H, CH2).

14.2) dimethyl{pentane-1,5-diylbis{(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)(2-methyl-4,1-phenylene)]}bicarbonat

In argon atmosphere, intermediate connection 14,1 (268 mg, 0.5 mmole) dissolved in anhydrous pyridine (10 ml), mixed with methylchloroform (0.8 ml, 10 mmol). Stirring was maintained for 18 hours at 90°C. the Reaction mixture was then poured into ice water and extracted with usingAcOEt (2 × 50 ml). The organic phases were combined and washed with brine (25 ml). The organic solution is dried over Na2SO4, filtered and the solvent �pariwat under reduced pressure. The residue is purified on a column of silica gel (eluent: heptane/AcOEt: from 4/6 to 0/1). The target compound was obtained as a white foam with a yield of 40% (130 mg).

1H NMR 400 MHz (DMSO-d6) δ: 8,92 (s, 2H, NH); the 7.43 (d, 2H, Ph); 7,17 (d, 2H, Ph); 7,12 (DD, 2H, Ph); 3,66 (s, 6H, 2 × OCH3); 3,29 (m, 4H, 2 × NCH2); Of 2.20 (s, 6H, 2 × CH3); Of 1.66 (m, 4H, 2 × CH2); To 1.42 (s, 12H, 4 × CH3); To 1.37 (m, 2H, CH2).

Example 15: 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile)

15.1) 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-methylbenzonitrile

The experimental Protocol is the same as that described for the synthesis of intermediate compounds 5.1, 4-fluoro-2-methylbenzonitrile substituted 4-fluoro-2-(trifluoromethyl)benzonitrile. After recrystallization in EtOH (75 ml) of target compound was obtained as a solid substance of white color with a yield of 5%.

1H NMR 400 MHz (DMSO-d6) δ: to 8.70 (s, 1H, NH); to 7.89 (d, 1H, Ph); 7,54 (s, 1H, Ph); the 7.43 (d, 1H, Ph); 2.49 USD (s, 3H, CH3); Of 1.40 (s, 6H, 2 × CH3).

15.2) 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile)

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate connection 15.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target compound was obtained as a white solid with a yield of 66%. Melting point: 148-149°C.

1H �MP 400 MHz (DMSO-d 6) δ: 7,81 (d, 2H, Ph); 7,49 (d, 2H, Ph); 7,39 (DD, 2H, Ph); 3,30 (m, 4H, 2 × NCH2); 2,43 (s, 6H, 2 × CH3); 1,62 (m, 4H, 2 × CH2); Of 1.39 (s, 12H, 4 × CH3); 1,31 (m, 2H, CH2).

Example 16: 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-chlorobenzonitrile)

16.1) 2-chloro-4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)benzonitrile

The experimental Protocol is the same as that described for intermediate connection 5.1, 2-chloro-4-perbenzoate substituted 4-fluoro-2-(trifluoromethyl)benzonitrile. The target connection receive in the form of a solid substance of white color with a yield of 23%.

1H NMR 400 MHz (DMSO-d6) δ: 8,76 (s, 1H, NH); 8,08 (d, 1H, Ph); 7,90 (d, 1H, Ph); 7,67 (DD, 1H, Ph); of 1.40 (s, 6H, 2 × CH3).

16.2) 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-chlorobenzonitrile)

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate compound 16.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target compound was obtained as a white solid substance with a yield of 51%. Melting point: 166-167°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,08 (d, 2H, Ph); 7,90 (d, 2H, Ph); to 7.68 (DD, 2H, Ph); 3,30 (m, 4H, 2 × NCH2); 1,64 (m, 4H, 2 × CH2); 1,45 (s, 12H, 4 × CH3); To 1.38 (m, 2H, CH2).

Example 17: 1,1'-propane-1,3-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

Experimental Protocol� the same, that described for the synthesis of compounds of Example 1, 1,3-diiodopropane replaces 1,4-dibromobutane. The target compound was obtained as a white solid substance with a yield of 15% (50 mg). Melting point: 164-165°C.

1H NMR 400 MHz (DMSO-d6) δ: of 8.33 (d, 2H, Ph); 8,21 (d, 2H, Ph); 8,09 (DD, 2H, Ph); for 3.45 (t, 4H, 2 × NCH2); 2,01 (m, 2H, CH2); 1,50 (s, 12H, 4 × CH3).

Example 18: chloride 2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-dioxoimidazolidin-1-yl}-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]2,4-dioxoimidazolidin-1-yl}ethyl-N-methylethanamine

The experimental Protocol is the same as that described for the synthesis of compounds of Example 1, wherein mechlorethamine hydrochloride replaces 1,4-dibromobutane. The target compound was obtained as a solid pale yellow substance with a yield of 30%. Melting point: 136-137°C.

1H NMR 400 MHz (DMSO-d6) δ: of 11.08 (broad, 1H, NH+); 8,31 (m, 4H, Ph); 8,10 (d, 2H, Ph); a 3.87 (m, 4H, 2 × NCH2); 3,51 (m, 2H, NCH2); 3,38 (m, 2H, NCH2); 2,99 (broad, 3H, CH3); At 1.55 (s, 12H, 4 × CH3).

Example 19: 1,1'-(2Z)-but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}

The experimental Protocol is the same as that described for the synthesis of compounds of example 1, wherein CIS-1,4-dichloro-2-butene replaces 1,4-dibromobutane. The target compound was obtained as a solid pale yellow substance with a yield of 40%. Melting point: 191-193°C.

1 H NMR 400 MHz (DMSO-d6) δ: of 8.34 (d, 2H, Ph); 8,22 (d, 2H, Ph); 8,09 (DD, 2H, Ph); 5,61 (square, 2H, CH=CH); 4,2 (q, 4H, 2 × CH2); 1,50 (s, 12H, 4 × CH3).

Example 20: 4,4'-[pentane-1,5-diylbis(5,7-diokso-4,6-diazaspiro[2.4]heptane-4,6-diyl)]bis[2-(trifluoromethyl)benzonitrile]

20.1) 1-({[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl}amino)cyclopropanecarbonyl acid

A solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (4,56 g, 21.5 mmole) in acetone (12 ml) is introduced dropwise in 1-aminocyclopropane acid (2,02 g, 20 mmol), dissolved in aqueous sodium hydroxide solution (12 ml, 08 g, 20 mmol). The reaction mass is stirred for 1 hour at room temperature, then poured into aqueous sodium hydroxide solution (1N, 40 ml). The resulting solution was washed with ethyl acetate (30 ml), then acidified by adding an aqueous solution of sulfuric acid (2M, 30 ml), and extracted with ethyl acetate (2 × 50 ml). The thus obtained organic phase was washed with water, then with saturated aqueous sodium chloride solution, dried over Na2SO4and filtered. The solvent is evaporated under reduced pressure. The obtained residue was treated with simple ethyl FYROM to obtain after filtration, the white solid substance with a yield of 50% (3,16 g).

20.3) 4-(5,7-diokso-4,6-diazaspiro[2.4]hept-6-yl)-2-(trifluoromethyl)benzonitrile

In argon atmosphere, oxaliplatin (1,12 ml, 13 mmol) is added to a solution of intermediate�connection 20.1 (3,16 g, 10 mmol) and DMF (0.5 ml) in 1,4-dioxane (20 ml). The reaction mixture was stirred under heating to reflux for one hour and the solvent is evaporated under reduced pressure. The residue was treated with water (30 ml) and the resulting solution was extracted with ethyl acetate (50 ml). The organic phase was sequentially washed with water and saturated sodium chloride solution and dried over Na2SO4.The solvent is evaporated under reduced pressure. The obtained residue was treated with simple ethyl ether to obtain after filtration, the white solid substance with a yield of 20% (0.6 g).

1H NMR 400 MHz (DMSO-d6) δ: 8,91 (s, 1H, NH); 8,27 (d, 1H, Ph); 8,18 (s, 1H, Ph); 8,04 (d, 1H, Ph); 1,3-1,45 (m, 4H, 2 × CH2Spiro).

20.3) 4,4'-[pentane-1,5-diylbis(5,7-diokso-4,6-diazaspiro[2.4]heptane-4,6-diyl)]bis[2-(trifluoromethyl)benzonitrile]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 2, the intermediate compound 20.2 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target compound was obtained as a white solid substance. Melting point: 154-155°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,27 (d, 2H, Ph); 8,17 (d, 2H, Ph); 8,03 (DD, 2H, Ph); 3,14 (t, 4H, CH2× 2); 1,64 (m, 4H, 2 × CH2); 1,55 (m, 4H, 2× CH2Spiro); of 1.36 (m, 6H, CH2Central, 2× CH2Spiro).

Example 21: 4,4'-[(2Z)but-2-ene-1,4-diylbis(4,4-dimethyl-2,5-dixoide�alidin-3,1-diyl)]bis[2-(trifluoromethyl)benzonitrile]

The experimental Protocol is the same as that described for the synthesis of compounds of example 1, wherein CIS-1,4-dichloro-2-butene replaces 1,4-dibromobutane and an intermediate connection 5.1 replace 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione. The target connection receive in the form of solid light beige substance. Melting point: 188-190°C.

1H NMR 400 MHz (DMSO-d6) δ: 8,32 (d, 2H, Ph); to 8.19 (d, 2H, Ph); with 8.05 (DD, 2H, Ph); 5,60 (square, 2H, CH=CH); 4,2 (q, 4H, 2 × CH2); 1,49 (s, 12H, 4 × CH3).

Example 22: 4,4'-{(2R,3S)-oxirane-2,3-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

In argon atmosphere, the compound of example 21 (90 mg, 0,139 mmole) was mixed with 3-metallocarboranes acid (72,5 mg, 0,210 mmole) in anhydrous dichloromethane (10 ml). The mixture is shaken at room temperature. Over the course of the reaction is monitored using SMS (eluent DCM/EtOH: 95/05). After 4 hours the original connection remains. Enter a new quantity metallocarboranes acid (0,214 g, of 0.36 mmole) to the reaction mass and the reaction medium is stirred at room temperature for another 4 hours later. The solvent is evaporated under reduced pressure and the residue purified flash chromatography (column biotage AB 25+M, a gradient of dichloro methane/acetone from 0% to 8% acetone). The target compound was obtained as a white solid substance with a yield of 50%. Melting point: 108-110°C./p>

1H NMR 400 MHz (DMSO-d6) δ: 8,32 (d, 2H, Ph); 8,21 (d, 2H, Ph); with 8.05 (DD, 2H, Ph); of 4.05 (q, 2H, CH-CH); or 3.28 (m, 4H, 2 × CH2); 1,53 (d, 12H, 4 × CH3).

Example 23: 4,4'-{(1R,2R)-cyclopropane-1,2-diylbis[meander(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]}bis[2-(trifluoromethyl)benzonitrile]

The experimental Protocol is the same as that described for the synthesis of compounds of Example 1, wherein the TRANS-1,2-bis(bromomethyl)cyclopropane (obtained according to Med. Chem. 2003, 46(21), 4586-4600) replaces 1,4-dibromobutane. The target connection receive in the form of a cream-colored solid. Melting point: 178-180°C.

1H NMR 400 MHz (DMSO-d6) δ: compared to 8.26 (d, 2H, Ph); 8,15 (d, 2H, Ph); 8,01 (DD, 2H, Ph); 3,2-3,4 (m, 4H, 2 × NCH2); 2.49 USD (s, 12H, 4 × CH3); 1,24 (m, 2H, 2 × CH); 0,61 (t, 2H, 1 × CH2).

Pharmacological study of compounds of the invention

Measurement of antiproliferative activity:

1. Antiproliferative activity against LNCaP in a full environment

Antiproliferative activity of the compounds of the present invention was determined in LNCaP cells in a full environment using the following experimental procedure:

Cell type LNCaP (ATSS, 1740) derived from carcinoma of the prostate expressing the androgen receptor, it is hormone-dependent.

Line LNCaP were kept in complete culture medium: RPMI, 10% fetal bovine serum, 2mm glutamine, 100 U/ml �of penicillin, 0.1 mg/ml streptomycin and 0.01 M HEPES, sodium pyruvate 1 mm, 40% D-glucose.

Sowing in tablets:

Line LNCaP were seeded at rate of 20,000 cells/well in 90 μl complete medium in 96-well plates, coated with poly-D-lysine (Biocoat, Castar).

Treatment of cells: 24 hours after seeding cells were treated with compound diluted in the culture medium, at a rate of 10 μl per well. Used the following concentrations: 1/10/30/100/300/1000/3000/10000/100000 nm. Cells were incubated for 144 hours at 37°C, 5% CO2.

Reading: After 6 hours of incubation, to each well was injected with 10 μl of the reagent cell proliferation WST-1” (Roche ref 1644807). Incubated 2 hours at 37°C, 5% CO2then the absorbance at 450 nm was measured by spectrophotometry (Envision, Perkin Elmer).

Results: the Experiments were performed twice and the best connections were tested twice. Calculated size concentration inhibiting 50% cell proliferation (CI50).

All compounds of examples 1-23, described above, had CI50less than or equal to 5000 nm against LNCaP cells in culture.

Of these, compounds of the following examples had CI50less than or equal to 1500 nm against LNCaP cells in culture: 1, 2, 4, 7, 10, 13, 14, 15, 16, 19, 20, 21 and 22.

Compounds of the following examples had CI50less than or equal to 500 nm against LNCaP cells in culture: 1, 2, 7, 15, 19, 20, 21 and 22.

2. Antiproliferative activity against LNCP in the environment without steroids

Pro - and/or antiproliferative activity of the compounds of the present invention was determined against LNCaP in the absence of steroids.

Line LNCaP (ATSS, 1740) derived from carcinoma of the prostate expressing the androgen receptor, it is hormone-dependent.

Line LNCaP were kept in standard conditions in RPMI, 10% fetal bovine serum, 2 mm glutamine, 100 U/ml penicillin, 0.1 mg/ml streptomycin and 0.01 M HEPES, sodium pyruvate 1 mm, 40% D-glucose.

For study without steroids for 24 hours before sowing culture medium of the cells was purified. Cells were washed with PBS, then incubated in the presence of RPMI medium without phenol red, 10% fetal bovine serum, from which removed the steroids (pre-treatment with charcoal-dextran), 2 mm glutamine, 100 U/ml penicillin, 0.1 mg/ml streptomycin and 0.01 M HEPES, sodium pyruvate 1 mm, 40% D-glucose.

Sowing in tablets:

Line LNCaP were seeded at rate of 20,000 cells/well in 90 μl medium with 10% fetal bovine serum, from which removed the steroids, in 96-well plates, coated with poly-D-lysine (Biocoat, Castar).

Treatment of cells: 24 hours after seeding cells were treated with compound diluted in the culture medium, at a rate of 10 μl per well. Used the following concentrations: 1/10/30/100/300/1000/3000/10000/100000 nm. Cells were incubated for 144 hours at 37°C, 5% CO2.

With�ativana: After 6 hours of incubation, to each well was injected with 10 μl of the reagent cell proliferation WST-1” (Roche ref 1644807). Incubated 2-4 hours at 37°C, 5% CO2then the absorbance at 450 nm was measured by spectrophotometry (Envision, Perkin Elmer).

Results: the Experiments were performed twice and the best connections were tested twice. Calculated size concentration inhibiting 50% cell proliferation (CI50).

As described above (Veldschlte J, Berrevoets CA, Bkinkmann AO, Grootegoed JA, Mulder E. Biochemistry 1992 Mar 3;31 (8): 2393-9), nilutamid in small concentrations has agonist activity, in high concentrations inhibitory activity.

Unexpectedly, compound 1-23 do not have agonist activity against LNCaP cells cultured without steroids. In addition, compounds 2 and 19 in low concentrations showed a clear inhibitory activity.

Effect of compounds 2 and 19 on the proliferation of LNCaP cells cultured without steroids, shown in Fig.1.

3. Measurement of protein expression of androgen receptor

Cell line LNCaP were plated from the calculation of 2.5 million cells on a Petri dish 10 cm in RPNI, 10% fetal bovine serum, 2 mm glutamine, 100 U/ml penicillin, 0.1 mg/ml streptomycin and 0.01 M HEPES, sodium pyruvate 1 mm, 40% D-glucose. After 4 days, cells were treated with test compound. 72 hours after treatment cells were literally in lysing buffer (Tris pH7,4 50 mm, NaCl 150 mm, EDTA 1 mm, 20 mm NaF, Na2VO3100 mm, NP40 0.5%, and Trion X-100 1%, EGTA 1 mm Pefabloc, a mixture of protease inhibitors 11836170001 RocheDiagnostics, a mixture of phosphatase inhibitors, the set II, Calbiochem). Then the cells are scraped and the lysate was transferred into a QIAshredder tubes (cat. No. 79656 Qiagen) for centrifugation at a speed of 13000 rpm for 15 minutes at 4°C. the Supernatant was transferred into a QIAshredder tubes for repeated centrifugation at a speed of 13000 rpm for 5 minutes for complete removal of DNA filaments. Then determined the protein concentration (Bio-Rad DC protein assay kit) and regulated so as to put the same amount of protein per well (10 and 20 µg per well in accordance with the experiments). Buffer for inclusion (sample loading buffer 3 X ref 7722 Cell signaling technology) with the addition of 1% beta-mercaptoethanol and DTT at a concentration of 50 mm was injected into the samples, which are then nagavalli within 10 minutes to 90°C. the Samples were applied in a volume of 20 ál on gel NuPAGE 4-12% Bis-Tri gel (cat. No. NP0322BOX, Invitrogen). Migration occurred in MOPS buffer (Invitrogen) and was carried out for 1 hour at 180V. Proteins were transferred to nitrocellulose membrane (Hybond ECL RPN78D, GE Healthcare) in semi-dry conditions in the presence of a transitional buffer (NP0006-1, Invitrogen) for 45 minutes at 15V. Then the membrane was blocked for 1 hour in blocking buffer (Non-fat dry milk, cat. 170-6404, Biorad) 5% in Tris buffer Beffer saline (TBS) with 0.1% Tween 20. Then it is incubated at 4°C overnight in the presence of a primary antibody directed against the-counter�ora androgen (AR441, sc-7305, Santa Cruz), diluted 1/2000 in blocking buffer and in the presence of a primary antibody directed against GAPDH (Cat. MAB374, Millipore), diluted 1/20000 in blocking buffer (control of input protein). Then the membrane was washed 3 times in wash buffer (TBS, 0,1% Tween 20). Then the membrane is incubated in the presence of secondary antiglobulin mouse antibody coupled with HRP (Goat anti-mouse IgG-HRP, sc-2031, Santa Cruz), diluted 1/5000 in blocking buffer. Then the membrane was washed 3 times in wash buffer. Proteins were detected by electrochemiluminescence (western Blotting detection system ECL+Amersham) or using photographic film (Biomax light, Sigma), or using a registration system chemiluminescence (G: Box, Syngene).

Effect of compounds 2, 7, 10, 15, 16, 19, 21, 22 shown in figures 2-9: these compounds reduce protein expression of androgen receptor. In contrast, as shown in figure 10, nilutamid does not reduce the protein expression of this receptor (figure 10).

1. The compound of the General formula (I)

in which:
R1denotes a radical cyano, nitro, amino, -NHCOOR4or-NHCOR4;
R2denotes halogen, C1-alkyl, Halogens1-alkyl or C1-alkoxy radical;
R3represents C1-alkyl radical; or both radicals R3form together with the carbon atom, with the cat�eye they are connected, cycloalkyl containing 3 members;
X denotes
either alkylenes a chain of 4 to 7 carbon atoms, linear or branched, and this chain may contain one or more identical or different additional units selected from-O-, -N(R5)-;
any group
where n1 and p1 denote two integers whose sum n1+p1 is an integer selected from 2;
R6and R7together form a covalent bond or R6and R7form together with the carbon atoms to which they are linked, a cycleor cycloalkyl containing 3 members;
R4represents C1-alkyl;
R5represents C1-alkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which X denotes alkylenes a chain of 4 to 7 carbon atoms, linear or branched, and this chain may contain one or more identical or different additional units selected from-O-, -N(R5)-, or its pharmaceutically acceptable salt.

3. The compound according to claim 2, in which X denotes alkylenes chain, which may contain one link, selected from-O-, -N(R5)-, or its pharmaceutically acceptable salt.

4. The compound according to claim 1, in which X denotes a group
where n1 and p1 denote two integers, the sum of Kotor�x n1+p1 is an integer selected from 2;
R6and R7together form a covalent bond or R6and R7form together with the carbon atoms to which they are linked, a cycleor cycloalkyl containing 3 members; orpharmaceutically acceptable salt.

5. The compound according to claim 4, in which n1 and p1 are equal.

6. The compound according to claim 1, in which X denotes a groupand X' denotes a group-O-, -N(R5)- orand n2 and p2 denote two integers that sum to n2+p2 is either an integer selected from 4, 5, 6 and 7, if X' represents a group-O-, -N(R5)-, or an integer selected from 2, 3, 4 and 5, if X' represents the groupor -(CH2)-.

7. The connection according to claim 6, in which X' denotes a group

8. The connection according to claim 6, in which X' denotes a group-O-, -N(R5)- or -(CH2)-.

9. The connection according to claim 6, in which n2 and p2 are equal.

10. The compound according to claim 1, in which R3represents C1-alkyl or both radicals R3form together with the carbon atom to which they are linked, cycloalkyl containing 3 members.

11. The compound according to claim 1, in which R1is in the para-position.

12. The compound according to claim 1, in which R2is in the meta-position.

13. The compound according to claim 1, in which R6and R together form a covalent bond.

14. The compound according to claim 1, in which R6and R7form together with the carbon atoms to which they are linked, a cycle

15. The compound according to claim 1, in which R6and R7form together with the carbon atoms to which they are linked, 3-membered cycloalkyl.

16. The compound according to claim 1 or 10, in which C1is an alkyl radical denotes a methyl group.

17. The compound of the General formula (I), selected from the following compounds:
- 1,1'-butane-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione};
- 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3(trifluoromethyl)phenyl]imidazolidin-2,4-dione};
- 1,1'-(oxititan-2,1-diyl)bis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione};
- 4,4'-[pentane-1,5-diylbis(4,4-dimethyl-2,5-dioxoimidazolidin-3,1-diyl)]bis(2-methylbenzonitrile);
- 1,1'-(2Z)but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione}
or its pharmaceutically acceptable salt.

18. The compound of the General formula (I), which represents a 1,1'-pentane-1,5-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione} or compound 1,1'-(2Z)but-2-ene-1,4-diylbis{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidin-2,4-dione} or their pharmaceutically acceptable salt.

19. Pharmaceutical composition for cancer treatment, sod�Rasa as active substance a compound of the formula (I), such as defined according to any one of claims.1-18, in combination with a pharmaceutically acceptable carrier.

20. Use of a compound of formula (I) according to any one of claims.1-18 for obtaining a medicinal product intended for the treatment of cancer.

21. The use according to claim 20, in which the drug is intended to treat hormone-dependent cancer.

22. The use according to claim 20, in which the drug is intended for treatment of a cancer expressing the androgen receptor.

23. The use according to any one of claims.20-22, in which the drug is intended to treat cancer of the breast or prostate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing pyrazoline carboxamidine derivatives of formula . Said compounds are known as powerful 5-HT6 antagonists. The disclosed method comprises reacting a corresponding substituted 4,5-dihydro-(1H)-pyrazole or an isomer thereof with isothiocyanate R6-N=C=S to obtain an amide of substituted 4,5-dihydro-(1H)-pyrazole-1-carbothioic acid or tautomeric substituted 4,5-dihydro-(1H)-pyrazole-1-carboxymidothioic acid . The obtained intermediate compounds are reacted with a corresponding alkylating agent to obtain an intermediate S-alkylated compound . Said intermediate compound is reacted with a sulphonamide derivative R7SO2NH2 and the target compound of formula (I) is separated from the reaction mixture. The invention also relates to novel intermediate products (IIIa), (IIIb) and (IV). Symbols given in the formulae have values given in the description.

EFFECT: providing an alternative method which improves atom efficiency of synthesis of desired compounds with higher output compared to existing methods for synthesis of said compounds.

8 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to compounds of formula (I), wherein R1 and R2 independently represent C6-C10 aryl optionally substituted by -OH, halogen, -OC1-C3 alkyl, -NO2, -CF3 or C1-C3 alkyl, or 5- or 6-merous heteroaryl containing one heteroatom specified in N, S and O; A and M independently represent a methylene group or a single bond; an adjacent aromatic cycle is attached directly to an amide group; the group Y=Z represents together and irregularly oxygen atom (-O-), cis-vinylidene group (-CH=CH-), iminogroup (-N=CH- or -CH=N-) or methylene group with sp2-hybridised carbon atom (=CH-); X irregularly represents methine group (=CH-), cis-vinylidene group (-CH=CH-) or carbon atom (=N-), and W represents hydroxyl group (-OH), C1-C6 alkyl optionally substituted by -SH, 5- or 6-merous heteroaryl containing 1 to 2 nitrogen heteroatoms, or C6-C10 aryl, optionally substituted by -SH, -NH2, and their pharmaceutically acceptable salts.

EFFECT: described are the methods for preparing the compounds, using as a drug for treating cancer and the based pharmaceutical composition.

14 cl, 6 tbl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of N-[-2[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azatidine-sulphonamide, which has an X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1.5418 E and containing, at least, one crystalline peak with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 2 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 3 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1. The said crystalline form can contain additional crystalline peaks with a value 2-theta (in degrees), selected from 12.9 and 18.0, obtained under the said conditions.

EFFECT: crystalline form has the X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1,5418 E, with the crystalline peaks with a value 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30,4, and has melting point (beginning) 152,7°C.

6 cl, 3 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (1), in which Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 denote an unsubstituted -C1-8-aliphatic; R3 denotes an unsubstituted -C6-16-aryl; R4 denotes -H or -C(=O)R0, where R0 denotes -C1-8-aliphatic, unsubstituted or mono- or polysubstituted with substitutes independently selected from a group consisting of -F, -Cl, -Br, -I and -CN; Q denotes unsubstituted -C1-8-aliphatic-heteroaryl; X denotes =O, =CR6R7 or =N-R6, wherein R5 denotes -NH2, -NH-(unsubstituted-C1-8-aliphatic) or -N-(unsubstituted-C1-8-aliphatic)2, if X denotes =O, or R5 and R6 together form a 5-member ring in which the remaining ring atoms independently denote C, N, S or O, wherein the 5-member ring denotes 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, oxazolyl or thiazolyl, in each case unsubstituted or monosubstituted with unsubstituted C1-C8aliphatic or =O, or unsubstituted tetrazolyl, if X denotes =N-R6, or R5 and R6 together form unsubstituted phenyl, and R7 denotes -H, if X denotes =CR6R7, where "aliphatic" in each case represents a branched or straight, saturated hydrocarbon residue; "aryl" in each case independently denotes a carboxylic ring system containing at least one aromatic ring which does not contain heteroatoms, where the aryl may be optionally condensed with other saturated, (partially) unsaturated or aromatic ring systems; "heteroaryl" denotes indolyl; in the form of a separate stereoisomer or a mixture thereof, in the form of free compounds and/or physiologically compatible salts thereof. The compound of formula

is used to obtain a medicinal agent having affinity for the µ-opioid receptor and the ORL1-receptor, and for treating pain.

EFFECT: substituted cyclohexyldiamines, having affinity for the µ-opioid receptor and the ORL1-receptor.

7 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I)

where Y represents a group of formula -(CR9R10)n-; X represents -C(=O)-; Z represents a group of formula -(CR13R14)q-; R1 is selected from a group, consisting of (a) C2-C12alkenyl, substituted with 4-chlorophenyl; or (b) C6-C10aryl, optionally substituted with one or two halogen atoms; R2 and R3 represent H; R4 is selected from a group, consisting of H, C1-C12alkyl, optionally substituted with hydroxyl, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted with an amino group or pyperidine, C-bound C1-C18heteroaryl, selected from pyridine and imidazole, C(=O)R15, C(=O)NR16R17 and ONR16C(=NR17)NR18R19; each R5a and R5b represents H, each R6, R7 and R8 is independently selected from a group, consisting of H, C1-C12alkyl and C6-C18aryl, each R9 and R10 represents H; each R13 and R14 represents H; R15 represents H, each R16, R17, R18, R19 and R20 is independently selected from a group, consisting of H, C1-C12alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or any two of R16, R17, taken together with atoms, to which they are bound, form a cyclic group, containing 5 carbon atoms, or n equals to 1; q represents an integer number, selected from a group, consisting of 1, 2, 3, 4 and 5; r equals to 1; or its pharmaceutically acceptable salt.

EFFECT: invention relates to a pharmaceutical composition for treatment of MC5R-associated conditions, which contains a formula (I) compound and a pharmaceutically acceptable carrier, a diluent or a filling agent.

23 cl, 6 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: described are novel crystalline forms of (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one: Form I, Form II, Form III, Form IV and Form VI, each characterised by X-ray powder diffraction (XRPD) data and infrared spectrum data, and a method of producing crystalline Form VI. The preferred form is Form VI, which has antifungal and antimicrobial activity, has the least impurity content, the highest uniform quality of the product, the highest uniform physical characteristics, including colour, rate of dissolution, easiness of handling and longest stability compared to the amorphous form.

EFFECT: improved properties of the compound.

19 cl, 22 ex, 25 tbl, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formulas

and or pharmaceutically acceptable salts thereof, wherein the values R1-R13, Ra, Rb, Rc, Rd, Rf, Rq, n are presented in the patent claim possessing the properties of protein p53 activator.

EFFECT: compounds may be used in treating cancer and diseases caused by a fungal, bacterial or parasitic infection, eg malaria.

16 cl, 38 dwg, 12 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazolone derivatives used as drugs being kinase inhibitors, described by formula (I), wherein; R1 represents a C1-C3 alkyl radical or a hydrogen atom, and/or an aryl radical, Ar1 is specified in or , R represents the group R2-S-, R2 is thereby specified in the radicals like T1-(CH2)n, wherein n=0, 1, 2 or 3, and T1 represents a metal, vinyl, alkyl, alkynyl, nitrile, C3- or C4-cycloalkyl radical, hal, Z-O, Z-CO, wherein Z represents C1-C3 alkyl or hal, hal represents F, Cl, Br or I, or the group CCl3, or the group R3-NH-, R3 is thereby specified in the radicals like T2-(CH2)n, wherein n=0, 1 or 2, and T2 represents a metal, vinyl radical, Z-O, Z-CONH-, -CH-(OZ)2, ZCO, wherein Z represents H or C1-C4 linear or branched alkyl, NH2, C3-cycloalkyl, aryl, substituted aryl, or R3 represents H, or the group R4-CONH-, R4 is thereby specified in C3-C5 branched alkyl, or Ar2- or Ar2-3-, Ar2 is specified in a phenyl radical, substituted phenyl or benzodioxolyl; and have IC50 less than 5 mcM.

EFFECT: invention also refers to pharmaceutical compositions based on the compounds of formula I for treating neurodegenerative disorders and to using these compounds as DYRKIA inhibitors.

11 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a combination of leucine source and ω-3 polyunsaturated fatty acid source applicable in therapeutic or preventive treatment of hypercalcemia.

EFFECT: invention provides extending the range of products applicable in the therapeutic or preventive treatment of hypercalcemia.

19 cl, 8 dwg, 2 tbl, 4 ex

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