Cis-2,4,5-triphenylimidazolines and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R means -C(O)R1 wherein R1 is chosen from the series: (C1-C6)-alkyl, -C=CH-COOH, -NHCH2-CH2R2, -N(CH2-CH2OH)CH2-CH2OH, -N(CH3)CH2-CH2-NHCH3, -N(CH3)CH2-CH2N(CH3)CH3, saturated 4-, 5- and 6-membered cycles and saturated and unsaturated 5- and 5-membered cycles comprising at least one heteroatom from a series sulfur (S), nitrogen (N) and oxygen (O), and optionally substituted with a group chosen from the series: (C1-C6)-alkyl, -C=O-R5, -OH, (C1-C6)-alkyl substituted with hydroxy-group optionally, (C1-C6)-alkyl substituted optionally with a group of the series: -NH2, -N-(C1-C6)-alkyl, -SO2CH3, =O, and 5- and 6-membered saturated cycles comprising at least one heteroatom chosen from N and O, and wherein R5 is chosen from the series: hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkyl substituted with hydroxy-group optionally, and (C1-C6)-alkyl substituted with NH2-group optionally; R2 is chosen from the series: -N(CH3)CH3, -NH2, morpholinyl and piperazinyl; X1, X2 and X3 are chosen independently from the series: -OH, (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CH2OCH3 and -CH2OCH2CH3, or one among X1, X2 or X3 means hydrogen atom, and two others are chosen independently from the series: hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2-CH2R3, -OCH2-CF3 and -OR4, morpholylmethyl, -N(CH3)CH3, -CH2OH, -COOH, or one among X1, X2 or X3 means hydrogen atom, and two others in common with two carbon atoms including bonds between them in benzene cycle to which they are bound optionally form 5- or 6-membered saturated cycle comprising at least one heteroatom chosen from S, N and O, and wherein R3 is chosen from the series: -F, -OCH3, -N(CH3)CH3, saturated 5-membered cycle comprising at least one heteroatom N; R4 means 3-5-membered saturated cycle, and each Y1 and Y2 is chosen independently from the series: -Cl, -Br, -NO2,-C≡N and C≡N, and compound of the formula (II) also given in the invention description. Also, invention relates to a pharmaceutical composition possessing anti-proliferative activity and based on these compounds. Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 39 ex

 

Protein p53 is a tumor-suppressor gene, which performs a major function in protection against tumor development. It helps to preserve the integrity of cells and prevents reproduction of clones damaged cells inducyruya cessation of growth or apoptosis. At the molecular level protein p53 is a transcription factor that can activate a set of genes involved in cell cycle regulation and apoptosis. Protein p53 is a potent inhibitor of the cell cycle, which is strictly regulated by the MDM2 protein at the cellular level. MDM2 and p53 form a control system on the basis of feedback. MDM2 can bind p53 and inhibit its ability to reactivate controlled by the p53 protein genes. In addition, MDM2 mediates ubiquitin-dependent degradation of p53 protein. Protein p53 can activate the expression of the MDM2 gene, thereby increasing cellular levels of MDM2 protein. This feedback system provides the lowest level of both MDM2 and p53 protein in normal proliferating cells. MDM2 is also a cofactor E2F, which plays a Central role in the regulation of cell cycle.

The ratio of MDM2/p53 (E2F) is violated in many types of malignant diseases. Installed, for example, that common molecular defects in the locus of p16INK4/p19ARF have an effect on the degradation of protein MD2. Inhibition of the interaction between MDM2/p53 in tumor cells protein p53 wild type should lead to the accumulation of p53, the cessation of cell growth and/or apoptosis. Therefore, antagonists of MDM2 can be used when developing a new approach in Oncology alone or in combination with a wide range of other anticancer agents. The effectiveness of this strategy is established by using different high-molecular-weight agents (e.g., antibodies, antisense oligonucleotides, peptides) to inhibit the interaction of MDM2/p53. As p53, MDM2 binds to E2F by conservative binding site and activates 2F-dependent transcription cyclina And svidetelstvo that MDM2 antagonists may affect the level of p53 in mutant cells.

The article Wells and others, J. Org. Chem., 37, 2158-2161 (1972) reported the synthesis of imidazoline. In the article, Hunter, and others, Can. J. Chem., 50, 669-677 (1972) reported the formation of compounds Amarin and Samarina, chemiluminescent properties of which were studied previously (McCapra and others, Photochem. and Photobiol., 4, 1111-1121 (1965)). In article Zupanc, etc., Bull. Soc. Chem. and Technol. (Yugoslavia), 27/28, 71-80 (1980-81) reported the use of triarylmethane as starting materials for obtaining derivatives of EDTA. In EP 363061 (Matsumoto) described the use of imidazoline derivatives as immunomodulators. It is established that the compounds possess is of low toxicity. It is proposed to use these compounds for the treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, lupus erythematosus, and rheumatic fever. In WO 00/78725 (Choueiry and others) describes a method for substituted compounds of amidine and found that the connection type imidazoline can be used for the treatment of diabetes and related diseases, including impaired glucose disposal.

The present invention relates at least to the compound of formula I

and its pharmaceutically acceptable salts and esters, where

R is-C=OR1where

R1choose from a range of C1-C6alkyl, -C=SSOON, -NHCH2CH2R2,

-N(CH2CH2OH)CH2CH2OH, -N(CH3)CH2CH2NCH3,

-N(CH3)CH2CH2N(CH3)CH3,

saturated 4-, 5 - and 6-membered cycles and saturated and unsaturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O and optionally substituted by a group selected from the range of C1-C6alkyl, -C=O-R5,

HE, C1-C6alkyl, optionally substituted by a hydroxy-group, C1-C6alkyl, optionally substituted by a group-NH2, -N-(C1-C6)alkyl, -SO2CH3, =O, CH2C=co 3and 5 - and 6-membered saturated cycles containing at least one heteroatom selected from the series S, N and O, where

R5choose from a range of H, C1-C6alkyl, -NH2, -N-(C1-C6)alkyl, C1-C6alkyl, optionally substituted by a hydroxy-group, and C1-C6alkyl, optionally substituted by a group-NH2,

R2choose from a range-N(CH3)CH3, -NCH2CH2NH2, -NH2morpholinyl and piperazinil,

X1, X2and X3independently selected from the series-HE1-C2alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CH2OCH3and CH2OCH2CH3or one of X1X2or X3means hydrogen, and the other two are independently selected from a number of hydroxy, C1-C6alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CF3, -CH2Och3, -CH2OCH2CH3, -OCH2CH2R3,

-Och2CF3and-OR4or one of X1, X2or X3means hydrogen, and the other two together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are necessarily attached, form a 5 - or 6-membered saturated cycle containing at least one heteroatom selected from the series S, N and O, where

R3choose from a number of-F, -och3, -N(CH3)The h 3, -Cl, -Br, unsaturated 5 - and 6-membered cycles containing at least ODI heteroatom selected from the series S, N and O,

R43-5-membered saturated cycle, and

Y1and Y2each independently selected from a number of-Cl, -Br, -NO2, -C=N and-C=CH.

Another object of the present invention is at least one compound of the formula II

and its pharmaceutically acceptable salts and esters, where

R is-C=OR1where

R1choose from a range of C1-C6alkyl, saturated 5 - and 6-membered cycles, saturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O and optionally substituted by a group selected from a range With1-C2alkyl, C1-C3alcohol, -N(CH3)CH3- =Co3and 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O,

X4choose from a number With1-C2alkyl, C1-C6alkoxy, floratone, -Cl, -Br, -F, -OCH2C=OOQ, -O-(C1-C6)alkyl, -co2-cyclopropyl, -CH2Och2-phenyl, a saturated or unsaturated 5 - and 6-membered cycles, saturated and unsaturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O, where

Q is chosen from the series hydrogen, C1-C6alkyl,

Y and Y2independently selected from a number of-Cl, -Br, -NO2, -C=N and C=CH,

if Y1and Y2both mean-Cl, a R1means-CH3or phenyl,

X4not mean-Cl.

Another object of the present invention is a pharmaceutical composition containing these compounds, and the use of such compounds in therapy, especially in the treatment of cancer.

Another object of the present invention is a method of obtaining such compounds.

The present invention relates to CIS-imidazolines, which are low molecular weight inhibitors of the interaction between MDM2/p53. When tested in a cell-free medium or in the cells established that the compounds of the present invention inhibit the interaction of MDM2 protein with a peptide analogue of p53 protein with an efficiency of 100 times higher compared to the peptide of p53 protein. When tested on cells, these compounds exhibit mechanistic activity. Incubation of tumor cells with wild type p53 leads to the accumulation of p53 protein, induction of the P21 gene, which is regulated by the p53 protein, and cell cycle arrest in the G1 phase and G2. This leads to a high antiproliferative activity in vitro against cells containing wild type p53. On the contrary, this activity is not observed for tumor cells containing mu is based p53, at comparable concentrations of the analyzed compounds. Therefore, the activity of MDM2 antagonists is probably related to the mechanism of action of the protein MDM2. These compounds may represent an effective and selective antitumor agents.

Unless otherwise stated, terms used in the description of the application to illustrate the extent and nature of the invention, have the following meanings.

"Effective amount" means an amount of compound that is effective to prevent, reduce or suppress the symptoms of disease or prolong the life of the subject in need of treatment.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Heteroatom" means an atom selected from the series N, O or S.

"IC50" means the concentration of a particular compound required for inhibition of specific defined activity by 50%. IC50you can define, as described below.

"Alkyl" means a saturated aliphatic hydrocarbon straight or branched chain. The term "(ness.)alkyl" group means C1-C6alkyl groups and includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-butyl, pentyl, hexyl, etc. In the General case (ness.)alkyl preferably means1-C4alkyl, more preferably C1-C3alkyl.

"Alkoxy" means --alkyl. "(Ness.)alkoxy" means-O-(C1-C6)alkyl.

The term "saturated 4-, 5 - and 6-membered cycle for R1preferably means cyclopentyl and cyclohexyl.

The term "saturated or unsaturated 5-and 6-membered cycles containing at least one heteroatom selected from the series S, N or O for R1preferably means a saturated or unsaturated cyclic system, such as morpholinyl, piperazinil, piperidinyl, thiophenyl, isoxazolyl, furanyl and piperazinyl, more preferably piperazinil.

The term "unsaturated 5 - and 6-membered saturated cycles containing at least one heteroatom" for R3preferably means imidazolyl.

The term "3-to 5-membered saturated cycle for R4preferably means an aliphatic cycle, such as cyclopentyl.

"Pharmaceutically acceptable ester" means, respectively, esterified compound of the formula I containing a carboxy group. And esters possess biological activity and properties of the compounds of formula I and are oxidized in vivo (in the body) with the formation of the corresponding active carboxylic acid.

Information on esters and their use for delivering pharmaceutical compounds can be found in the monographs Design of Prodrugs, ed. by H.Bundgaard, Elsevier (1985); and H.Ansel and others, Pharmaceutical Dosae Forms and Drug Delivery Systems, 6thEd., p.108-109 (1995), Krogsgaard-Larsen and others, in Textbook of Drug Design and Development, 2d Ed., str-191 (1996).

"Pharmaceutically acceptable salt" means ordinary acid additive salts or basic additive salts, which possess the biological activity and properties of the compounds of the present invention and which are derived from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of the acid additive salts include inorganic salts such as chloride-hydrogen acid, Hydrobromic acid, Modesto-hydrogen acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acid salts such as paratoluenesulfonyl acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. are Examples of basic additive salts include salts of ammonium, potassium, sodium and salts of Quaternary ammonium hydroxides, such as a hydroxide of Tetramethylammonium. Chemical modification of pharmaceutical compounds (i.e. medicines) with the formation of salts are known in the art and is used to improve the physical and chemical stability, hygroscopicity, flowability and races is foremost compounds. Cm. H.Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6thEd., str and 1456-1457 (1995).

"Pharmaceutically acceptable"such as pharmaceutically acceptable carrier, excipient etc., means pharmacologically acceptable and practically non-toxic in relation to the subject, which enter the specified material.

"Substituted, for example substituted alkyl, means that the Deputy can be in one or more position and, unless otherwise specified, the substituents in each position is chosen independently of the specified groups. "Therapeutically effective amount" means an amount of at least one compound of the present invention, which significantly inhibits the proliferation and/or prevents differentiation of tumor cells, including line human tumor cells.

The present invention relates to a compound of formula I

and its pharmaceutically acceptable salts and esters, where

R is-C=OR1where

R1choose from a range of C1-C6alkyl, -C=SSOON, -NHCH2CH2R2,

-N(CH2CH2OH)CH2CH2OH, -N(CH3)CH2CH2NCH3, -N(CH3)CH2CH2N(CH3)CH3,

saturated 4-, 5 - and 6-membered cycles and saturated and unsaturated 5 - and 6-membered cycles containing what about the at least one heteroatom, selected from the series S, N and O and optionally substituted by a group selected from a range With1-C6alkyl,

-C=O-R5-HE , C1-C6alkyl, optionally substituted by a hydroxy-group, C1-C6alkyl, optionally substituted by a group-NH2, -N-(C1-C6)alkyl, -SO2CH3, =O, CH2-C=co3and 5 - and 6-membered saturated cycles containing at least one heteroatom selected from the series S, N and O, where

R5choose from a range of H, C1-C6alkyl, -NH2, -N-(C1-C6)alkyl, C1-C6alkyl, optionally substituted by a hydroxy-group, and C1-C6alkyl, optionally substituted by a group-NH2,

R2choose from a range-N(CH3)CH3, -NCH2CH2NH2, -NH2morpholinyl and piperazinil,

X1, X2and X3independently selected from the series-HE1-C2alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CH2OCH3and CH2OCH2CH3or one of X1X2or X3means hydrogen, and the other two are independently selected from a number of hydroxy, C1-C6alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3,

-Och2CH2R3, -Och2CF3and-OR4or one of X1X2or X3oz ACHAT hydrogen, and the other two together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are necessarily attached, form a 5 - or 6-membered saturated cycle containing at least one heteroatom selected from the series S, N and O, where

R3choose from a number of-F, -och3, -N(CH3)CH3, -Cl, -Br, unsaturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O,

R43-5-membered saturated cycle, and

Y1and Y2each independently selected from a number of-Cl, -Br, -NO2, -C=N and C=CH.

In a preferred embodiment, the invention includes compounds of formula I, where Y1and Y2each independently selected from a number of-Cl and-Br.

In another preferred embodiment, the present invention relates to compounds of formula I, where R1choose from a range morpholinyl, piperazinil, piperidinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl, furanyl, piperazinil, substituted by at least one group selected from a number of

C1-C3alkyl, -C1-C2alkoxy, -C=co3, -SO2CH3, -C=O, -OH, -CH2NH2,

-C=OCH2NH2- =Co2OH, -C=OS(OH)CH2OH, -CH2S(HE)-CH2OH,

-C=ON(CH2-)2, -C ONH2and- =ON(CH3)CH3- =Cos(CH3)2, -CH2C=is CH 3,

-CH2CH(OH)CH3, -CH(CH3)CH(OH)CH3and CH2CH2OH.

In another preferred embodiment, the present invention relates to compounds of formula I where one of X1X2or X3means hydrogen,

and the other two are independently selected from a number of hydroxy, C1-C5alkoxy, -Cl, -Br, -F, -CH2OCH3, -CH2OCH2CH3With1-C2alkyl, -co2CH2R3and-OR4where R3choose from a number of-F, -och3, -N(CH3)CH3unsaturated 5-membered cycles containing at least one heteroatom selected from the series S, N and O, and where R4means cyclopentyl, more preferably R3means imidazolyl, or one of X1X2or X3means hydrogen, and the other two together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are necessarily attached, form a 5-membered saturated cycle containing at least one heteroatom selected from the series S, N and O.

Preferably, if one of X1, X2or X3means hydrogen, then the other two are independently selected from a number-och3and CH2Och2CH3.

More preferably, if one of X1, X2or X3means hydrogen, one or two other oznacza the t-O-C 1alkyl, -O-C2alkyl or-O-C3alkyl.

Another variant of the present invention relates to compounds of formula I, where X3means hydrogen, and X1and X2together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are attached, form a 6-membered saturated cycle containing one heteroatom, which means Acting

Another variant of the present invention relates to compounds of formula I, where one of the groups X1, X2and X3means hydrogen metaprogram, group orthopaedie choose from With1-C5alkoxy, and-och2CF3and group paraprotein means (ness.)alkoxy. Preferably the group X1, X2and X3in anthopology choose from a number of ethoxy, isopropoxy and-och2CF3but in paraprotein selected from methoxy, ethoxy. In this preferred embodiment, R1choose from a number piperazinil and substituted piperazinil.

Another variant of the present invention relates to compounds of formula I, where one of the groups X1, X2and X3means hydrogen metaprogram, group orthopaedie means C1-C6alkoxy, and the group paraprotein means-Cl, -Br or F, or one of the groups X1X2and X3means hydrogen paraprotein, two each the e group orthopaedie mean C 1-C6alkoxy, and the group metaprogram means-Cl, -Br, or-F.

Another variant of the invention relates to the compound of formula II

and its pharmaceutically acceptable salts and esters, where

R is-C=OR1where

R1choose from a range of C1-C6alkyl, saturated 5 - and 6-membered cycles, saturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O and optionally substituted by a group selected from a range With1-C2alkyl, C1-C3alcohol, -N(CH3)CH3- =Co3and 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O,

X4choose from a number With1-C2alkyl, C1-C6alkoxy, floratone, -Cl, -Br, -F,

-OCH2C=OOQ, -O-(C1-C6)alkyl, -co2-cyclopropyl, -CH2OCH2-phenyl,

saturated and unsaturated 5 - and 6-membered cycles, saturated and unsaturated 5 - and 6-membered cycles that contain at least one

heteroatom selected from the series S, N and O, where

Q is chosen from the series hydrogen, C1-C6alkyl,

Y1and Y2independently selected from a number of-Cl, -Br, -NO2, -C=N and C=CH, if Y1and Y2both mean-Cl, a R1means-CH3or phenyl,

X4not mean-Cl.

the preferred embodiment, the present invention relates to compounds of the formula II, where X4choose from a number of-CH3C1-C6alkyl, -Cl, -Br, -och2C=OOQ, phenyl and pyrrolidinyl, more preferably X4choose from a number of-CH3C1-C6alkoxy,

-Och2C=OOQ, phenyl and pyrrolidinyl, where Q denotes hydrogen or-CH2CH3.

Another preferred variant of the present invention relates to compounds of formula II, where R1choose from a number of-CH(CH3)CH3, piperazinil, piperazinil substituted by a group selected from a range, -CH3, -CH2CH2HE is C=co3piperazinyl and piperidinyl substituted by a group selected from a range, pyrrolidinyl, piperidinyl and-N(CH3)CH3.

More preferably, C1-C6alkyl in the compounds of formula II are selected from a range With1alkyl, C2alkyl and C3alkyl.

More preferably, the present invention includes compounds of formula II where Y1and Y2independently selected from-Cl and-Br.

Another preferred variant of the present invention relates to compounds of formula I, where X4means C1-C6alkoxy in anthopology, more preferably C1-C6alkoxy choose from a number, ethoxy, isopropoxy and 2 floratone. In this preferred embodiment, R1choose from a number piperazinil and substituted piperazinil.

On toadie the invention relates to compounds of the formula I, selected from the set:

a) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

b) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]alanon,

C) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2,2-DIMETHYLPROPANE-1-he,

g) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclopentylamine,

d) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclohexylmethanol,

(e) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]thiophene-2-ylmethanol,

W) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]isoxazol-5-ylmethanol,

C) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]furan-2-ylmethanone,

s) 1-[4,5-bis-(4-chlorophenyl)-2-(2,3-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

K) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

l) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

m) [4,5-bis-(4-chlorophenyl)-2-(2-fluoro-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

h) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

o) [4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-ylmethanone,

p) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

R) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

(C) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

t) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

u) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

f) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

x) 4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

C) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

h) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

W) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

y) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](2,5-dimethylpiperazine-1-yl)methanon,

e) bis-(2-hydroxyethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbon is th acid,

Yu) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon,

I) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

AA) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

BB) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

et [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

gg) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon,

DD) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

her [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxyethylpiperazine-1-yl)methanon,

LJ) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperidine-1-yl]metano,

ZZ) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanon,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-2-methylpiperazin-1-yl}Etalon,

QC) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-digidroid Gasol-1-yl](4-methanesulfonyl-3-methylpiperazin-1-yl)methanon,

FL) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxypiperidine-1-yl)methanon,

mm) (4-aminomethylpyridine-1-yl)[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

NN) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

OO) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

PP) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

PP) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

her [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

TT) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde,

SU) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

FF) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

XX) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon,

TP) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-he

In another embodiment, the present invention includes compounds of formula I, selected from the set:

a) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

b) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

in) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

g) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

e) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

(e) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon,

g) 4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

C) [4,5-bis-(4-cyanophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

s) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon,

K) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon,

l) 4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

m) hydrochloride [4,5-bis-(4-shall lorgeril)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

n) triptorelin methyl(2-methylaminomethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

on triptorelin (2-dimethylaminoethyl)methylamine 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

p) triptorelin (2-dimethylaminoethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

R) triptorelin (2-amino-ethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

C) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanone,

t) triptorelin [4,5-bis-(4-chlorophenyl)-2-(4-methoxy-2-propoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

y) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone,

f) hydrochloride (2-morpholine-4-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

x) hydrochloride (2-piperazine-1-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

C) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isobutoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

4) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanone,

W) triptorelin {4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

y) {4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

e) hydrochloride {4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}(4-pyrrolidin-1-reparacin-1-5 Il)methanone,

h) 2-amino-1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

I) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-hydroxyethane,

AA) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2,3-dihydroxypropane-1-he,

BB) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2,3-dihydroxypropyl)piperazine-1-yl]metano,

BB) dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

yy) amide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

DD [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

her [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

LJ) [4,5-bis-(4-harfe who yl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)piperazine-1-yl]metano,

ZZ) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

QC) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

FL) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

mm [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

NN) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon,

OO) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

PP) amide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

PP) dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

her [4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

TT) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

su) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

FF) [4,5-bis-(4-chlorophenyl)-2-(4-ethyl-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperaz the n-1-ylmethanone,

XX) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

TP) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

HH) triptorelin [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone.

In another embodiment, the present invention includes compounds of formula I, selected from the set:

a) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

in) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

g) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

d) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

(e) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

W) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

I) 4-[4,5-bis-(4-chlorophenyl)-2-(4-fluoro-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

K) [4,5-bis-(4-chlorophenyl)-2-chroman-8-yl-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

l) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

m) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

n) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

o) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

p) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

R) [4,5-bis-(4-chlorophenyl)-2-(2-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) {4,5-bis-(4-chlorophenyl)-2-[2-(2-dimethylaminoethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

t) {4,5-bis-(4-chlorophenyl)-2-[2-(2-imidazol-1-ylethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

y) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

f) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone,

x) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanone,

C) [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-digidroid the evils-1-yl]morpholine-4-ylmethanone,

h) 1-{4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

W) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

u) 4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

e) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

Yu) triptorelin [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

I) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

AA) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

BB) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

et [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

gg) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

DD) 4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

her [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

LJ) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

ZZ) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

QC) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

FL) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

mm) triptorelin [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

NN) [4,5-bis-(4-chlorophenyl)-2-(2,4-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

OO) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2,5-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

PP) 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxy-5-morpholine-4-ylmethylene)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

PP) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

it) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]alanon,

TT) 1-[4,5-bis-(4-chlorophenyl)-2-(3-methoxy-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

yy) 3-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]-5-methoxypyrazine acid,

FF) 1-[,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

XX) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone and

TP) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone.

In another embodiment, the present invention includes compounds of formula I, selected from the set:

a) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxypropyl)piperazine-1-yl]metano,

b) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-threo-[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano,

in) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-Erythro-[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano,

g) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}propane-2-it,

d) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][1,4]diazepan-1-ylmethanone,

e) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-it,

W) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-methylpropan-1-he,

C) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde,

I) 4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

K) 4-{4,5-bis-(4-bromophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

l) [4,5-bis-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

m) 1-{4-[2-(5-chloro-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

n) [5-(4-chlorophenyl)-4-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon.

In another embodiment, the present invention includes compounds of formula II, selected from the set:

a) 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

b) 1-[4,5-bis-(4-chlorophenyl)-2-para-tolyl-4,5-dihydroimidazole-1-yl]alanon,

C) ethyl ester {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid,

g) {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid,

d) 2-methyl-1-[2,4,5-Tris(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]propane-1-he,

e) 1-[4,5-bis-(4-chlorophenyl)-2-(4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]alanon,

W) [2-(2-chlorophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) [2-(3-bromophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

and) [2-biphenyl-3-yl-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)m is the Thanon beach,

K) [4,5-bis-(4-chlorophenyl)-2-(3-pyrrolidin-1-ylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

l) [4,5-bis-(4-bromophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

m) 1-[5-(4-chlorophenyl)-2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

n) 1-[4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

o) 1-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

p) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

R) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

(C) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

t) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

u) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

f) {4,5-bis-(4-chlorophenyl)-2-[2-(2-methylbutoxy)phenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

x) [4,5-bis-(4-chlorophenyl)-2-(2-pentyloxide)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) triptorelin [4,5-bis-(4-chlorophenyl)-2-(3-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

h) triptorelin [4,-bis-(4-chlorophenyl)-2-(3-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

W) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

y) [4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

e) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

Yu) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano.

Compounds of the present invention exhibit extremely high antitumor activity against different lines of tumor cells. This antitumor activity suggests that the compounds of the present invention can be used as anticancer agents.

One of the variants of the present invention also includes a pharmaceutical composition comprising the compound according to the invention as an active ingredient and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition according to the invention suitable for oral or parenteral administration.

The pharmaceutical compositions can be administered orally by the way, for example, in the form of pills, tablets in the shell, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions. Connections can also enter the rectal method, for example, and the use of suppositories, local or percutaneous manner, for example, using ointments, creams, gels or solutions, or by parenteral means, for example, intravenous, intramuscular, subcutaneous, intrathecal or percutaneous manner, for example, using injection solutions.

To obtain tablets, tablets in the shell, coated tablets or hard gelatin capsules of the compounds of the present invention can be mixed with pharmaceutically inert inorganic or organic excipients. Examples of suitable excipients for tablets, pellets in the shell, coated tablets or hard gelatin capsules include lactose, corn starch or its derivatives, talc or stearic acid or its salts.

Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like; depending on the nature of the active components in the case of soft gelatin capsules usually do not require any of the excipients.

To obtain solutions and syrups are suitable excipients are, for example, water, polyols, saccharose, invert sugar and glucose.

Excipients for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils.

Suitable excipients for suppositories and drugs for local or Crisco the aqueous injection include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

Pharmaceutical compositions may also contain preservatives, solubilizing agents, stabilizing agents, moistening agents, emulsifying agents, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, coating agents or antioxidants. In addition, they can contain other therapeutically valuable agents.

In General, the pharmaceutical composition for oral administration can be a granule, a pill, a tablet coated sucrose, capsule, pill, suspension or emulsion. The compositions for parenteral injection, such as intravenous injection, intramuscular and subcutaneous method, can be used in the form of a sterile aqueous solution which may contain other substances, for example salts or glucose to make the solution isotonic properties. The antitumor agent can also enter in the form of a suppository or pessary, or such agents can enter the local way in the form of a lotion, solution, cream, ointment or spray powder.

The present invention relates also to the use of the above compounds to obtain drugs, preferred drugs, dedicated to superior quality products is obtained for the treatment or suppression of disorders of cell proliferation, more preferably for the treatment or suppression of cancer.

For example, the medicaments are preferably used for the treatment or suppression of cancer of the breast, colon, lung or prostate cancer.

Another option of the present invention is a method of treatment of disorders of cell proliferation, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of the present invention. More preferably the method according to the invention relates to a method, where the violation of cell proliferation means cancer, most preferably breast cancer, colon, lung or prostate cancer.

Finally, the present invention relates to compounds of formula I and compounds of formula II for use in therapeutic purposes.

Compounds of the present invention preferably are characterized by values of the IC50from about 70 nm to about 100 mm.

A therapeutically effective amount of the compounds of the present invention means the amount of compound that is effective to prevent, reduce or suppress the symptoms of disease or prolong the life of the subject in need of treatment. Ways to determine the value of therapeutically effective amounts known in the art.

Therapeutically effective amount or dose of a compound of the present invention may be varied within a wide range and it is determined by known methods. These doses should be adjusted to the individual requirements in each particular case, including the nature of specific compounds (compounds)intended for injection, route of administration, the condition to be cured, and the patient's condition. In General, oral or parenteral administration to adult humans weighing approximately 70 kg is sufficient daily dose from about 10 mg to about 10000 mg, preferably from about 200 mg to about 1000 mg, although the upper limit can be exceeded in accordance with the indications. The daily dose can be administered as a single dose or divided doses, or when parenteral administration by continuous infusion.

Compounds of the present invention produced by the method shown in the following diagrams. The initial compounds known in the art or are commercial products. Shown in the schemes group, and the substituents have the following meanings:

V1, V2, V3, V4, V5each independently selected from the group comprising hydrogen, -OV6, -SV7, -NV8V9, -CONV8Vsup> 9, -COOV10, halogen, nitro, trifluoromethyl, C1-C6alkyl, optionally substituted by a group V11and cycloalkyl,

V1, V2together form part of a heterocycle, containing one or more heteroatoms and optionally substituted group V10,

V2, V3together form part of a heterocycle, containing one or more heteroatoms and optionally substituted group V10,

Y1, Y2each independently selected from the group-Cl, -Br, nitro, cyano

and-C=CH,

V choose from COV12and CONV13V14,

V6selected from the group including hydrogen, C1-C6alkyl, optionally substituted by a group V11and cycloalkyl,

V7selected from the group including hydrogen, C1-C6alkyl,

V8, V9each independently selected from the group including hydrogen, C1-C6alkyl and cycloalkyl,

V8, V9together form part of a heterocycle, containing one or more heteroatoms,

V10selected from the group including hydrogen, C1-C6alkyl and cycloalkyl,

V11selected from the group comprising-CONV8V9, -NV8V9, -COOV10, aryl, halogen, C1-C6alkoxy, morpholinyl and heterocycles,

V12selected from the group including hydrogen, C -C6alkyl, cycloalkyl, aryl, heterocycle and heteroaryl,

V13and V14each independently selected from the group including C1-C6alkyl, cycloalkyl,1-C4alkyl, substituted group V11or

V13and V14together form part of a heterocycle such as morpholine, piperidine, pyrrolidine and piperazine and piperazine substituted group number C1-C6alkyl, hydroxyalkyl, acyl, acyl, substituted hydroxy - and amino groups, alkylsulfonyl, CONH2, -CONV8V9, keto, hydroxy, and substituted piperidine dialkylamino, pyrrolidino or piperidine.

The compound of formula 2, which is a known compound or compound, obtained by known methods, is converted into a compound of formula 3 by treatment with gaseous HCl in ethanol over time from several hours to several weeks. Then the compound of formula 3 is introduced into reaction with the compound of the formula 4 in a solvent such as ethanol, at a temperature of from 60°to 100°With formation of the compound of formula 5.

If V is mean COV12the compound of formula 5 is introduced into reaction with the compound of the formula ClCOV12(known compound or compound that is obtained by the known methods) at a temperature of from 0°to 25°in the presence of a base, such as triethyl is in, with the formation of the compounds of formula 1.

If V means-CONV13V14(provided that NHV13V14is a known compound or compound, obtained by known methods), the compound of formula 5 is introduced into the reaction with phosgene at 0°in the presence of a base such as triethylamine, followed by treatment of the compound NHV13V14with the formation of the compounds of formula 1.

As shown in scheme II, if V15substituted piperazines are not commercial preparations (V15can mean acyl, acyl, substituted by hydroxyl, an amino group, a protected amino group and sulfonyl), the compound of formula 7 was obtained as follows: the compounds of formula 5 is introduced into the reaction with phosgene and triethylamine with subsequent treatment with piperazine to form compounds of formula 6. The connection 6 is introduced into reaction with the compound V15X with the formation of compound 7.

As shown in scheme III, a compound of formula 8 can be obtained from compounds of formula 6 by reaction with phosgene and triethylamine followed by treatment of the compound NHV8V9that is a known compound or compound obtained by the known methods.

Meso-1,2-diamine of formula 4 (Y1=Y2) get the technique is (Jennerwein, M. and others, Cancer Res. Clin. Oncol., 114, 347-358 (1988), F. Vogtle, Goldschmitt E., Chem. Ber., 109, 1-40 (1976)).

If necessary, the compound of formula 4, where Y1=Y2you can get modified by known methods. To obtain a mixture of 1,2-diamines can be used equimolar mixture of benzaldehyde and meso-1,2-bis-(2-hydroxyphenyl)ethane-1,2-diamine (scheme IV) (Knolker H.J. and others, Tetrahedron Letters, 39, 9407 (1998)). Then it is introduced into the reaction with di-tert-BUTYLCARBAMATE in the presence of dimethylaminopyridine with the formation of the compounds of formula 9, which cleanse methods GHUR. Then, compound 9 is converted into a compound of formula 4 in the processing of Hydrobromic acid in hot acetic acid.

To obtain the compounds of formula 2, which is not a commercial product, you can use a variety of known methods. Suitable methods of synthesis of these benzonitriles are given in the examples. These methods are shown in the following diagrams.

The compound of formula 11 (V16can mean any suitable group, such as V1, V2, V3, V4or V5) can be obtained by alkylation of compounds of formula 10 connection V6X (X=Cl, Br, I) with known methods (scheme V). Peroxid-anion is obtained by treatment with base, such as cesium carbonate or potassium carbonate. Usually the reaction is carried out at the boiling reverse the m a fridge in acetone. Deputy V6you can also enter by the reaction of Mitsunobu (see, for example, D.L. Hughes, Org. React., 42, 335-656 (1992)).

The compound of formula 12 (V16can mean any suitable group, such as V1, V2, V3, V4or V5) can be turned into benzonitrile 13 by known methods (Karmarkar S.N., Kelkar S.L., Wadia M.S., Synthesis, 510-512 (1985), Bergeron R.J., and others, J. Med. Chem., 42, 95-108 (1999)). Then the group V you can enter when using reagent V6X (X is Cl, Br, I) or by the reaction of Mitsunobu with the formation of benzonitrile 13 (scheme VI).

The compound of formula 15 can be obtained by bromirovanii or moderowaniem phenol 14 (scheme VII ((V16can mean any suitable group, such as V1, V2, V3, V4or V5). The reaction is carried out using N-bromosuccinimide/tetrahydrofuran or iodine/acetate thallium(I) (see, for example, Carreno M.C., Garcia Ruano J.L., G. Sanz, Toledo M.A., Urbano, A., Synlett, 1241-1242 (1997), R.C. Cambie, Rutledge P.S., Smith-Palmer T., Woodgate P.D., J. Chem. Soc., Perkin Trans., 1, 1161-1164 (1976)). Then injected Deputy V6when using reagent V6X (X is Cl, Br, I) or by the reaction of Mitsunobu. Methods of transformation of aromatic halides into the corresponding NITRILES are known in the art (see, for example, T. Okano, M. Iwahara, J. Kiji, Synlett, 243 (1998)). The cyanidation of halide 15 (X' is Br, I) in the cyanide of zinc in the presence of a catalyst, such as tetrakis(triphenylphosphine)palladium(0). As the solvent used dimethylformamide, and the temperature of the reaction mixture is maintained within the range 80-110°.

In scheme VIII shows that to obtain benzonitrile formula 17 can be used amination of aromatic halide reagent HNV7V8in the presence of a palladium catalyst (see, for example, M.C. Harris, Geis O., S.L. Buchwald, J. Org. Chem., 64, 6019 (1999)).

The compound of formula 13 (V16can mean any suitable group, such as V1, V2, V3, V4or V5) can be obtained by nucleophilic substitution of 2-halogenmethyl 18 (scheme IX). (See, for example, X means F: Wells C.M., Shi Y.-J., Lynch, J.E., Humphrey G.R., Volante R.P., Reider, P.J., Tetrahedron Lett., 37, 6439-6442 (1996); X indicates NO2: C.R. Harrison, Lett R., McCann S.F., R. Shapiro, T.M. Stevenson, WO 92/03421 (1992)).

To obtain benzonitrile formula 21 where V1, V2, V3, V4or V5mean OV6use sequential alkylation of diol 19 suitable reagent V6X (X is Cl, Br, I). Then from bromides 20 get NITRILES 21 when using cyanide zinc and catalyst Pd(0).

Some of the examples presented in prior the th application U.S. ser. room 60/341729. Examples of this prior application is entered into the description by reference.

The following examples illustrate the preferred methods of preparing compounds of the present invention and do not limit its scope. It is assumed that in these compounds the atoms of oxygen and nitrogen contain free pair of electrons capable of forming hydrogen bonds, as specified in the connection name.

Examples

Example 1

1-[4,5-Bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he

Through a solution of 2,4-dimethoxybenzonitrile (5.20 g, 32 mmole) in anhydrous ethanol (200 ml) at 0°missed gaseous hydrogen chloride. After 7 h the flow of gaseous hydrogen chloride was off and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue triturated in diethyl ether, was obtained the hydrochloride of the ethyl ester of 2,4-dimethoxybenzonitrile (4.5 g, 57%). The compound obtained was used without further purification.

A solution of meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (1,21 g, 4,30 mmole)obtained by the method described by Jennerwein, M. and others, Cancer Res. Clin. Oncol. 114, 347-8, (1988); F. Vogtle, Goldschmitt E., Chem. Ber. 109, 1-40, (1976), and hydrochloride of the ethyl ester of 2,4-dimethoxybenzonitrile (1,58 g, to 6.43 mmole) in ethanol (30 ml) to time make and under reflux for 16 hours The reaction mixture was podslushivaet solution of sodium bicarbonate (10 ml) and was extracted with ethyl acetate. The organic extracts were washed with saline and dried over anhydrous sodium sulfate. A solid substance was separated by filtration, the filtrate was concentrated in vacuum. The crude residue was purified Express chromatography (Biotage system, KP-Sil™, 32-63 μm, silica gel 60 (E) (eluent: 2-6% methanol in methylene chloride), was obtained 4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydro-1H-imidazole (1.10 g, 60%).

To a solution of triethylamine (25 μl, of 0.18 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydro-1H-imidazole (70 mg, 0,164 mmole) was added isobutyramide (19 μl, of 0.18 mmole). The reaction mixture was stirred at room temperature for 2 h, diluted with methylene chloride, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent: 0.5-1% methanol in methylene chloride), was obtained 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it. MS-BP (EI, m/z): Rasch. for C27H26N2O3Cl2496,1320, neid. 496,1319 (M+).

Example 2

The following compounds were obtained in the same way as described in example 1:

a) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-Digue is dromadol-1-yl]alanon, MS-BP (EI, m/z): Rasch. for C25H22N2O3Cl2468,1007, neid. 468,1020 (M+),

b) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2,2-DIMETHYLPROPANE-1-it, MS-BP (EI, m/z): Rasch. for C28H28N2O3Cl2510,1477, neid. 510,1476 (M+),

in) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclopentylamine, MS-BP (EI, m/z): Rasch. for C29H28N2O3Cl2522,1477, neid. 522,1470 (M+).

g) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclohexylmethanol, MS-BP (EI, m/z): Rasch. for C30H30N2O3Cl2536,1633, 10 calc. 536,1633 (M+),

d) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]thiophene-2-ylmethanol, MS-BP (EI, m/z): Rasch. for C28H20N2O3Cl2S 534,0572, neid. 534,0566 (M-2N)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]isoxazol-5-ylmethanol, MS-BP (EI, m/z): Rasch. for C27H21N3O4Cl2521,0909, neid. 521,0892 (M+),

W) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]furan-2-ylmethanone, MS-BP (EI, m/z): Rasch. for C28H20N2O4Cl2518,0800, neid. 518,0802 (M-2N)+,

C) 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it, MS-THE R (EI, m/z): Rasch. for C26H25N2O2Cl2467,1289, neid. 467,1295 (M+N)+,

s) 1-[4,5-bis-(4-chlorophenyl)-2-para-tolyl-4,5-dihydroimidazole-1-yl]alanon, MS-BP (EI, m/z): Rasch. for C24H20N2OCl2422,0953, neid. 422,0950 (M+),

K) ethyl ester {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid, MS-BP (ES, m/z): Rasch. for C29H29N2O4Cl2539,1499, neid. 539,1506 (M+N)+; original ethyl ester (4-cianfrocca)acetic acid was obtained from 4-hydroxybenzonitrile and ethyl ether bromoxynil acid, as described Kirkiachriah S., Goma J.R., and others, Ann. Pharm. Fr. 47, 16-23, (1989),

l) {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid was obtained by hydrolysis of the ethyl ester {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid, MS-BP (ES, m/z): Rasch. for C27H25N2O4Cl2511,1186, neid. 511,1191 (M+),

m) 2-methyl-1-[2,4,5-Tris(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]propane-1-it, MS-BP (FAB, m/z): Rasch. for C25H22N2OCl3471,0797, neid. 471,0814 (M+N)+,

n) 1-[4,5-bis-(4-chlorophenyl)-2-(4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-Etalon, MS-BP (FAB, m/z): Rasch. for C24H21N2O2Cl2439,0980, neid. 439,0967 (M+N)+,

o) 1-[4,5-bis-(4-chlorophenyl)-2-(2,3-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it, MS-BP (ES, m/z): Rasch. for C27H27N2O3Cl2497,1393, neid. 497,1398 (M+N)+.

Example 3

[4,5-Bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-(4-methylpiperazin-1-yl)methanon

To a cooled (0° (C) a mixture of triethylamine (0,37 ml of 2.64 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydro-1H-imidazole (225 mg, of 0.53 mmole, example 1) in THF (5 ml) was added dropwise phosgene (1.31 ml 2,53 mmole, of 1.93 M solution in toluene). The reaction mixture was stirred for 2.5 h and evaporated. The residue was kept under high vacuum for 30 min and again dissolved in methylene chloride (10 ml). The obtained suspension was added dropwise to a solution of N-methylpiperazine (1,05 g, 10,48 mmole) in methylene chloride (5 ml). After 1 h the reaction mixture was treated with sodium bicarbonate solution and was extracted with methylene chloride. The organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was evaporated, the residue was purified by chromatography on silica gel (eluent: 1-4% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon. MS-BP (ES, m/z): Rasch. for C29H31N4O3Cl3 553,1768, neid. 553,1773 (M+N)+.

Example 4

The following compounds were obtained in the same way as described in examples 1 and 3:

a) [2-(2-chlorophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C26H24N4OCl3513,1009, neid. 513,1013 (M+N)+,

b) [2-(3-bromophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C26H24N4OCl2Br 557,0505, neid. 557,0506 (M+N)+,

C) [2-biphenyl-3-yl-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C33H31N4OCl2569,1870, neid. 569,1875 (M+H)+,

g) [4,5-bis-(4-chlorophenyl)-2-(3-pyrrolidin-1-ylphenyl)-4,5-dihydro-imidazol-1-yl]piperazine-1-ylmethanol was obtained from 3-pyrrolidineethanol (described in the previous patent), MS-BP (ES, m/z): Rasch. for C30H32N5OCl2548,1979, neid. 548,1980 (M+H)+,

d) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C28H29H4O3Cl2539,1610, neid. 539,1613 (M+N)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(2-fluoro-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C29H30N4 3FCl2571,1674, neid. 571,1678 (M+N)+,

W) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydro-imidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C30H31N4O4Br2669,0707, neid. 669,0710 (M+N)+,

C) [4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C30H33N4O4Br2671,0863, neid. 671,0870 (M+N)+,

and) [4,5-bis-(4-bromophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C29H31N4O3Br2641,0758, neid. 641,0765 (M+N)+.

Example 5

1-[5-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1 he and 1-[4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he

To a solution of meso-1,2-bis-(2-hydroxyphenyl)ethane-1,2-diamine (5,38 g, 22 mmole), obtained as described Vogtle F., Goldschmitt E., Chem. Ber. 109, 1-40, (1976), in acetonitrile (50 ml) was added 4-nitrobenzaldehyde (3.33 g, 22 mmole) and 4-chlorobenzaldehyde (of 3.31 g, 23.5 mmole). The reaction mixture was heated under low boiling under reflux for 12 hours After cooling to room temperature the solvent was removed in vacuum.

The residue is suspended in 3 N. sulfuric acid and the reaction mixture is boiled under reflux for 2 hours After cooling to room temperature a by-product, salicylaldehyde was removed by extraction with diethyl ether (1×10 ml). The resulting diamine was besieged by neutralizing transparent water layer of 5% sodium hydroxide solution (pH>9). The crude 1-(4-chlorophenyl)-2-(4-nitrophenyl)ethane-1,2-diamine (4.61 in) was separated by filtration, washed with water and dried in vacuum over night.

To a solution of crude 1-(4-chlorophenyl)-2-(4-nitrophenyl)ethane-1,2-diamine (2,92 g) in acetonitrile (100 ml), cooled in an ice bath, was added di-tert-BUTYLCARBAMATE (6,77 g, 31 mmol). Then add dimethylaminopyridine (122 mg, 1 mmol) and the ice bath was removed. After 1 h was added an additional amount of dimethylaminopyridine (122 mg, 1 mmol). After several minutes, the mixture was heated at 50°within 10 minutes After evaporation of the solvent and purification of the crude mixture by reversed-phase GHUR received di-tert-butyl ester 4-(4-chlorophenyl)-5-(4-nitrophenyl)-2-oxocyclopent-1,3-dicarboxylic acid (1.19 g).

A mixture of di-tert-butyl ester 4-(4-chlorophenyl)-5-(4-nitrophenyl)-2-oxocyclopent-1,3-dicarboxylic acid (1.0 g, 2.0 mmole) in Hydrobromic acid (4,37 ml, 48%) and acetic acid (3,21 ml) was boiled under reflux overnight. After cooling to room temperature was added water. The mixture was washed with diethyl ether, and Podlachia is 10 N. NaOH. The aqueous layers was extracted with methylene chloride. The organic extracts were washed with saline, dried over magnesium sulfate and evaporated, to receive 1-(4-chlorophenyl)-2-(4-nitrophenyl)ethane-1,2-diamine (464 mg, 80%).

To a solution of 1-(4-chlorophenyl)-2-(4-nitrophenyl)ethane-1,2-diamine (200 mg, 0,685 mmole) and ethyl ester hydrochloride 4-methoxybenzimidazole (148 mg, China 0,686 mmole) in ethanol (5 ml) was added triethylamine (of 0.11 ml, 0.79, which mmole). The reaction mixture is boiled under reflux for 12 hours the Solvent was removed, it was obtained a clear oil, which was transferred in methylene chloride (2 ml) and aqueous sodium carbonate. The resulting product was extracted with methylene chloride (2×20 ml). The organic layers were washed with saline (1×5 ml), dried over sodium sulfate and concentrated. The crude residue was purified Express chromatography system (Biotage, eluent: 70% ethyl acetate in hexane), was obtained 4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydro-1H-imidazole (103 mg, 37%). To a solution of triethylamine (71 μl, of 0.51 mmole) and 4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydro-1H-imidazole (103 mg, 0.25 mmole) was added isobutyramide (32 μl, 0.30 mmole). The reaction mixture was stirred at room temperature for 2 h and then diluted with methylene chloride and a solution of sodium carbonate. Organic CL and washed with water and brine, was dried over sodium sulfate. The solvent was removed under reduced pressure, the crude residue was purified by chromatography on silica gel (eluent: 10-40% ethyl acetate in hexane), was obtained 2 product:

a) 1-[5-(4-chlorophenyl)-2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydro-imidazol-1-yl]-2-methylpropan-1-it (48 mg, 40%), MS-BP (ES, m/z): Rasch. for C26H25N3O4Cl 478,1528, neid. 478,1533 (M+N)+,

b) 1-[4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydro-imidazol-1-yl]-2-methylpropan-1-he (31 mg, 26%). MS-BP (ES, m/z): Rasch. for C26H25N3O4Cl 478,1528, neid. 478,1533 (M+N)+.

Example 6

1-[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he

The reaction mixture 2-cyanophora (5.0 g, 42 mmole), cesium carbonate (27,1 g, 82,9 mmole) and 2-iodopropane (7,63 ml, 76 mmol) in acetone (80 ml) was heated at 60°and With vigorous stirring. After 45 min the mixture of gray-brown decantation and the layer of acetone was concentrated in vacuum. For dissolved solids was added water and the mixture was extracted with diethyl ether (3×200 ml). The organic layers were washed with water, 1 H. ammonium hydroxide, brine and dried over anhydrous sodium sulfate. A solid substance was separated by filtration and the filtrate conc the Wali in vacuum. The crude residue was purified Express chromatography (Biotage system, KP-Sil™, 32-63 μm, silica gel 60 (E) (eluent: 5% ethyl acetate in hexane), was obtained 2-isopropoxybenzonitrile in the form of a colourless liquid (6.6 g, 97%).

Through a solution of 2-isopropoxybenzonitrile (6.6 g, 40.9 mmole) in anhydrous ethanol (75 ml), placed in a pressure-resistant test tube, at 0°missed gaseous hydrogen chloride. After 30 min the flow of gaseous hydrogen chloride was off and the reaction vessel was closed. The reaction mixture was stirred at room temperature for 3 days. The mixture was cooled to 0°and only then dumped the pressure. The solvent was removed, to receive the oil is light yellow in color (10.1 g), which was triturated in diethyl ether (100 ml), it was obtained a solid white color. Hydrochloride ethyl ester 2-isopropoxybenzonitrile (9,17 g, 92%) was separated by filtration, washed with diethyl ether (3×25 ml) and dried under vacuum. The compound obtained was used without further purification.

To a solution of triethylamine (0,88 ml, 6,26 mmole) in ethanol (3.5 ml) was added meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (0,80 g, to 2.85 mmole), obtained as described Vogtle F., Goldschmitt E., Chem. Ber. 109, 1-40, (1976), and hydrochloride of the ethyl ester of 2-isopropoxybenzonitrile (0,86 g to 3.52 mmole). The resulting reaction mixture Ki is atili under reflux overnight. After cooling to room temperature the reaction mixture was diluted with methylene chloride, washed with 1 N. HCl and 5% sodium bicarbonate solution. The organic layer was washed with saline and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by chromatography on silica gel (eluent: 2% methanol in methylene chloride), was obtained 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydro-1H-imidazole (0,86 g, 71%).

To a solution of triethylamine (10,8 μl, 0,077 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydro-1H-imidazole (30 mg, 0,071 mmole) in methylene chloride (3 ml) was added isobutyramide (8,1 μl, 0,077 mmole). The reaction mixture was stirred at room temperature for 3 h and then diluted with methylene chloride, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent: 25% ethyl acetate in hexane), was obtained 1-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it. MS-BP (ES, m/z): Rasch. for C28H29N2O2Cl2495,1601, neid. 495,1606 (M+N)+.

Example 7

[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon

To a cooled (0°the mixture of triethylamine (1.3 ml, 9.4 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydro-1H-imidazole (0,80 g, a 1.88 mmole, example 6) in methylene chloride (15 ml) was added dropwise phosgene (2,95 ml, 5,69 mmole, of 1.93 M in toluene). The reaction mixture was stirred at 0°C for 30 min and evaporated. The residue was dried in high vacuum for 30 min and purified by chromatography on silica gel (eluent 60-80% methylene chloride in hexane), was obtained acid chloride 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid (0.71 g, 77%).

To a solution of triethylamine (0,23 ml of 1.64 mmole) and 4-(1-pyrrolidinyl)piperidine (0.11 g, 0.70 to mmole) in methylene chloride (8 ml) at 0°C for 15 min was added the acid chloride 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid (200 mg, 0,41 mmole). After 30 min the reaction mixture was treated with water, the mixture was extracted with methylene chloride, washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (eluent 1-2% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon (0.18 g, 72%) as a foam off-white color. MS-BP (ES, m/z): Rasch. for C34H39N4O2Cl2605,2445, neid. 605,2448 (M+H)+.

Use the 8

The following compounds were obtained in the same way as described in examples 6 and 7:

a) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H31N4O2Cl2537,1819, neid. 537,1828 (M+N)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H37N4O2Cl2579,2288, neid. 579,2293 (M+N)+,

in) [1,4']bipyridinyl-1'-yl-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]metano, MS-BP (ES, m/z): Rasch. for C35H41N4O2Cl2619,2601, neid. 619,2606 (M+N)+,

g) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hidroxietil)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2082 (M+N)+,

e) {4,5-bis-(4-chlorophenyl)-2-[2-(2-methylbutoxy)phenyl]-4,5-15 dihydroimidazole-1-yl}piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H35N4O2Cl2565,2132, neid. 565,2140 (M+N)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(2-pentyloxide)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H35N4O2Cl2565,2132, neid. 565,2138 (M+N)+,

g) triptorelin [4,5-bis-(4-chlorphen is)-2-(3-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]-piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C28H29N4O2Cl2523,1662, neid. 523,1666 (M+N)+,

C) triptorelin [4,5-bis-(4-chlorophenyl)-2-(3-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H31N4O2Cl2537,1819, neid. 537,1824 (M+N)+,

s) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C30H31N4O3Br2653,0758, neid. 653,0771 (M+N)+,

K) [4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C30H33N4O3Br2655,0914, neid. 655,0928 (M+H)+,

l) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C31H33N4O3Br2667,0914, neid. 667,0920 (M+N)+,

m) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C31H35N4O3Br2669,1071, neid. 669,1069 (M+N)+.

Example 9

Hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone

A mixture of 2-hydroxy-4-methoxybenzaldehyde (of 25.0 g, 164 the mole), sodium acetate (26,4 g, 322 mmole), nitroethane (23 g, 307 mmol) in acetic acid (45 ml) was boiled under reflux for 6 hours Then the mixture was cooled to room temperature and poured into ice-cold water. A solid substance was separated by filtration, washed with water and dried. The crude solid is recrystallized from ethyl acetate, was obtained 2-hydroxy-4-methoxybenzonitrile in a solid brown color (15.9 g, 65%).

To a solution of 2-hydroxy-4-methoxybenzonitrile (11.8 g, 79 mmol) in acetone (100 ml) was added cesium carbonate (51,5 g, 158 mmol) and 2-iodopropane (12.5 ml, 125 mmol). The mixture was boiled under reflux for 3 h, was added water and the resulting mixture was extracted with diethyl ether (4×100 ml). The combined organic extracts were washed with dilute ammonium hydroxide solution, brine and dried (MgSO4). The solvent was evaporated, the residue was purified by chromatography on silica gel (eluent: 5% diethyl ether in hexane), was obtained 2-isopropoxy-4-methoxybenzonitrile (13,2 g, 87%).

Through a solution of 2-isopropoxy-4-methoxybenzonitrile (13,2 g, 69 mmol) in absolute ethanol (200 ml), placed in a pressure-resistant test tube, at -10°C for 1 h missed gaseous hydrogen chloride. The tube was closed and the reaction mixture was stirred at room themes is the temperature value within 7 days. The mixture was cooled to -10°C, was added 100 ml of ethanol at -10°missed gaseous hydrogen chloride for a further 30 minutes the Tube was again closed and the mixture was stirred at room temperature for 7 days. The solvent was evaporated and the resulting residue triturated in diethyl ether, was obtained the hydrochloride of the ethyl ester of 2-isopropoxy-4-methoxybenzimidazole in a solid white color (17.5 g, 99%). The compound obtained was used without further purification.

A mixture of the hydrochloride of the ethyl ester of 2-isopropoxy-4-methoxybenzo-iridociliary (8,21 g, 30 mmol) and meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (to 7.59 g, 27 mmol, obtained as described Vogtle F., Goldschmitt E., Chem. Ber. 109, 1-40, (1976)) and triethylamine (8,35 ml, 60 mmol) in ethanol (200 ml) was boiled under reflux for 24 hours To the mixture was added an additional amount of the hydrochloride of the ethyl ester of 2-isopropoxy-4-methoxybenzimidazole (1.64 g, 6 mmol) and the reaction mixture is boiled under reflux for a further 24 h and Then was added aqueous sodium bicarbonate and three times was extracted with methylene chloride. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The residue was purified by chromatography on silica gel (eluent: 0.5-2% methanol in methylene chloride), the product of precrystallization and from diethyl ether in pentane, it was obtained 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole (9 g, 73%).

To a mixture of triethylamine (3.75 ml, 26.9 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole (3.50 g, 7,69 mmole) in methylene chloride (80 ml) at 0°With dropwise added phosgene (12 ml, 23 mmole, of 1.93 M in toluene). The reaction mixture was stirred at 0°C for 30 min and evaporated. The residue was dried in high vacuum for 30 min and was added methylene chloride (50 ml). The resulting solution at 0°C for 15 min was added dropwise to a solution of 2-piperazine-1-retinol (10 g) in methylene chloride (200 ml). After 30 min the reaction mixture was treated with water, was extracted with methylene chloride, the extract washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (eluent: 1-2% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)-piperazine-1-yl]metano foam light yellow (4,07 g, 87%).

[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano (2.20 g, 3,60 mmole) was dissolved in diluted hydrochloric acid (0,23 N., 20 ml), the solution is light yellow color was filtered and the filtrate Visu ivali freeze, when this was received hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)-piperazine-1-yl]methanone in the form of powder off-white color (of 2.26 g, 97%). MS-BP (ES, m/z): Rasch. for C32H37N4O4Cl2611,2187, neid. 611,2195 (M+N)+.

Example 10

The following compounds were obtained in the same way as described in example 9:

a) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C30H33N4O5SCl2631,1543, neid. 631,1549 (M+N)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C31H35N4O4Cl2597,2030, neid. 597,2038 (M+N)+,

in) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H30N3O4Cl2554,1608, neid. 554,1614 (M+N)+,

g) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567,1929 (M+N)+,

d) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}etano is, MS-BP (ES, m/z): Rasch. for C31H33N4O4Cl2595,1874, neid. 595,1882 (M+N)+,

e) 4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-15 dihydroimidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C29H29N4O4Cl2567,1561, neid. 567,1571 (M+N)+,

W) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567,1927 (M+N)+,

C) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C32H35N4O4Cl2609,2030, neid. 609,2036 (M+N)+,

and) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example I), MC-BP (ES, m/z): Rasch. for C31H35H4O5SCl2645,1700, neid. 645,1710 (M+N)+,

K) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](2,5-dimethylpiperazine-1-yl)methanon, MC-BP (ES, m/z): Rasch. for C32H37N4O3Cl2595,2237, neid. 595,2240 (M+N)+,

l) bis(2-hydroxyethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyp the Nile)-4,5-dihydroimidazole-1-carboxylic acid, MC-BP (ES, m/z): Rasch. for C30H34N3O5Cl2586,1870, neid. 586,1878 (M+N)+,

m) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon, MC-BP (ES, m/z): Rasch. for C32H37N4O3Cl2595,2237, neid. 595,2241 (M+N)+,

n) [1,4']bipyridinyl-1'-yl[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano, MC-BP (ES, m/z): Rasch. for C36H43N4O3Cl2649,2707, neid. 649,2712 (M+N)+,

o) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MC-BP (ES, m/z): Rasch. for C35H41N4O3Cl2635,2550, neid. 635,2559 (M+N)+,

p) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon, MC-BP (ES, m/z): Rasch. for C33H39N4O3Cl2609,2394, neid. 609,2395 (M+N)+,

R) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone, MC-BP (ES, m/z): Rasch. for C30H32N3O4Cl2568,1765, neid. 568,1768 (M+N)+,

(C) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon, MC-BP (ES, m/z): Rasch. for C33H39N4O3Cl2609,2394, neid. 609,2395 (M+N)+; IP is alsoany in the synthesis of the compounds N-isopropylpiperazine received by the method, described Renau, Thomas E., Sanchez Joseph R., and others, J. Med. Chem. 39, 729-35, (1996);

t) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-he, MC-BP (ES, m/z): Rasch. for C30H31N4O4Cl2581,1717, neid. 581,1723 (M+N)+,

u) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxyethylpiperazine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H36N3O4Cl2596,2078, neid. 596,2081 (M+H)+,

f) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperidine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C33H38N3O4Cl2610,2234, neid. 610,2236 (M+N)+,

x) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2081 (M+N)+,

C) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-2-methylpiperazin-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C33H37N4O4Cl2623,2187, neid. 623,2190 (M+N)+,

h) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonyl-3-methylpiperazin-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-is](3-methylpiperazin-1-yl)methanone (example 10), MS-BP (ES, m/z): Rasch. for C32H37N4O5SCl2659,1856, neid. 659,1856 (M+N)+,

W) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxypiperidine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H34N3O4Cl2582,1921, neid. 582,1926 (M+N)+,

y) (4-aminomethylpyridine-1-yl)[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano, MS-BP (ES, m/z): Rasch. for C32H37N4O3Cl2595,2237, neid. 595,2243 (M+N)+,

e) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C31H35N4O4Br2685,1020, neid. 685,1031 (M+N)+,

Yu) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H31H40O3Br2641,0758, neid. 641,0762 (M+N)+,

I) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example 10) by well-known methods, MS-BP (ES, m/z): Rasch. for C30H33N4O5SBr2719,0533, neid. 719,0540 (M+N)+,

AA) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-IU is oxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C31H33N4O4Br2683,0863, neid. 683,0866 (M+N)+,

BB) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C30H33N4O3Br2655,0914, neid. 655,0917 (M+N)+,

C) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde, MS-BP (ES, m/z): Rasch. for C30H31N4O4Br2669,0707, neid. 669,0713 (M+N)+,

gg) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C34H39N4O3Br2709,1384, neid. 709,1401 (M+N)+,

DD [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H37N4O3Br2683,1227, neid. 683,1250 (M+N)+,

her [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H37N4O3Br2683,1227, neid. 683,1231 (M+N)+,

LJ) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C29H29N4O4Br2655,0550, neid. 655,0557 (M+N)+,

ZZ) [45-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O3Br2655,0914, neid. 655,0918 (M+N)+,

AI) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C32H35N4O4Br2697,1020, neid. 697,1028 (M+N)+,

QC) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example SS) by well-known methods, MS-BP (ES, m/z): Rasch. for C31H35N4O5SBr2733,0690, neid. 733,0696 (M+N)+,

FL) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H35N4O3Br2669,1071, neid. 669,1078 (M+N)+,

mm [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanol. MS-BP (ES, m/z): Rasch. for C30H32N3O4Br2656,0754, neid. 656,0762 (M+N)+,

NN) [1,4']bipyridinyl-1'-yl[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano, MS-BP (ES, m/z): Rasch. for C36H43N4O3Br2737,1697, neid. 737,1707 (M+H)+,

OO) [4,5-bis-(4-bromophenyl)-2-(2-isop is epoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H37N4O3Br2683,1227, neid. 683,1232 (M+N)+,

PP) 4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C30H31N4O4Br2669,0707, neid. 669,0718 (M+N)+,

RR) [4,5-bis-(4-cyanophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C32H33N6O3549,2609, neid. 549,2614 (M+N)+,

it) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon, MS-BP (ES, m/z): Rasch. for C32H35N4O5Cl2625,1979, neid. 625,1987 (M+N)+,

TT) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon, MS-BP (ES, m/z): Rasch. for C31H32N4O4FCl2613,1779, neid. 613,1775 (M+N)+,

yy) 4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it, MS-BP (ES, m/z): Rasch. for C29H28N4O4FCl2585,1466, neid. 585,1475 (M+N)+.

Example 11

The following compounds were obtained in the same way as described in example 9:

a) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): rassle 29H31N4O3Cl2553,1768, neid. 553,1773 (M+N)+,

b) triptorelin methyl-(2-methylaminomethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C29H33N4O3Cl2555,1924, neid. 555,1929 (M+N)+,

C) triptorelin (2-dimethylaminoethyl)methylamine 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C30H35N4O3Cl2569,2081, neid. 569,2085 (M+N)+,

d) triptorelin (2-dimethylaminoethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C29H33N4O3Cl2555,1924, neid. 555,1940 (M+N)+,

e) triptorelin (2-amino-ethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C27H29N4O3Cl2527,1611, neid. 527,1621 (M+N)+,

e) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanone, MS-BP (ES, m/z): Rasch. for C34H39N4O3Cl2621,2394, neid. 621,2400 (M+N)+,

g) triptorelin [4,5-bis-(4-chlorophenyl)-2-(4-methoxy-2-propoxyphenyl)-4,5-dihydroimidazo the-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567.1932 (M+H)+,

h) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2086 (M+N)+,

and) hydrochloride (2-morpholine-4-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C32H37N4O4Cl2611,2187, neid. 611,2197 (M+N)+,

K) hydrochloride (2-piperazine-1-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C32H38N5O3Cl2610,2346, neid. 610,2348 (M+N)+,

l) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isobutoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2081 (M+H)+,

m) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanone, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2084 (M+N)+,

n) triptorelin {4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone, msvr (ES, m/z): Rasch. for C30H33N4O4Cl2583,1874, neid. 583,1875 (M+N)+,

o) {4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H30N4O3FCl2571,1674, neid. 571,1676 (M+N)+,

p) hydrochloride {4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}(4-pyrrolidin-1-reparacin-1-yl)methanone, MS-BP (ES, m/z): Rasch. for C34H38N4O3FCl2639,2300, neid. 639,2303 (M+N)+.

Primer

2-Amino-1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}alanon

To a solution of N-(tert-butoxycarbonyl)glycine (21 mg, 0,119 mmole) in THF (12 ml) was added [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (52 mg, 0,092 mmole, example 10) and diisopropylcarbodiimide (19,7 μl, 0.125 mmole). After 3 h the reaction mixture was concentrated and diluted with methylene chloride. The mixture is washed with aqueous sodium carbonate, water, brine and dried over sodium sulfate. The solvent was evaporated, the residue was purified by chromatography on silica gel (eluent: 1-2% methanol in methylene chloride), was obtained tert-butyl ether (2-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro idazole-1-carbonyl]piperazine-1-yl}-2-oxoethyl)carbamino acid (54 mg, 81%).

To a solution of tert-butyl methyl ether (2-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-oxoethyl)carbamino acid (40 mg, 0,054 mmole) in methylene chloride (6 ml) was added triperoxonane acid (2 ml, 26 mmol). The reaction mixture was stirred for 2.5 h and was diluted with methylene chloride. The mixture was washed with sodium carbonate solution, water, brine and dried over sodium sulfate. The solvent was evaporated, the residue was purified by chromatography on silica gel (eluent: 5-10% methanol in methylene chloride), was obtained 2-amino-1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon (22 mg, 65%). MS-BP (ES, m/z): Rasch. for C32H36N5O4Cl2624,2139, neid. 624,2147 (M+N)+.

Example 13

The following compounds were obtained in the same way as described in example 12:

a) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-hydroxyethane, MS-BP (ES, m/z): Rasch. for C32H35N4O5Cl2625,1979, neid. 625,1984 (M+N)+,

b) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2,3-dihydroxypropane-1-it. MS-BP (ES, m/z): Rasch. for C33H37N4O6Cl 2655,2085, neid. 655,2090 (M+N)+,

Example 14

[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2,3-dihydroxypropyl)piperazine-1-yl]metano

[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (50 mg, 0,088 mmole, example I) was dissolved in anhydrous methanol (10 ml), was added glycidyl alcohol (0.15 ml, of 2.26 mmole) and the reaction mixture was heated at 40°C for 20 hours the Mixture was cooled to room temperature and concentrated in vacuum. The residue was purified by chromatography on silica gel (eluent: 1-6% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2,3-dihydroxypropyl)piperazine-1-yl]metano (25 mg, 44%). MS-BP (ES, m/z): Rasch. for C33H39N4O5Cl2641,2292, neid. 641,2300 (M+N)+.

Example 15

Dimethenamid-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid

To a solution of [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (60 mg, of 0.11 mmole, example g) and triethylamine (97 μl, 0,70 mmole) in methylene chloride (10 ml) was added phosgene (of 0.26 ml, 0.5 mmole, of 1.93 M in toluene). The reaction mixture was stirred is within 1 h, the solvent was evaporated, the residue was dried in high vacuum for 30 min and again dissolved in methylene chloride (10 ml). To the mixture was added dimethylamine (0,993 ml, 1,986 mmole, 2 M in THF) and stirred over night. The reaction mixture was washed with salt solution and the aqueous layer was extracted with methylene chloride. The combined organic extracts were dried (MgSO4) and was evaporated. The residue was purified by reversed-phase GHUR, got dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid (48 mg, 68%). MS-BP (ES, m/z): Rasch. for C33H38N5O4Cl2638,2296, neid. 638,2299 (M+N)+.

Example 16

Amide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid

Specified in the title compound was obtained in the same way as described in example 15. MS-BP (m/z): Rasch. for C31H34N5O4Cl2610,1983, neid. 610,1985 (M+H)+.

Example 17

Triptorelin [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

A mixture of 2,4-diethoxyaniline (5.0 g, of 25.7 mmole), sodium acetate (to 4.23 g, 51,6 mmole) and nitroethane (3,86 g, 51,4 mmole) in acetic acid (7 ml) boiling whom or under reflux for 6 hours The mixture is then cooled and poured into ice-cold water. A solid substance was separated by filtration, washed with water and dried. The residue was purified by chromatography on silica gel (eluent: 2-5% ethyl acetate in hexane) and recrystallized from ethyl acetate, was obtained 2,4-diethoxybenzene (1.86 g, 38%).

Through a solution of 2,4-diethoxybenzene (1.86 g, 9.7 mmole) in absolute ethanol (20 ml), placed in a pressure-resistant test tube, at -10°C for 1 h missed gaseous hydrogen chloride. The tube was closed and the mixture was stirred at room temperature for 12 days. After evaporation of the solvent and trituration of the residue in diethyl ether was obtained the hydrochloride of the ethyl ester of 2,4-diethoxymethylsilane (2,53 g, 95%).

A mixture of the hydrochloride of the ethyl ester of 2,4-diethoxymethylsilane (0,76 g, and 2.79 mmole), meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (0.65 mg, 2,327 mmole, obtained by the method described by F. Vogtle, Goldschmitt E., Chem. Ber., 109, 1-40 (1976)) and triethylamine (0,489 ml, 3,49 mmole) in ethanol (10 ml) was boiled under reflux for 4 hours the Solvent was removed, while received a paste of yellow. Then was added a solution of sodium bicarbonate and was extracted with methylene chloride. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The residue was purified by chromatography on a silica compound the gel (eluent: 70% ethyl acetate in hexane), it was obtained 4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydro-1H-imidazole (0.50 g, 47%).

To a mixture of triethylamine (0,216 ml of 1.54 mmole) and 4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydro-1H-imidazole (0.10 g, 0.22 mmole) in methylene chloride (10 ml) at 0°With dropwise added phosgene (0,558 ml, 1.1 mmole, of 1.93 M solution in toluene). The reaction mixture was stirred at 0°C for 1 h and evaporated. The residue was dried in high vacuum for 30 min, then was dissolved in methylene chloride (5 ml) and the resulting solution at 0°C for 15 min was added dropwise to a solution of piperazine (0,38 g, 4.4 mmole) in methylene chloride (5 ml). After 1 h the reaction mixture was treated with sodium bicarbonate solution, was extracted with methylene chloride, the extract washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. After cleaning GHUR received triptorelin [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (4,07 g, 87%). MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567,1928 (M+N)+.

Example 18

The following compounds were obtained in the same way as described in example 17:

a) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H32N3O4Cl2568,1765, neid. 58,1766 (M+N) +,

b) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C32H37N4O4Cl2611,2187, neid. 611,2203 (M+N)+,

in) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2087 (M+N)+,

g) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C32H35N4O4Cl2609,2030, neid. 609,2035 (M+N)+,

d) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example 17), MS-BP (ES, m/z): Rasch. for C31H35N4O5SCl2645,1700, neid. 645,1704 (M+N)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl}mechanon, MS-BP (ES, m/z): Rasch. for C35H41N4O3Cl2635,2550, neid. 635,2561 (M+N)+,

W) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H35N4O3Br2 669,1071, neid. 669,1074 (M+N)+,

C) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H37N4O3Br2683,1227, neid. 683,1228 (M+N)+,

and) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H32N3O4Br2656,0754, neid. 656,0760 (M+N)+,

Example 19

The following compounds were obtained in the same way as described in example 15, from [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example 17):

(a) amide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid, MS-BP (ES, m/z): Rasch. for C31H34N5O4Cl2610,1983, neid. 610,1983 (M+N)+,

b) dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid. MS-BP (ES, m/z): Rasch. for C33H38N5O4Cl2638,2296, neid. 638,2297 (M+N)+.

Example 20

[4,5-Bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

To a stirred suspension acetate thallium (I) (of 7.90 g, 30 mmol) and 3-dimethylaminophenol (3,43 g, 25 mmol) chloride in the stands is e (300 ml) dropwise over 3 h was added iodine (6,35 g, 25 mmol). The resulting mixture was stirred at room temperature for 24 h and filtered. After evaporation of the solvent and chromatography of the residue on silica gel (eluent: 0-5% diethyl ether in hexane) was obtained 5-dimethylamino-2-itfinal (2.35 g, 36%).

A mixture of 5-dimethylamino-2-itfinal (0,90 g of 3.42 mmole), cesium carbonate (2,79 g, 8,55 mmole) and iodata (0,81 ml, 10 mmol) in acetone (5 ml) was boiled under reflux for 2 hours, the Reaction mixture was cooled to room temperature, added water and was extracted three times with diethyl ether. The combined organic extracts were washed with saline, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel (eluent: hexane), was obtained N,N-dimethyl-2-ethoxy-4-iodoaniline (0.75 g, 76%).

N,N-Dimethyl-2-ethoxy-4-iodoaniline (0.75 g, 2,58 mmole) was dissolved in DMF (4 ml), then added cyanide zinc (0.18 g, and 1.54 mmole), through the mixture for 10 min missed argon was added tetrakis(triphenylphosphine)palladium (148 mg, of 0.13 mmole). The mixture was heated at 110°C for 24 h, then cooled, poured into water and was extracted with ethyl acetate. The extract was washed with saline and dried over magnesium sulfate. The solvent is evaporated, the residue was purified by chromatography on silica gel (eluent: 20% ethyl acetate in hexane), was obtained N,N-dimethyl-2-ethoxy-4-Canaan the Lin (187 mg, 38%).

Through a solution of N,N-dimethyl-2-ethoxy-4-cyanoaniline (0,185 g, 0.97 mmole) in ethanol (5 ml), placed in a pressure-resistant test tube, at 0°C for 30 min missed gaseous hydrogen chloride. The tube was closed and the mixture was stirred at room temperature for 2 days. Then the tube was cooled to 0°and the pressure dropped. The solvent evaporation, the residue is triturated in diethyl ether, was obtained the hydrochloride of the ethyl ester of 4-(N,N-dimethylamino)-2-ethoxybenzonitrile in the form of a white powder (0.25 g, 95%).

To a mixture of the hydrochloride of the ethyl ester of 4-(N,N-dimethylamino)-2-ethoxy-benzimidazole (250 mg, of 0.92 mmole) and meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (190 mg, 0.68 mmole, obtained by the method described by F. Vogtle, Goldschmitt E., Chem. Ber., 109, 1-40 (1976)) in ethanol (5 ml) was added triethylamine (of 0.28 ml, 2.0 mmole) and the mixture is boiled under reflux during the night. Then the mixture was treated with sodium bicarbonate solution and was extracted with methylene chloride. The organic extracts were washed with saline, dried over sodium sulfate, the solvent was evaporated, the residue was purified by chromatography on silica gel (eluent: 10-30% methanol in methylene chloride), received {4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}dimethylamine in the form of a white foam (0.18 g, 59%).

For mixed races is the thief {4-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxyphenyl}amine (83 mg, of 0.18 mmole) and triethylamine (of 0.14 ml, 1 mmol) in THF (3 ml) at 0°C for 5 min was added phosgene (0,47 ml of 0.91 mmole, of 1.93 M solution in toluene). The reaction mixture was stirred for 1 h and evaporated. The residue was dissolved in methylene chloride (2 ml) and at room temperature for 1 h was added dropwise to a stirred solution of piperazine (0,239 g, 2,77 mmole) in methylene chloride (2 ml). The mixture is then diluted with an aqueous solution of sodium bicarbonate and was extracted with methylene chloride. The organic extract was washed with saline and dried over sodium sulfate. The solvent is evaporated, the residue was purified by chromatography on silica gel (eluent: 0-10% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanol in the form of a white foam (68 mg, 66%). MS-BP (ES, m/z): Rasch. for C30H34N5O2Cl2566,2084, neid. 566,1088 (M+N)+.

Example 21

The following compounds were obtained in the same way as described in example 20:

a) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O2Cl2551,1975, neid. 551,1984 (M+N)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-were)-4,5-dihydroimidazole-1-yl]piperazine-1-yl is Manon, MS-BP (ES, m/z): Rasch. for C29H31N4O2Cl2537,1819, neid. 537,1824 (M+H)+,

in) [4,5-bis-(4-chlorophenyl)-2-(4-ethyl-2-isopropoxyphenyl)-4,5-dihydro-imidazol-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H35N4O2Cl2565,2132, neid. 565,2135 (M+N)+,

g) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-were)-4,5-5 dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O2Cl2551,1975, neid. 551,1980 (M+N)+,

d) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z); Rasch. for C32H36N5O3Cl2608,2190, neid. 608,2201 (M+N)+.

Example 22

The following compounds were obtained in the same way as described in example 20:

a) triptorelin [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C32H31N4O2Cl2537,1819, neid. 537,1826 (M+N)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C33H36N4O2Cl2F 609,2194, neid. 609,2204 (M+N)+,

in) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine--yl)methanon, MS-BP (ES, m/z): Rasch. for C31H34N4O2Cl2F 583,2038, neid. 583,2041 (M+N)+,

g) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C28H28N4O2Cl2F 541,1568, neid. 541,1571 (M+N)+,

d) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C34H38N4O2Cl2F 623,2351, neid. 623,2360 (M+H)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C32H36N4O2Cl2F 597,2194, neid. 597,2197 (M+N)+,

W) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-5 dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C30H32N4O2Cl2F 569,1881, neid. 569,1887 (M+N)+,

C) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H30N4O2Cl2F 551,1725, neid. 551,1726 (M+N)+,

and) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C30H32N4O4SCl2F 633,1500, neid. 633,1506 (M+N)+,

K) 4-[4,5-is IP-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydro-imidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C29H28N4O3Cl2F 569,1517, neid. 569,1529 (M+N)+,

l) [4,5-bis-(4-chlorophenyl)-2-chroman-8-yl-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanol was obtained from 8-brahaman (obtained from 2,6-dibromophenol according to the method described Thomas GH, etc., Tetrahedron Lett. 39, 2219-22 (1998)), MS-BP (ES, m/z): Rasch. for C29H29N4O2Cl2535,1662, neid. 535,1672 (M+N)+,

m) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C28H26N4O3Br2F 643,0350, neid. 643,0349 (M+N)+,

n) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone, MS-BP (ES, m/z): Rasch. for C28H27N3O3Cl2F 630,0398, neid. 630,0414 (M+N)+,

o) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C33H36N4O2Br2F 697,1184, neid. 697,1188 (M+N)+,

p) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C31H34N4O2Br2F 671,1027, neid. 671,1036 (M+N)+,

R) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C28H28N4O2 2F 629,0558, neid. 629,0569 (M+H)+.

Example 23

[4,5-Bis-(4-chlorophenyl)-2-(2-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

To a solution of 2-hydroxy-4-methoxybenzonitrile (90 mg, 0.60 mmole, example 9), Cyclopentanol (55 mg, of 0.64 mmole) and triphenylphosphine (167 mg, of 0.64 mmole) in THF (3 ml) at -78°With added diethyl ester of azodicarboxylic acid (0.16 ml, 0,860 mmole, 85%). The cooling bath was removed and the reaction mixture was heated to room temperature for 1.5 hours the Reaction mixture was concentrated in vacuo, the residue was purified Express chromatography (Biotage system, KP-Sil 32-63 μm, silica gel 60, eluent: 0-8% diethyl ether in hexane), was obtained 2-cyclopentyloxy-4-methoxybenzonitrile in the form of a transparent liquid (125 mg, 90%).

Through a solution of 2-cyclopentyloxy-4-methoxybenzonitrile (0.12 g, 0.55 mmole) in absolute ethanol (15 ml), placed in a pressure-resistant test tube, at 0°C for 1 h missed gaseous hydrogen chloride. The tube was closed and the mixture was stirred at room temperature for 3 days. After evaporation of the solvents and trituration of the residue in diethyl ether was obtained the hydrochloride of the ethyl ester of 2-cyclopentyloxy-4-methoxybenzimidazole (0.17 g, 100%).

A mixture of the hydrochloride of the ethyl ester of 2-cyclopentyloxy-4-methoxy-benzamide is islote (0.16 g, 0.57 mmole), meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (0.17 g, of 0.56 mmole, obtained by the method described Vogtle F,, Goldschmitt E., Chem. Ber., 109, 1-40 (1976)), in ethanol (2 ml) was boiled under reflux for 18 hours Then the solvent was removed, while received a paste of yellow. To the paste was added a solution of sodium bicarbonate and was extracted with methylene chloride. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The residue was purified by chromatography on silica gel (eluent: 0-5% methanol in methylene chloride), was obtained 4,5-bis-(4-chlorophenyl)-2-(2-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole.

To a mixture of triethylamine (of 0.14 ml, 1 mmol) and 4,5-bis-(4-chlorophenyl)-2-(2-cyclo-pentyloxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole (89 mg, 0,185 mmole) in THF (2 ml) at 0°With added phosgene (of 0.48 ml, 0,925 mmole, of 1.93 M solution in toluene). The reaction mixture was stirred at 0°C for 1 h and evaporated. The residue was dried in high vacuum for 30 min, then was dissolved in methylene chloride(2 ml) and the resulting solution at 0°With added dropwise to a solution of piperazine (0.24 g, 2,78 mmole) in methylene chloride (2 ml). After 1 h the mixture was treated with sodium bicarbonate solution, was extracted with methylene chloride, washed with water and brine. The organic layer was extracted with 0.5 N. HCl (2×50 ml). the joint aqueous layers were cooled to 0° With and podslushivaet adding 2 N. NaOH. Then the mixture was extracted with methylene chloride (3×50 ml), the organic extracts were dried over sodium sulfate and evaporated. The residue was purified rapid chromatography on silica gel (eluent: 3-6% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (89 mg, 81%). MS-BP (ES, m/z): Rasch. for C32H35N4O3Cl2593,2081, neid. 593,2084 (M+N)+.

Example 24

The following compounds were obtained in the same way as described in example 23 and example 9:

a) {4,5-bis-(4-chlorophenyl)-2-[2-(2-dimethylaminoethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H36N5O3Cl2596,2190, neid. 596,2196 (M+N)+,

b) {4,5-bis-(4-chlorophenyl)-2-[2-(2-imidazol-1-ylethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone. MS-BP (ES, m/z): Rasch. for C32H33N6O3Cl2619,1986, neid. 619,1988 (M+N)+.

Example 25

Hydrochloride [2-(5-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

To a solution of 4-chloro-2-perbenzoate (1.0 g, 6,428 mmole) in ethanol (10 ml) was added a solution of ethoxide sodium (4.8 ml, 12,86 mmole, 21 wt.% Rast is the PR in ethanol). The reaction mixture was heated under low boiling under reflux for 12 hours Then the solvent was removed, the residue was distributed between water (10 ml) and diethyl ether (20 ml), the layers were separated and the product was extracted with diethyl ether (20 ml). The organic layers were washed brine (5 ml) and dried over anhydrous sodium sulfate. A solid substance was separated by filtration and the filtrate was concentrated in vacuum. The residue was purified Express chromatography (Biotage system, KP-Sil 32-63 μm, silica gel 60, eluent: 5% ethyl acetate in hexane), was obtained 4-chloro-2-ethoxybenzonitrile (0,67 g, 57%).

Hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone was obtained from 4-chloro-2-ethoxybenzonitrile same way as described in example 23. MS-BP (ES, m/z): Rasch. for C28H28N4O2Cl3557,1273, neid. 557,1277 (M+N)+.

Example 26

The following compounds were obtained in the same way as described in example 23 and example 25:

a) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone, MS-BP (ES, m/z): Rasch. for C29H30N4O2Cl2571,1429, neid. 571,1438 (M+N)+,

b) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-yl is piperidin-1-yl)methanone, MS-BP (ES. m/z): Rasch. for C33H36N4O2Cl3625,1899, neid. 625,1908 (M+N)+,

C) [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-yl)methanon, MS-BP (ES, m/z): Rasch. for C28H27N3O3Cl3558,1113, neid. 558,1118 (M+N)+,

g) 1-{4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C30H30N4O3Cl3599,1378, neid. 599,1388 (M+N)+,

d) hydrochloride [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydro-imidazol-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone, MS-BP (ES, m/z): Rasch. for C30H32N4O3Cl3601,1535, neid. 601,1543 (M+N)+,

e) 4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C28H26N4O3Cl3571,1065, neid. 571,1071 (M+N)+.

Example 27

[4,5-Bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

To a solution of 4-Brabanthal-1,3-diol (1.50 g, 7,94 mmole) in acetone (10 ml) was added potassium carbonate (1.1 g, 7,94 mmole) and 2-iodopropane (1,58 ml, $ 15.87 with mmole). The reaction mixture was heated under low boiling under reflux for 12 hours Then the solvent was removed, while got pasta blogosfera. The paste was transferred into diethyl ether (50 ml), the solid was separated by filtration and the filtrate was concentrated. The residue was purified Express chromatography system (Biotage, eluent: 10% ethyl acetate in hexane), was obtained 4-bromo-3-isopropoxyphenol (0,77 g, 42%).

To a solution of 4-bromo-3-isopropoxyphenol (0.50 g, of 2.16 mmole) in acetone (3 ml) was added potassium carbonate (0,30 g of 2.16 mmole) and ethyl iodide (0.35 ml, 4,33 mmole). The reaction mixture was heated under low boiling under reflux for 12 h, the solvent was removed, while got pasta in white. The paste was transferred into diethyl ether (50 ml), the solid was separated by filtration and the filtrate was concentrated. The residue was purified Express chromatography system (Biotage, eluent: 10% ethyl acetate in hexane), was obtained 1-bromo-4-ethoxy-2-isopropoxyphenol (0,48 g, 86%).

To a solution of 1-bromo-4-ethoxy-2-isopropoxybenzoic (0,48 g of 1.85 mmole) in DMF (5 ml) was added cyanide zinc (217 mg, of 1.85 mmole). The reaction mixture was degirolami, passing a stream of argon for 2 h, and then was added tetrakis(triphenylphosphine)palardy (0) (0.21 g, 0,185 mmole). The reaction mixture was heated at 100-105°C in argon atmosphere for 12 h, and then transferred in diethyl ether (50 ml) and saturated sodium bicarbonate solution (5 ml). The product was extracted with diethyl ether (2×30 ml), the organic layers washed in the Oh (1× 10 ml), brine (1×10 ml), dried (over sodium sulfate) and concentrated. The crude residue was purified Express chromatography system (Biotage, eluent: 10-15% ethyl acetate in hexane), was obtained 4-ethoxy-2-isopropoxybenzonitrile in the form of a clear oil (0.31 g, 81%).

Through a solution of 4-ethoxy-2-isopropoxybenzonitrile (0,30 g of 1.46 mmole) in absolute ethanol (100 ml), placed in a pressure-resistant test tube, at 0°C for 45 min missed gaseous hydrogen chloride. The tube was closed and the mixture was stirred at room temperature for 4 days. The tube was cooled to 0°and then dumped the pressure. The solvents are evaporated, the residue triturated in diethyl ether, was obtained the hydrochloride of the ethyl ester of 4-ethoxy-2-isopropoxybenzonitrile, which was used without further purification.

A mixture of the crude hydrochloride of the ethyl ester of 4-ethoxy-2-isopropoxybenzonitrile, meso-1,2-bis-(4-chlorophenyl)ethane-1,2-diamine (0,41 g of 1.46 mmole, obtained by the method described by F. Vogtle, Goldschmitt E., Chem. Ber., 109, 1-40 (1976)), and triethylamine (0,205 ml of 1.46 mmole) in ethanol (25 ml) was boiled under reflux for 3 hours Then the solvent was removed, while received a paste of yellow. To the paste was added a solution of sodium bicarbonate and the mixture was extracted with methylene chloride. Obyedinenie the e organic extracts were washed with water, saline solution and dried over sodium sulfate. The residue was purified by chromatography on silica gel (eluent: 70% ethyl acetate in hexane), was obtained 4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-1H-imidazole (0.50 g, 47%).

To a mixture of triethylamine (0,126 ml, 0,896 mmole) and 4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-1H-imidazole (60 mg, 0,128 mmole) in methylene chloride (5 ml) at 0°With dropwise added phosgene (0,325 ml of 0.64 mmole, of 1.93 M solution in toluene). The reaction mixture was stirred for 30 min at 0°and evaporated. The residue was dried in high vacuum for 30 min, then was dissolved in methylene chloride (5 ml) and the resulting solution at 0°C for 15 min was added dropwise to a solution of piperazine (0.22 mg, of 2.56 mmole) in methylene chloride (5 ml). After 1 h the mixture was treated with sodium bicarbonate solution, was extracted with methylene chloride, washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. After reversed-phase GHUR received [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (6.5 mg, 8%). MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2086 (M+N)+.

Example 28

The following compounds were obtained in the same way as described in example 27:

a) triptorelin [4,5-bis-4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C29H31N4O3Cl2553,1768, neid. 553,1776 (M+N)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example 28a), MS-BP (ES, m/z): Rasch. for C30H33N4O5SCl2631,1543, neid. 631,1548 (M+N)+,

in) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone, MS-BP (ES, m/z): Rasch. for C31H35N4O4Cl2597,2030, neid. 597,2037 (M+N)+,

g) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydro-imidazol-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567,1928 (M+N)+,

d) [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example 28G), MS-BP (ES, m/z): Rasch. for C31H35N4O5SCl2645,1700, neid. 645,1714 (M+H)+,

(e) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-imidazol-1-yl][4-(2-hydroxyethyl)PIP the Razin-1-yl]metano, MS-BP (ES, m/z): Rasch. for C33H39N4O4Cl2625,2343, neid. 625,2350 (M+N)+,

g) 4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-imidazole-1-carbonyl]piperazine-2-it, MS-BP (ES, m/z): Rasch. for C31H33N4O4Cl2595,1874, neid. 595,1879 (M+N)+,

C) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-imidazol-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H35N4O3Cl2581,2081, neid. 581,2088 (M+N)+,

and) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-imidazol-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon received by sulfonylamine [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example s), MS-BP (ES, m/z): Rasch. for C32H37N4O5SCl2659,1856, neid. 659,1864 (M+N)+,

K) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone, MS-BP (ES, m/z): Rasch. for C33H39N4O4Cl2625,2343, neid. 625,2352 (M+N)+,

l) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C33H37N4O4Cl2623,2187, neid. 623,2194 (M+N)+,

m) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxy enyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon, MS-BP (ES, m/z): Rasch. for C33H37N4O4Cl2623,2187, neid. 623,2195 (M+N)+,

n) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydro-imidazol-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C36H43N4O3Cl2649,2707, neid. 649,2717 (M+N)+,

on triptorelin [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C30H33N4O3Cl2567,1924, neid. 567,1929 (M+N)+,

p) [4,5-bis-(4-chlorophenyl)-2-(2,4-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C32H37N4O3Cl2595,2237, neid. 595,2244 (M+N)+,

R) hydrochloride [4,5-bis-(4-chlorophenyl)-2-(2,5-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C32H37N4O3Cl2595,2237, neid. 595,2243 (M+H)+.

Example 29

1-[4,5-Bis-(4-chlorophenyl)-2-(2-methoxy-5-morpholine-4-ylmethylene)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he

To a solution of 4-{3-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxybenzyl}of the research (100 mg, of 0.20 mmole, obtained as described in provisional applications U.S., included in the description as references, example 31) in methylene chloride (10 ml) in series is added triethylamine (0.10 ml, 0,712 mmole) and isobutyrate (42 ml, 0,392 mmole) and the reaction mixture was stirred for 12 h the Solvent was removed under reduced pressure, was added a saturated solution of sodium bicarbonate (2 ml), methylene chloride (20 ml) and the layers were separated. The aqueous layer was extracted with methylene chloride (1×100 ml), the combined organic extracts were evaporated, the crude residue was purified Express chromatography system (Biotage, eluent: 0-5% methanol in ethyl acetate), was obtained 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxy-5-morpholine-4-ylphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it. MS-BP (ES, m/z): Rasch. for C31H34N3O3Cl2566,1972, neid. 566,1977 (M+N)+.

Example 30

The following compounds were obtained in the same way as described in example 29:

a) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he received from {3-[4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-2-yl]-5-methoxyphenyl}methanol as described in provisional applications U.S., included in the description as references, example 33, MC-BP (ES, m/z): Rasch. for C27H27N2O3Cl2497,1393, neid. 497,1402 (M+N)+,

b) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]alanon received from {3-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-5-methoxymethyl enyl}methanol as described in provisional applications U.S., included in the description as reference example 35, MC-BP (ES, m/z): Rasch. for C26H24N2O3Cl2482,1164, neid. 482,1161 (M)+,

C) 1-[4,5-bis-(4-chlorophenyl)-2-(3-methoxy-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it was obtained from 4,5-bis-(4-chlorophenyl)-2-(3-methoxy-5-methoxy-were)-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description as references, example 34, MC-BP (m/z): Rasch. for C28H29N2O3Cl2511,1550, neid. 511,1556 (M+N)+,

g) 3-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]-5-methoxymethylethoxy acid was obtained from 3-[4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-yl]-5-methoxyethylamine, as described in provisional applications U.S., included in the description as references, example 40, MC-BP (ES, m/z): Rasch. for C28H27N2O4Cl2525,1343, neid. 525,1347 (M+N)+,

d) 1-[4,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-it was obtained from 4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-methyl-2,4-acid)-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description as reference example 32.

Example 31

[4,5-Bis-(4-chlorophenyl)-2-(2-ethoxy-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

To a stirred solution of 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-6-methoxyphenyl)-4,5-dihydro-1H-imidazole (25 mg, 0,0566 mmole, obtained as described in the previous patent) and triethylamine (39 ml, 0,283 mmole) in THF (2 ml) at 0°C for 5 min was added phosgene (0,147 ml, 0,283 mmole, of 1.93 M solution in toluene). The mixture was stirred for 3 h and evaporated. The residue was dissolved in methylene chloride (2 ml) and was added dropwise to stir at room temperature for 3 h to a solution of piperazine (24 mg, 0,283 mmole) in methylene chloride (2 ml). Then the mixture was diluted with sodium bicarbonate solution and was extracted with methylene chloride. The organic extracts were washed with saline and dried over sodium sulfate. The solvent is evaporated, the residue was purified by chromatography on silica gel (eluent: 0-10% methanol in methylene chloride), were obtained [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (19 mg, 61%). MS-BP (ES, m/z): Rasch. for C29H31N4O3Cl2553,1768, neid. 553,1770 (M+N)+.

Example 32

[4,5-Bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

Specified in the title compound was obtained from 4,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydro-1H-imida the Ola (described in the previous patent) same as described in example 31. MS-BP (ES, m/z): Rasch. for C31H35N4O4Cl2597,2030, neid. 597,2034 (M+N)+.

Example 33

[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxypropyl)piperazine-1-yl]metano

The connection was received while processing [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example I) propylene oxide in methanol in a sealed tube at 45°C for 7 h century MS-BP (ES, m/z): Rasch. for C33H38N4O4Cl2625,2343, neid. 625,2350 (M+N)+.

Example 34

The following compounds were obtained in the same way as described in example 33:

a) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-imidazol-1-yl]tree[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C34H40N4O4Cl2639,2500, neid. 639,2508 (M+H)+,

b) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-imidazol-1-yl]Erythro[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano, MS-BP (ES, m/z): Rasch. for C34H40N4O4Cl2639,2500, neid. 639,2507 (M+N)+.

Example 35

1-{4-[4,5-Bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}propane-2-he

The connection was received while processing [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone (example I) chloroacetone and triethylamine at 40°With during the night. MS-BP (ES, m/z): Rasch. for C33H36N4O4Cl2623,2187, neid. 623,2194 (M+N)+.

Example 36

The following compounds were obtained in the same way as described in example 9:

a) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-imidazol-1-yl][1,4]diazepan-1-ylmethanone, MS-BP (ES, m/z): Rasch. for C31H34N4O3Cl2581,2081, neid. 581,2086 (M+N)+,

b) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-it, MS-BP (ES, m/z): Rasch. for C31H32N4O4Cl2595,1874, neid. 595,1880 (M+N)+,

C) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-methylpropan-1-it, MS-BP (ES, m/z): Rasch. for C34H38N4O4Cl2637,2343, neid. 637,2348 (M+N)+,

g) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde, MS-BP (ES, m/z):. Rasch. for C31H32N4O4Cl2595,1874, neid. 595,1882 (M+N)+.

Example 37

The following compounds were obtained in a similar way as described in example 9:

a) 4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it was obtained from 4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description of the application as references, example 47A, MS-BP (ES, m/z): Rasch. for C29H25N4O4F3Cl2621,1278, neid. 621,1285 (M+N)+,

b) 4-{4,5-bis-(4-bromophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it was obtained from 4,5-bis-(4-bromophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description of the application as references, example 47b, MS-BP (ES, m/z): Rasch. for C29H25N4O4F3Br2709,0268, neid. 709,0280 (M+H)+,

in) [4,5-bis-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon was obtained from 4,5-bis-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description of the application as references, example 47 g, MS-BP (ES, m/z): Rasch. for C29H25N4O4F3Cl2615,3330, neid. 615,3319 (M+H)+,

g) 1-{4-[2-(5-chloro-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-Digi the Rho-imidazole-1-carbonyl]piperazine-1-yl}Etalon was obtained from 2-(5-chloro-2-isopropoxy-phenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description of the application as references, example 46, MS-BP (ES, m/z): Rasch. for C31H31N3About3Cl3613,1535, neid. 613,1543 (M+N)+.

Example 38

The following compound was obtained from 4-(4-chlorophenyl)-5-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole, as described in provisional applications U.S., included in the description of the application as references, example d, in the same way as described in example 3:

a) [5-(4-chlorophenyl)-4-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C37H41N4O3Cl 625,2940, neid. 625,2943 (M+N)+,

b) [4-(4-chlorophenyl)-5-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon, MS-BP (ES, m/z): Rasch. for C37H41N4About3Cl 625,2940, neid. 625,2943 (M+N)+,

4-{4,5-bis(4-bromophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it.

Example 39

The definition of activity in vitro

The ability of compounds to inhibit the interaction of protein p53 and MDM2 protein was determined by enzyme-linked immunosorbent assay (ELISA analysis using immobilized on immunosorbent assay enzyme), which recommended pinentry protein MDM2, containing a GST tag, binds to the peptide, similar to the binding site of the protein p53 with MDM2 protein (Bottger and others, J. Mol. Biol., t, str-756 (1997)). The specified peptide was immobilized on the surface of 96-well tablet via N-terminal fragment of Biotin bound to streptavidin, which coated wells. To each well was added MDM2 in the presence of mouse monoclonal antibodies against MDM2 (SMP-14, the company Santa Cruz Biotech). After removal of unbound protein MDM2 number associated with peroxidase secondary antibodies (antimachine IgG, firm Roche Molecular Biochemicals) and the number associated with the peptide of the protein MDM2 was identified colorimetrically method after addition of peroxidase substrate (MTV Microwell Peroxydase Substrate System, Kirkegaard &Perry Labs).

Microplates were coated with streptavidin (5 mg/ml in phosphate-saline buffer solution, FSB) for 2 h, then washed FSB and blocked by adding to each well with 150 ál of buffer solution to block, containing 2 mg/ml bovine serum albumin (Sigma) and 0.05% tween-20 (Sigma) in FSB, 4°C. Then each well was added 50 μl of 1 μm biotinylated peptide in buffer solution to lock and after 1 h incubation, the wells were carefully washed. The analyzed compounds were diluted in a separate 96-well tablet and was added in three repetitions in wells for incubation containing a mixture of proteins is MDM2 and antibodies against MDM2. After 20 min incubation the contents of the tablet was transferred into the analytical tablet, and incubated for another 1 h After adding the secondary mouse antibody anti-IgG analytical tablet three times washed with 0.05% tween-20, the FSB. Finally, each well was added a peroxidase substrate and measured the absorbance at 450 nm on a tablet reader (MR7000, the company Dynatech). Inhibitory activity of the analyzed compounds was determined as the percentage of binding of MDM2 in the wells containing the analyzed compound, compared to wells that do not contain the analyzed compound, and calculates the value of the IC50.

1. The compound of the formula I

and its pharmaceutically acceptable salts and esters, where

R is-C(O)R1where

R1choose from a range of C1-C6alkyl, -C=CHCOOH, -NHCH2CH2R2, -N(CH2CH2OH)CH2CH2OH, -N(CH3)CH2CH2NHCH3, -N(CH3)CH2CH2N(CH3)CH3saturated 4-, 5 - and 6-membered cycles and saturated and unsaturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series S, N and O and optionally substituted by a group selected from the range of C1-C6alkyl, -C=O-R5-HE , C1-C6alkyl, optionally substituted by a hydroxy-group, C1-C 6alkyl, optionally substituted by a group of series-NH2, -N-(C1-C6)alkyl, -SO2CH3, =O, and 5 - and 6-membered saturated cycles containing at least one heteroatom selected from the series N and O, where

R5choose from a range of H, C1-C6alkyl, C1-C6alkyl, optionally substituted by a hydroxy-group, and C1-C6alkyl, optionally substituted by a group-NH2,

R2choose from a range-N(CH3)CH3, -NH2morpholinyl and piperazinil,

X1, X2and X3independently selected from the series-HE1-C2alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CH2Och3and CH2Och2CH3or one of X1, X2or X3means hydrogen, and the other two are independently selected from a number of hydroxy, C1-C6alkyl, C1-C6alkoxy, -Cl, -Br, -F, -CF3, -CH2Och3, -CH2Och2CH3, -Och2CH2R3, -Och2CF3and-OR4morpholinyl, -N(CH3)CH3, -CH2HE, -COOH, or one of X1X2or X3means hydrogen, and the other two together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are necessarily attached, form a 5 - or 6-membered saturated cycle containing IU is greater least one heteroatom, selected from the series S, N and O, where

R3choose from a number of-F, -och3, -N(CH3)CH3unsaturated 5-membered cycle containing at least one heteroatom N,

R43-5-membered saturated cycle, and

Y1and Y2each independently selected from a number of-Cl, -Br, -NO2That is C≡N and≡CH.

2. The compound according to claim 1, where Y1and Y2each independently selected from-Cl and-Br.

3. The compound according to claim 1, where R1choose from a range morpholinyl, piperazinil, piperidinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl, furanyl, piperazinil, substituted by at least one group selected from the range of C1-C3alkyl, -C=co3, -SO2CH3, -C=O, -OH, -CH2NH2- =Co2NH2- =Co2HE-WITH-OS(OH)CH2HE, -CH2S(HE)-CH2HE, -C=cos(CH3)2, -CH2CH(OH)CH3, -CH(CH3)CH(OH)CH3and CH2CH2HE.

4. The compound according to claim 1, where one of X1, X2or X3means hydrogen, and the other two are independently selected from a number of hydroxy, C1-C6alkoxy, -Cl, -Br, -F, -CH2Och3, -CH2Och2CH3C1-C2alkyl, -co2CH2R3and-OR4where R3choose from a number of-F, -och3, -N(CH3)CH3unsaturated 5-membered cycles, the content is bearing at least one heteroatom N, and where R4means cyclopentyl, or one of X1, X2or X3means hydrogen, and the other two together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are attached, form a 5-membered saturated cycle containing at least one heteroatom selected from the series S, N and O.

5. The compound according to claim 4, where one of X1, X2or X3means hydrogen, and the other two are independently selected from a number-och3and CH2Och2CH3.

6. The compound according to claim 4, where one of X1, X2or X3means hydrogen, and one or two other mean-O-C1alkyl, -O-C2alkyl or-O-C3alkyl.

7. The compound according to claim 4, where R3means imidazolyl.

8. The compound according to claim 1, where X3means hydrogen, and X1and X2together with the two carbon atoms, including relationships between them in the structure of the benzene cycle to which they are attached, form a 6-membered saturated cycle containing one heteroatom, which means Acting

9. The compound according to claim 1, where one of the groups X1, X2or X3means of hydrogen in the meta-position, the group orthopaedie selected from C1-C6alkoxy, and-och2CF3and group paraprotein means C1-C6alkoxy.

10. The connection according to claim 9, where the group X1, X2and the and X 3in anthopology choose from a number of ethoxy, isopropoxy and-och2CF3but in paraprotein selected from methoxy, ethoxy.

11. The connection of claim 10, where R1choose from a number piperazinil and substituted piperazinil.

12. The compound according to claim 1, where one of the groups X1, X2or X3means of hydrogen in the meta-position, the group orthopaedie means C1-C6alkoxy, and the group paraprotein means-Cl, -Br or F, or one of the groups X1, X2or X3means hydrogen paraprotein, two other groups in anthopology mean C1-C6alkoxy, and the group in meta-position means-Cl, -Br, or-F.

13. The compound of formula II

and its pharmaceutically acceptable salts and esters, where

R is-C=OR1,

R1choose from a range of C1-C6alkyl, saturated 5 - and 6-membered cycles, saturated 5-and 6-membered cycles containing at least one heteroatom selected from the series S, N and O and optionally substituted by a group selected from the range of C1-C2alkyl, C1-C3alcohol, -C=co3and 5 - and 6-membered cycles containing at least one heteroatom N,

X4choose from a range of C1-C2alkyl, C1-C6alkoxy, floratone, -Cl, -Br, -F, -OCH2C-OOQ, -O-(C1 -C6)alkyl, -co2-cyclopropyl, -CH2Och2-phenyl, a saturated or unsaturated 5 - and 6-membered cycles, saturated and unsaturated 5 - and 6-membered cycles containing at least one heteroatom selected from the series N and O, where

Q is chosen from the series hydrogen, C1-C6alkyl,

Y1and Y2independently selected from a number of-Cl, -Br, -NO2With≡N, if Y1and Y2both mean-Cl, a R1means-CH3or phenyl,

then X4not mean-Cl.

14. The connection indicated in paragraph 13, where X4choose from a number of-CH3With1-C5alkoxy, -Cl, -Br, -och2C=OOQ, phenyl and pyrrolidinyl, where Q denotes hydrogen or-CH2CH3.

15. The connection 14, where X4choose from a number of-CH3C1-C6alkoxy, -och2C=OOQ, phenyl and pyrrolidinyl, where Q denotes hydrogen or-CH2CH3.

16. The connection indicated in paragraph 13, where R1choose from a number of-CH(CH3)CH3, piperazinil, piperazinil substituted by a group selected from a number of-CH3, -CH3CH3HE is C=co3piperazinyl and piperidinyl substituted by a group selected from a range pyrrolidinyl, piperidinyl and-N(CH3)CH3.

17. The connection indicated in paragraph 13, where C1-C6alkyl selected from C1alkyl, C2alkyl or C3alkyl.

18. The connection is .13, where Y1and Y2independently selected from-Cl and-Br.

19. Connection p, where X4means C1-C6alkoxy in anthopology.

20. The connection according to claim 19, where C1-C6alkoxy selected from ethoxy, isopropoxy and 2 floratone.

21. Connection claim 20, where R1choose from piperazinil and substituted piperazinil.

22. The compound according to claim 1, selected from the group

a) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

b) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]alanon,

C) 1-[4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]-2,2-DIMETHYLPROPANE-1-he,

g) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclopentylamine,

d) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]cyclohexylmethanol,

(e) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]thiophene-2-ylmethanol,

W) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]isoxazol-5-ylmethanol,

C) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]furan-2-ylmethanone,

s) 1-[4,5-bis-(4-chlorophenyl)-2-(2,3-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

K) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-yl)methanon,

l) [4,5-bis-(4-chlorophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

m) [4,5-bis-(4-chlorophenyl)-2-(2-fluoro-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

h) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

o) [4,5-bis-(4-bromophenyl)-2-(2,4-acid)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

p) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

R) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

(C) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

t) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

u) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

f) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

x) 4-[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

C) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-the l]piperazine-1-ylmethanone,

h) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

W) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

y) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](2,5-dimethylpiperazine-1-yl)methanon,

e) bis-(2-hydroxyethyl)amid,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

Yu) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon,

I) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

AA) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

BB) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

et [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

gg) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon,

DD) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

her [4,5-is IP-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxyethylpiperazine-1-yl)methanon,

LJ) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperidine-1-yl]metano,

ZZ) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanon,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-2-methylpiperazin-1-yl}Etalon,

QC) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonyl-3-methylpiperazin-1-yl)methanon,

FL) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-hydroxypiperidine-1-yl)methanon,

mm) (4-aminomethylpyridine-1-yl)[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

NN) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

OO) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

PP) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

PP) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

her [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

TT) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde,

su) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

FF) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

XX) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-isopropylpiperazine-1-yl)methanon,

TP) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-he

HH) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone.

23. The compound according to claim 1, selected from the group

a) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

b) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

in) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

g) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

e) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

(e) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-ethylpiperazin-1-yl)methanon,

g) 4-[,5-bis-(4-bromophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

C) [4,5-bis-(4-cyanophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

s) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon,

K) 1-(4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-1-yl)Etalon,

l) 4-{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

m) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

n) triptorelin methyl(2-methylaminomethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

on triptorelin(2-dimethylaminoethyl)methylamine 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

p) triptorelin(2-dimethylaminoethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

R) triptorelin(2-amino-ethyl)amide 4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

C) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanone,

t) triptorelin[4,5-bis-(4-chlorophenyl)-2-(4-methoxy-2-propoxy the Nile)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

y) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone,

f) hydrochloride(2-morpholine-4-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

x) hydrochloride(2-piperazine-1-retil)amide 4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carboxylic acid,

C) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-isobutoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

h) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](3-methylpiperazin-1-yl)methanone,

W) triptorelin{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2-methoxyethoxy)phenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

y) {4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

e) hydrochloride{4,5-bis-(4-chlorophenyl)-2-[2-(2-floratone)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}(4-pyrrolidin-1-reparacin-1-yl)methanone,

h) 2-amino-1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

I) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-hydroxyethane,

AA) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2,3-dihydroxypropane-1-he,

BB) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2,3-dihydroxypropyl)piperazine-1-yl]metano,

BB) dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

yy) amide 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

DD [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

her [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

LJ) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]-[4-(2-hydroxyethyl)piperazine-1-yl]metano,

ZZ) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

QC) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

FL) [4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

mm [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

NN) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-digitime the azole-1-yl](4-ethylpiperazin-1-yl)methanon,

OO) [4,5-bis-(4-bromophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

PP) amide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

PP) dimethylamide 4-[4,5-bis-(4-chlorophenyl)-2-(2,4-dioxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carboxylic acid,

her [4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

TT) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-ethylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

su) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

FF) [4,5-bis-(4-chlorophenyl)-2-(4-ethyl-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

XX) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

TP) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-dimethylamino-2-ethoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

HH) triptorelin[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-were)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone.

24. The compound according to claim 1, selected from the group

a) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

b) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-Digi ronidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

in) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

g) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

d) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

(e) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

W) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) [4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

I) 4-[4,5-bis-(4-chlorophenyl)-2-(4-fluoro-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

K) [4,5-bis-(4-chlorophenyl)-2-chroman-8-yl-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

l) 4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

m) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

n) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

o) [4,5-bis-(4-bromophenyl)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

p) [4,5-bis-(4-b is Amphenol)-2-(2-ethoxy-4-forfinal)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

R) [4,5-bis-(4-chlorophenyl)-2-(2-cyclopentyloxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) {4,5-bis-(4-chlorophenyl)-2-[2-(2-dimethylaminoethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

t) {4,5-bis-(4-chlorophenyl)-2-[2-(2-imidazol-1-ylethoxy)-4-methoxyphenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

y) hydrochloride[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

f) hydrochloride[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanone,

x) hydrochloride[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanone,

C) [2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]morpholine-4-ylmethanone,

h) 1-{4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

W) hydrochloride[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

u) 4-[2-(4-chloro-2-ethoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

e) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

Yu) triptorelin[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

I) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

AA) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

BB) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

et [4,5-bis-(4-chlorophenyl)-2-(2,5-dioxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

gg) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

DD) 4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-2-it,

her [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

LJ) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-methanesulfonylaminoethyl-1-yl)methanon,

ZZ) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]methanone,

AI) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

QC) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(5-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon,

FL) [4,5-bis-(4-chlorophenyl)-2-(4-ethoxy-2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

mm) triptorelin[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

NN) [4,5-bis-(4-chlorophenyl)-2-(2,4-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

OO) hydrochloride[4,5-bis-(4-chlorophenyl)-2-(2,5-diisopropylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

PP) 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxy-5-morpholine-4-ylmethylene)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

PP) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

it) 1-[4,5-bis-(4-chlorophenyl)-2-(3-hydroxymethyl-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]alanon,

TT) 1-[4,5-bis-(4-chlorophenyl)-2-(3-methoxy-5-methoxymethyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

yy) 3-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]-5-methoxypyrazine acid,

FF) 1-[4,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

XX) [4,5-bis-(4-chlorophenyl)-2-(2-ethoxy-6-methoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone and

TP) [4,5-bis-(4-chlorophenyl)-2-(5-ethoxymethyl-2,4-acid)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone

25. The compound according to claim 1, selected from the group

a) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxypropyl)piperazine-1-yl]metano,

b) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-threo-[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano,

in) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-Erythro-[4-(2-hydroxy-1-methylpropyl " piperazine-1-yl]metano,

g) 1-{4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}propane-2-it,

d) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl][1,4]diazepan-1-ylmethanone,

e) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]-1-methylpiperazin-2-it,

W) 1-(4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}-2-methylpropan-1-he,

C) 4-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-carbaldehyde,

I) 4-{4,5-bis-(4-chlorophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

K) 4-{4,5-bis-(4-bromophenyl)-2-[4-methoxy-2-(2,2,2-triptoreline)phenyl]-4,5-dihydroimidazole-1-carbonyl}piperazine-2-it,

l) [4,5-bis-(4-ethynylphenyl)-2-(2-isopropoxy and-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

m) 1-{4-[2-(5-chloro-2-isopropoxyphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

n) [5-(4-chlorophenyl)-4-(4-ethynylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon.

26. The connection 13, selected from the group

a) 1-[4,5-bis-(4-chlorophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

b) 1-[4,5-bis-(4-chlorophenyl)-2-para-tolyl-4,5-dihydroimidazole-1-yl]alanon,

C) ethyl ester{4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid,

g) {4-[4,5-bis-(4-chlorophenyl)-1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl]phenoxy}acetic acid,

d) 2-methyl-1-[2,4,5-Tris(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]propane-1-he,

e) 1-[4,5-bis-(4-chlorophenyl)-2-(4-methoxyphenyl)-4,5-dihydroimidazole-1-yl]alanon,

W) [2-(2-chlorophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) [2-(3-bromophenyl)-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

and) [2-biphenyl-3-yl-4,5-bis-(4-chlorophenyl)-4,5-dihydroimidazole-1-yl](4-methylpiperazin-1-yl)methanon,

K) [4,5-bis-(4-chlorophenyl)-2-(3-pyrrolidin-1-ylphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

l) [4,5-bis-(4-bromophenyl)-2-(2-methoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

m) 1-[5-(4-chlorophenyl)-2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

n) 1-[4-(4-chlorophenyl)-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

o) 1-[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]-2-methylpropan-1-he,

p) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-pyrrolidin-1-reparacin-1-yl)methanon,

R) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

(C) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl](4-dimethylaminopyridine-1-yl)methanon,

t) [1,4']-bipiperidine-1'-yl[4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]metano,

u) [4,5-bis-(4-chlorophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

f) {4,5-bis-(4-chlorophenyl)-2-[2-(2-methylbutoxy)phenyl]-4,5-dihydroimidazole-1-yl}piperazine-1-ylmethanone,

x) [4,5-bis-(4-chlorophenyl)-2-(2-pentyloxide)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

C) triptorelin[4,5-bis-(4-chlorophenyl)-2-(3-ethoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

h) triptorelin[4,5-bis-(4-chlorophenyl)-2-(3-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl]piperazine-1-ylmethanone,

W) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydr is imidazol-1-carbonyl]piperazine-1-yl}Etalon,

y) [4,5-bis-(4-bromophenyl)-2-(2-ethoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano,

e) 1-{4-[4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazine-1-yl}Etalon and

Yu) [4,5-bis-(4-bromophenyl)-2-(2-isopropoxyphenyl)-4,5-dihydroimidazole-1-yl][4-(2-hydroxyethyl)piperazine-1-yl]metano.

27. Pharmaceutical composition having anti-proliferative activity, comprising a compound according to any one of claims 1 to 26 as an active ingredient and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition according to item 27, which is suitable for oral or parenteral administration.



 

Same patents:

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

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

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine.

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

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

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

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R1 represents hydrogen atom (H); R2 represents a linear or branched (C1-C8)-alkyl possibly substituted with phenyl; or R1 and R2 in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R3 represents (C1-C4)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R1 and R2 have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to novel derivatives of imidazolidine and describes compound of the formula (I): wherein R1 is chosen from the group consisting of (C1-C9)-alkyl, (C1-C2)-alkyl-Ar; R2 is chosen from the group consisting of phenyl, (C1-C4)-alkyl-Ar', -NC(O)R4, (C2-C4)-alkyl-NR3R4, (C1-C3)-alkyl-C(O)-Ar'; R3 is chosen from the group consisting of hydrogen atom (H), (C1-C2)-alkyl-Ar and Ar; R4 represents R3, or R4 can be taken in common with R3 and nitrogen atom to which they are bound for formation of morpholinyl; Ar is chosen from the group consisting of phenyl that can be optionally substituted with one, two or three substitutes chosen from the group consisting of F, Cl, Br and J; Ar' is chosen from the group consisting of phenyl, biphenyl, benzofuranyl and benz[b]thiophene that can be optionally substituted with one, two or three substitutes chosen from the group consisting of (C1-C6)-alkyl, -(CH2)0-5CO2R1, F, Cl, Br, J and COOH; A is chosen from -C(O)NHOH or -N(CHO)OH; X means -NH if Y means -C(O), or its pharmaceutically acceptable salt. Also, invention describes a method for treatment of bacterial infection based on compounds of the formula (I). Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds.

4 cl, 3 ex

FIELD: organic chemistry, chemical technology.

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

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.

EFFECT: valuable medicinal properties of inhibitors.

7 cl, 1 tbl, 410 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, biochemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of pure enantiomers of inhibitors of HMG-CoA-reductase. Invention describes a method for synthesis of compound of the formula (I): or its salt, especially pharmaceutically acceptable salt with a base, or its lactone wherein a member represents -CH2-CH2- or -CH=CH-, and R represents a cyclic residue. Invention provides the enantioselective synthesis of compounds of the formula (I) with high yields, decreasing ecological pollution of environment and possibility for carrying out the large-scale manufacturing.

EFFECT: improved method of synthesis.

6 cl, 1 ex

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

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

40 cl, 4 tbl, 55 ex

FIELD: organic chemistry, medicine.

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

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

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to novel derivatives of imidazolidine and describes compound of the formula (I): wherein R1 is chosen from the group consisting of (C1-C9)-alkyl, (C1-C2)-alkyl-Ar; R2 is chosen from the group consisting of phenyl, (C1-C4)-alkyl-Ar', -NC(O)R4, (C2-C4)-alkyl-NR3R4, (C1-C3)-alkyl-C(O)-Ar'; R3 is chosen from the group consisting of hydrogen atom (H), (C1-C2)-alkyl-Ar and Ar; R4 represents R3, or R4 can be taken in common with R3 and nitrogen atom to which they are bound for formation of morpholinyl; Ar is chosen from the group consisting of phenyl that can be optionally substituted with one, two or three substitutes chosen from the group consisting of F, Cl, Br and J; Ar' is chosen from the group consisting of phenyl, biphenyl, benzofuranyl and benz[b]thiophene that can be optionally substituted with one, two or three substitutes chosen from the group consisting of (C1-C6)-alkyl, -(CH2)0-5CO2R1, F, Cl, Br, J and COOH; A is chosen from -C(O)NHOH or -N(CHO)OH; X means -NH if Y means -C(O), or its pharmaceutically acceptable salt. Also, invention describes a method for treatment of bacterial infection based on compounds of the formula (I). Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds.

4 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide of the formula (I): . Method involves: (A) contacting compound of the formula (II) with transient-base metal as a catalyst, hydrogen source and a base in solvent medium to form compound of the formula (III): wherein R1 represents -XR wherein X represents oxygen atom (O), sulfur atom (S) or selenium atom (Se), or R1 represents -NR2R3 wherein each R2 and R3 represents independently alkyl, cycloalkyl, arylalkyl or aryl, or R2 and R3 taken in common represent -(CH2)4-, -(CH2)5-, -(CH(R4)-CH2)3-, -(CH(R4)-CH2)4-, -(CH(R4)-(CH2)2-CH(R4)-, -(CH(R4)-(CH2)3-CH(R4)-, -CH2-CH2-A-CH2-CH2-, -CH(R4)-CH2-A-CH2-CH2-, -CH(R4)-CH2-A-CH2-CH(R4)- wherein R4 represents alkyl comprising of from one to four carbon atoms; A represents oxygen atom (O), sulfur atom (S), -NH or -NR wherein R represents alkyl, aryl, arylalkyl or heteroaryl; (b) conversion of compound of the formula (III) wherein R1 is given above to compound of the formula (IV) with using a base in an aqueous methanol medium, and (c) contacting compound of the formula (IV) with acid in solvent medium to form compound of the formula (I). Invention provides the development of safety and effective method for synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide for the large-scale production.

EFFECT: improved preparing method.

13 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzofuran of the formula (1): wherein R represents L; R1 represents 2-R2-5-R3-pyrrol-1-yl-carbonyl, -CON(C2H5)2, -CON(CH2C6H5)2, -CON[CO2C(CH3)2]2; L represents bromine atom (Br); R2 and R3 in each case and independently of one another represent alkyl comprising 1-6 carbon (C)-atoms, and to their salts also. These compounds are intermediate substances used in synthesis of medicinal preparations showing effect on the central nervous system, for example, 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine. Invention provides synthesis if new intermediate compounds allowing synthesis of medicinal preparations such as 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine by the available method.

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

4 cl, 8 ex

FIELD: organic chemistry, chemical technology.

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

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted diketopiperazines of the general formula (I) or their physiologically acceptable salts wherein R1 means 5-membered cycloalkyl group optionally substituted with one or some hydroxyl groups that is condensed with optionally substituted benzene ring; R2 means (C1-C6)-alkyl; R3 means optionally substituted phenyl, 5- or 6-membered heteroaryl group, or condensed bicyclic ring system comprising 9-10 ring members; R4 means -OH, -O-(C1-C4)-alkyl or -NR5R6. Compounds possess antagonistic effect with respect to oxytocin in oxytocin receptors. Also, invention describes a pharmaceutical composition based on compound of the formula (I), using compounds of the formula (I) for preparing a medicinal agent and methods for synthesis of compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 227 ex

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