Derivatives of 3-substituted 4-originalen-2-it is as modulators of potassium channels

 

(57) Abstract:

The invention relates to new derivatives of 3-substituted 4-originalen-2-it formula

where R and R1each independently represents hydrogen or methyl; R2, R3and R4each independently represents hydrogen or trifluoromethyl, provided that R2, R3and R4are not simultaneously hydrogen; R5denotes bromine or chlorine; R6denotes hydrogen or fluorine; n denotes an integer from 0 to 6; m represents an integer of 0 or 1 and R7denotes CH3, CRR1OH, SNO, C=NOH, PINES3or aryl, possibly substituted by one or two substituents selected from the group consisting of hydroxy, methoxy, amino, acetylamino, or their non-toxic pharmaceutically acceptable salts. The technical result is to provide new compounds which are modulators of activated calcium TO+channels with a high conductivity and is suitable for treatment of disorders responsive to opening of potassium channels. 1 N. and 7 C.p. f-crystals, 1 table.

The scope to which the invention relates.

This invention relates to new derivatives of 3-substituted 4-originalen-2-it, which ablauts the s to protect nerve cells and for protection from disease, resulting from dysfunction of polarization of cell membranes and conductivity.

This invention also provides a method of treatment using derivatives of substituted quinoline-2-she and pharmaceutical compositions based on them.

Background of invention

Potassium channels play a key role in regulating the potential of the cell membrane and modulation of the excitability of the cells. Potassium channels in heavily regulated amplitude, cell metabolism, processes, mediated by calcium and receptors [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21, and Quast U., et al., Trends in Pharmacol. Sciences (1989), 10, 431]. Activated calcium potassium (Kca) channels represent another group of ion channels whose activity depends on intracellular calcium ions. Activity TOcachannels is governed by the potential intracellular [CA2+] membrane and phosphorylation. Based on the conductance of single channels in symmetrical solutions TO the+TOCAthe channels are divided into three subclasses: Wysocki conductivity (VK)>150 PS; with intermediate conductivity 50-150 PS; low conductivity of <50 PS. Activated calcium potassium channels with high held the dust of smooth muscle cells [Singer, et al., Pflugess Archiv. (1987), 408, 98; Baro, I., et al., Pflugess Archiv. (1989) 414 (Suppl. 1), S168, and Ahmed F. et al., Br.J.Pharmacol. (1984) 83, 227].

Potassium ions play a major role in the regulation of residual membrane potential in most of the excited cells and support the transmembrane voltage potential level of balance TO+(Eto), equal to about 90 mV. It was found that the opening of potassium channels shifts the potential of the cell membrane in the direction of equilibrium of potassium ions (Eto), resulting in the hyperpolarization of the cell [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21]. Hyperpolarization cells show reduced response to potentially harmful depolarizing stimuli. Channels VK, which are regulated by both voltage and intracellular ions of CA2+limit depolarization and calcium intake and may partially effectively block harmful stimuli. Therefore, the hyperpolarization of the cell through the opening of channels VK can lead to the protection of nerve cells.

A number of synthetic and natural compounds with the ability to open VK known. Piron, extracted from the seed oats avena sativa, has been described as the discoverer of channels VC when using the two-layer Eski experiments it was found, 6-bromo-8-(methylamino)imidazo[1,2-a]pyrazin-2-carbonitrile (SCA-40) is the discoverer of the channels VK [Laurent, F. et al., Br. J. Pharmacol. (1993) 108, 622-626]. It was found that the flavonoids Phloretin increases the possibility of opening the activated CA2+potassium channels in myelinating nerve fibers of Xenopus laevis using an external patches [Koh, D-S, et al., Neuroscience Lett. (1994) 165, 167-170].

In the application EP-A-477819, published on 4 January 1992, and in the corresponding U.S. patent 5200422, issued April 6, 1993 Olesen and others, describes the various derivatives of benzimidazole as discoverers of channels VK using experiments with isolated channels and fixing the potential of all cells in the smooth muscle cells of the aorta. Subsequent studies were described by Olesen et al. in European J. Pharmacol., 251, 53-59(1994).

P. Hewawasam et al. in U.S. patent 5565483, issued October 15, 1996, described a number of substituted oxindoles with the ability to open BK channels. Sit et al. in the application WO 98/23273, published June 4, 1998, and in the corresponding U.S. patent 5892042, issued April 6, 1999, revealed the group of derivatives of 4-aryl-3-hydroxyquinolin-2-it, a Hewawasam et al. in the application WO 99/09983, published on March 4, 1999, described the group of derivatives of 4-aryl-3-aminoquinoline-2-it, Alaudinov.

E. S. Hamanaka in U.S. patent 5565472, issued October 15, 1996, described a series of 4-aryl-3-(heteroaromatic)-1,2-dihydro-2-oxacilin, are inhibitors of alloenzyme A; cholesterolcholesterol and useful as hypolipidemic and antiatherosclerotic agents.

The purpose of this invention is to provide new compounds which are capable of modulating potassium channels, in particular activated calcium potassium channels with a high conductivity (VK), and which would be suitable for treatment of diseases resulting from the dysfunction of the polarization and conductivity of the cell membrane.

The invention

The present invention provides new derivatives of 3-substituted 4-originalen-2-it, having the General formula

where R, R1, R2, R3, R4, R5, R6and R7defined below,

and their pharmaceutically acceptable non-toxic salts, which are openers of activated calcium potassium channels with a high conductivity, also known as Maxi-K or BK channels.

A detailed description of the invention

This invention provides new derivatives of 3-Samusenko is of analy high conductivity (channels VK) and have the formula

where R and R1each independently represents hydrogen or methyl;

R2, R3and R4each independently represents hydrogen or trifluoromethyl, provided that R2, R3and R4are not both hydrogen;

R5denotes bromine or chlorine;

R6denotes hydrogen or fluorine;

n denotes an integer from 0 to 6;

m denotes an integer of 0 or 1, and

R7denotes CH3, CRR1OH, CHO, C=NOH, PINES3or aryl, possibly substituted by one or two substituents selected from the group consisting of hydroxy, methoxy, amino, acetylamino,

or their non-toxic pharmaceutically acceptable salt.

The term “nontoxic pharmaceutically acceptable salt” used in the description and in the claims, includes non-toxic salts joining inorganic bases. Suitable inorganic bases such as alkali and alkaline earth metals include base metals such as sodium, potassium, magnesium, calcium, etc., If not otherwise stated, the term “halogen”, as used in the description and in the claims, includes bromine, chlorine, iodine and FPO is meniu can exist in the form of desolvation forms and salvatorem forms, including hydrates, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc. Products can be a true solvate, while in other cases the products can simply hold a random solvent or mixture of MES and some random solvent. Specialists in this field it is obvious that the solvated forms are equivalent and nonsolvated included in the scope of this invention. Some compounds of formula I can exist in two tautomeric forms. Experts obviously, when R1denotes hydrogen at the nitrogen atom, adjacent to the carbon atom of the carbonyl group, quinoline ring can exist in the enol form. Both enol tautomer compounds of formula I are included in the scope of this invention.

Preferred to use compounds include the compounds of formula I listed below:

4-(5-chloro-2-methoxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(hydroxymethyl)-7-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-chinainternational;

4-(5-chloro-2-methoxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(is he;

4-(5-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(E)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(Z)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(E)-4-(5-chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(Z)-4-(5-chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(4-methoxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3,4-acid)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(2,4-dihydroxyphenyl)-6 is non;

4-(5-chloro-2-hydroxyphenyl)-3-[(4-hydroxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(4-acetamidophenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-[2-(4-hydroxyphenyl)ethyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-methyl-6-(trifluoromethyl)-2(1H)-chinoline;

4-[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]-3-butene-2-he;

4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium;

4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium and

4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-2(1H)-chinoline.

The compounds of formula I can be obtained in various ways, such as described in the examples and shown in the reaction schemes shown in the specific examples, modification of these described methods are obvious to experts in this field.

The reaction scheme 1-11 illustrate examples of common methods of obtaining intermediate compounds and method of preparing compounds according to image the s is also in the scope of this invention.

Reaction scheme 1

(a) ClC(O)CH2CO2Ra, pyridine, CH2Cl2, 0°C to room temperature;

(b) KO+Bu, THF, reflux;

(c) Dibal-H, THF-hexane, -78°C To room temperature;

(d) MnO2CH2Cl2.

Getting 2(1H)-khinolinov formulas 4 and 5 shown in reaction scheme 1. As shown in this diagram, the acylation of compounds of formula I acylchlorides led to the amide of formula 2 where Radenotes hydrogen or C1-4alkyl, which may cilitates and degidratirutego getting Hinayana formula 3 when processing base, such as tert-piperonyl potassium, in an inert organic solvent. Treatment of an ether of formula 3 a reducing agent, such as diisobutylaluminium, leads to the formation of a primary alcohol of formula 4, which can then be oxidized with an oxidant such as manganese dioxide, to give the desired aldehyde of formula 5.

Reaction scheme 2

(a) EtOC(O)CH2P(O)(OEt)2, NaH, DMF;

(b) Dibal-H, THF,-78°C;

(c) tO2, tO-Hcl, N2(60 F./inch2=413,7 kPa).

As shown in the reactions is placed ester of formula 6 in the form of a mixture of (E)- and (Z)-isomers, which are then separated by chromatography on a column. Recovery ester of formula 6 can be realized by a reducing agent, such as diisobutylaluminium, with the formation of the corresponding allyl alcohol of the formula 7. In addition, when it is desirable to obtain the compound of formula 9, the ester of formula 6 is selectively restore the conditions for hydrogenation of the double bond recovery and get busy ether of the formula 8. Treatment of the ester of formula 8 in conditions similar to the conditions of recovery of the ester of formula 6, leads to the corresponding alcohol of formula 9.

Reaction scheme 3

(a) VVG3CH2Cl2, -78 -0°C;

(b) l(O)CH2CO2IU, pyridine, CH2CL2;

(c) KO+Bu, THF, reflux;

(d) Dibal-H, THF, -78°C;

(e) Dibal-H, CH2Cl2-78°C.

In reaction scheme 3 shows that butyloxycarbonyl (VOS) and the methyl group can be removed simultaneously by treating the compounds of formula 1A by tribromide boron (VVG3) to give the aniline of formula 10. The acylation of aniline of formula 10 was possible to obtain the corresponding amide of formula 11, which is easily the loop 12. Partial restoration of the lactone diisobutylaluminium in THF led to the production of intermediate lactol formula 13. In addition, it was found that when replacing THF with methylene chloride lactone of formula 12 can be restored using diisobutylaluminium to give the desired alcohol of formula 14.

Reaction scheme 4

(a) EtOC(O)CH2P(O)(ORa)2, NaH, DMF;

(b) Dibal-H, THF - hexane, -78°C To room temperature;

(c) PtO2, tO-Hcl, N2(60 F./inch2=413,7 kPa);

(d) NaOH, EtOH, room temperature.

When you need to obtain the compound of formula 17 and 20, the intermediate lactol formula 13 can be processed, as shown in figure 4, the phosphonate with obtaining unsaturated ester of formula 15, and then, if desirable, to carry out saponification with obtaining unsaturated acid of the formula 16. In addition, hydrogenation of the double bond of compounds of formula 15 leads to the formation of an ether of formula 18, which may or subjected to saponification to obtain the acid of formula 19, or to restore alumilite with obtaining alcohol of formula 20.

Reaction scheme 5

(a) EtOC(O)CHFP(O)(OEt)2, NaH, DMF;

(b) Dibal-H, CH2Cl2 is Tola formula 13 perphosphate, as shown in stage (a) reaction scheme, resulting in an unsaturated fluorinated ether of the formula 21 in the form of a mixture of (E)-and (Z)-isomers. The technical mixture of esters of formula 21 can be restored by aluminohydrides and the obtained mixture of alcohols separated by chromatography on a column of obtaining (E)-olefin of formula 23 and (Z)-olefin of formula 25. Similarly aldehyde of formula 5, which contains a methoxy group, can be converted into the corresponding olefins of formula 24 and 26.

Reaction scheme 6

(a) ClC(O)(CH2)nCO2Ra, pyridine, CH2Cl2;

(b) KHMDS, THF, -78°C;

(c) 35% HBr - Asón, toluene, 80-90°C;

(d) pyridine·Hcl,180-200°C;

(e) NR3·Me2, THF, -10°C - room temperature.

Obtaining compounds of formula 31A and 31b shown in reaction scheme 6. The acylation of aniline of formula 1, the acid chloride of the acid leads to the formation of the corresponding amide. Amide of formula 27 can be subjected to cyclization in the basic conditions to receive dihydrohydroxycodeinone formula 28, which can then be degidratiruth and deteriorate in acidic conditions, for example, using NVG/Asón or p-TsOH, getting Hinayana farmoperator to obtain the corresponding phenol of formula 30. Recovery of the acid of formula 30 results in alcohol of formula 31A in the form of phenol. In addition, if desired methyl ether of phenol, provide direct recovery of carboxylic acids of formula 29 borane, which leads to the corresponding alcohol of formula 31b.

Reaction scheme 7

(a) ClC(O)(CH2)n+1R8, pyridine, CH2Cl2;

(b) KHMDS, THF, -78°C;

(c) H+

(d) pyridine · HCl, 180-200°C.

Compounds of formula 34 and 35, where n=0-6 and R8stands WITH1-4alkyl or aryl, possibly substituted by one or two substituents selected from the group consisting of halogen, hydroxy, methoxy, amino, acetylamino and trifloromethyl can be obtained in a manner analogous shown in reaction scheme 6. Thus, the reaction scheme 7 illustrates the acylation of compounds of formula 1 with subsequent cyclization and de-hydration with 3-substituted quinoline of formula 34 in the form of a methyl ester. Demethylation of compounds of formula 34 with hydroxychloride pyridine at elevated temperatures leads to the formation of phenol of formula 35.

Reaction scheme 8

(a) (MeO)2P(O)CH2< is shown in reaction scheme 8, the homologation intermediate lactol formula 13 centofante or phosphonate leads to the formation of the corresponding unsaturated nitrile of formula 36A or acetate of formula 37A, respectively. Similarly, the methyl esters of the formula 36b and 37b can be synthesized from aldehyde of the formula 5 processing or centofante or phosphonate respectively. The oxime of formula 38A can be obtained from the intermediate lactol formula 13 by processing lactol hydroxylamine. Similarly, the methyl ether of the formula 38b can be obtained from the aldehyde of the formula 5.

Reaction scheme 9

(a) cat. p-TsOH, toluene, heating under reflux;

(b) Meon, silica gel;

(c) RR1Li, THF, -78°C.

Reaction scheme 9 illustrates the formation of a lactone of formula 39, when the hydroxy acid of formula 30A is treated with a catalytic amount of acid in the environment of toluene at reflux. After cleaning the lactone of formula 39 on silica gel using methanol as one of the eluents, you can turn the lactone in the ether of formula 30b. If it is desirable to obtain the substituted alcohol of formula 40, a lactone of formula 39 is treated with an excess of lithium reagentsand obtaining monosubstituted alcohol.

Reaction scheme 10

(a) TlPSCl, imidazole, DMF;

(b) n-BuLi, CH3I, THF;

(c) F, THF;

(d)2CO3, (CH3O)2SO2the acetone.

Obtaining N-methyl compounds of formula 43 and 44 are reflected in reaction scheme 10. Similarobama alcohol of formula 31A triisopropylsilyl(IS)chloride results in silylamines ether of formula 41. N-Alkylation of alkylhalogenide, such as methyliodide, allows to obtain a compound of formula 42, which may be desilicious fluoride, stage (C), to obtain the compounds of formula 43. If it is desirable to obtain methylated phenol, a compound of formula 41 is treated with dimethylsulfate with subsequent disilylgermane obtaining dimethyl analogue of formula 44.

Reaction scheme 11

(a) LiHMDS/THF, -78°C, room temp.;

(b) 12NHCl;

(c) p-TSA, toluene, heating under reflux;

(d) LiHMDS;

(e) UV, Meon.

Obtaining the compounds of formula 31A is carried out, as shown in reaction scheme 11. Coumarin of formula 45 is obtained by condensation-butyrolactone with methyl ether chlorosalicylic acid, then it cichlisuite p shown in stage (d), results dihydrofuran formula 47, which is then subjected to photocyclization in an inert solvent to obtain compounds of formula 31A.

According to a preferred variant of the invention the compounds of formula I have the formula

where R and R1each independently represent hydrogen or methyl; R2, R3and R4, each independently, represent hydrogen, halogen, nitro or trifluoromethyl, provided that R2, R3and R4are not all simultaneously hydrogen; R5denotes bromine, chlorine or nitro; R6denotes hydrogen or fluorine; n denotes an integer from 0 to 6; m represents an integer 0 or 1; R7denotes CH3, -CRR1OH, CHO, O,=NOH, -PINES3or aryl, possibly substituted by one or two substituents selected from the group consisting of halogen, hydroxy, methoxy, amino, acetylamino and trifloromethyl, or their non-toxic pharmaceutically acceptable salt.

According to another preferred variant of the invention compounds are those in which R and R1each independently represents hydrogen or methyl; R2, R3and R4, each independently, represent hydrogen, chlorine, nitro or triform the denotes hydrogen or fluorine; n is 0, 1 or 2; m is 0 or 1 and R7denotes-CH3, -CH2HE, CHO, -C=NOH, -COCH3or aryl, possibly substituted with halogen, hydroxy, methoxy, amino, acetylamino or trifluoromethyl, or their non-toxic pharmaceutically acceptable salts.

According to another preferred variant of the invention the compounds of formula I include compounds in which R denotes hydrogen or methyl; R1and R4denote hydrogen; R2and R3each independently represents trifluoromethyl; R5denotes chlorine; R6denotes hydrogen; n is 0, 1 or 2; m is 0 or 1 and R7denotes-CH2HE or aryl, possibly substituted with halogen, hydroxy, methoxy, amino, acetylamino or trifluoromethyl, or their non-toxic pharmaceutically acceptable salt.

According to another aspect of the invention provides a method of treatment or prevention of disorders mediated by the opening of activated calcium potassium channels with a high conductivity (BK channels) in a mammal in need of such treatment or prevention, which includes the introduction of the specified mammal a therapeutically effective amount of the compounds of formula I or its natok and, shock, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, urinary incontinence and sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause), and in women by improving blood flow to the sexual organs, especially to the corpus cavemosum, and other disorders sensitive to BK channel.

According to another aspect, the invention provides pharmaceutical compositions containing at least one compound of formula I in combination with a pharmaceutical adjuvant, carrier or diluent.

Biological activity

Potassium (K+the channels are structurally and functionally diverse group selective for K+proteins that are present in the cells, playing a major role in the regulation of a number of key functions of cells [Rudy, B., Neuroscience, 25: 729-749 (1988)]. As widely distributed as a class TO the+the channels are distributed differently as individual members of this class or as groups [Gehlert, D. R., et al., Neuroscience, 52: 191-205 (1993)]. In General, activation of K++channels can respond to important events in cells, such as changes in intracellular concentrations of ATP or intracellular concentration of calcium (CA2+). A Central role FOR the+channels in the regulation of many functions of the cells makes them particularly important targets for therapeutic intervention [Cook, N. S., Potassium channels: Structure, classification, function and therapeutic potential. Ellis Horwood. Chinchester (1990)]. One class TO the+channels activated CA2+TO+channels of high conductance (Maxi-K or BK channels) is regulated by the transmembrane potential, intracellular CA2+and a variety of other factors such as the degree of phosphorylation of the protein channels [Latorre, R., et al., Ann. Rev. Physiol., 51: 385-399 (1989)]. The high conductance of a single channel (usually >150 PS) and a high degree of specificity for K+BK channels suggest that only a small number of channels can have a profound effect on the conductivity of the membranes and the excitability of the cells. In addition, the increased probability of opening with the increase of intracellular CA2+shows that BK channels are involved in 77-1285 (1993)].

Openers BK channels manifest their effect on cells by increasing the probability of opening of these channels [Mscow, M. S., et al., J. Neurophysiol. 71: 1873-1882 (1994); Olesen, S.-P., Exp. Opin. Invest. Drugs, 3: 1181-1188 (1994)]. This increase opening a separate VC channels leads to hyperpolarization of cell membranes, especially in depolarized cells caused a significant increase in conductivity of the whole cell-mediated VK.

The ability of compounds described in this application to open BK channels and increase the number of out of cell TO+mediated VK, evaluated in terms of volt-clamp by determining their ability to increase the number of ions emerging from human cells, cloned, mediated VK (mSlo or hSlo), expressed heterologic in Xenopus oocytes [Butler, A., et al., Science, 261:221-224 (1993), and Dworetzky, S. I., et al., Mol. Brain Res., 27: 189-193 (1994)]. Two used the VC model was almost identical to the structure of homologous proteins, found themselves, as has been proven pharmacologically identical in our experiments. To isolate flow from VK natural (primary, non-VC) flow was used in supermaximal concentration (50 nm) specific and potent toxin, Iberico the Ah in General the flow of ions from the cells was determined by subtracting the flow, remaining in the presence of IBTX (non-VC flow) of the flow profiles obtained in all other experimental conditions (control samples, medicine and flushing). It was found that the tested concentrations of the compounds do not affect non-VK natural flows in the oocytes. All compounds were tested in at least 5 oocytes at a single concentration equal to 20 μm; the effect of selected compounds of formula I on the flow of ions in VK is expressed in percent of the flow of ions, IBTX-sensitive (control), the data in the table. The results were recorded using a standard method volt-clamp with two electrodes [Stuhmer, W., et al., Methods in Enzymology, Vol.207:309-339 (1992)]. Method volts-clamp consisted of the stages of depolarization duration 500-750 MS from the resting potential, equal to -60 mV to +140 mV with the stages in 20 mV. Environment (modified solution Bart) contained (in mm): NaCl (88), Nano3(2,4), KCl (1,0), HEPES (10), MgSO4(0,82), Sa(NO3)2(0,33), l2(0,41); pH 7.5.

To determine the ability of these compounds to reduce the cell loss due to neural ischemia used a standard rodent model with permanent focal ischemia, including occlusion in the middle of cerebra., et al., Journal of Cerebral Blood Flow and Metabolism, Volume 1, 53-60 (1981)]. Selected compounds were tested in models of focal stroke, including permanent MCAO in spontaneously hypertensive rats. This procedure leads to extensive neocortical infarction volume of which is measured by the exclusion of the vital dye in serial sections of brain tissue 24 h after MCAO. This experience of connection was injected intravenously over 2 h after occlusion. For example, in this model, the compound from example 21 was reduced cortical infarction by about 25% with the introduction of a single bolus (0.003 mg/kg) 2 h after occlusion of middle cerebral artery compared with kontrolni experience with the introduction of media (2% DMSO, 98% propylene glycol).

In vivo model for determining erectile function are described in detail in the scientific literature [Rehman, J., Chenven, E., Brink, P., Peterson, C., Wolcott, B., Wen, Y. P., MelmanA., Christ, G.: Diminished neurogenic but not pharmacological elections in the 2-3-month experimentally diabetic F-344 rat. Am. J. Physiol. 272: H1960-H1971 (1997)]. Briefly, rats (varying between 250 and 600 g) were subjected to anesthesia using pentobarbital sodium, opened the abdominal cavity and identified the cavernous nerve. In the right corpus cavemosum for measuring vnutrikavernozno pressure (SR) were placed catheter. A second catheter was introduced for measuring the imposition of the (0,1, 0.3 and 1 mg/kg, intravenously) or vehicle (PEG 400).

Control vnutrikavernozno pressure was determined by electrical stimulation of the cavernous nerve using a bipolar stimulating electrodes (20 Hz, pulse 0,22 MS). The amplitude of the stimuli (0.2 to 20 mA) was regulated to obtain submaximal vnutrikavernozno pressure (usually 0.2 or 0.5 mA). Then, using a constant value of the amplitude of the stimuli received a number of control values vnutrikavernozno pressure. Then entered the test compound or vehicle (200 μl, intravenous bolus) again stimulated the cavernous nerve in order to measure the cavernous pressure at different time intervals after drug administration. If the initial ICP values were unstable (“peak” response) or if there has been a variation of the magnitude of the control reaction, depending on the time, these animals were excluded. Animals also were excluded if reference values ICP/BP (BP - blood pressure) were outside the interval of 0.3 to 0.6. To estimate statistics was performed by repeated measure ANOVA.

The compound from example 20 (0.1 to 1 mg/kg) caused an increased response ICP/BP caused by submaximal stimulation of cavernoso CLASS="ptx2">The results of the above biological tests show that the compounds according to the invention are potent openers of activated calcium TO+channels of high conductance (Maxi-K or BK channels). Thus, the compounds according to the invention is suitable for treatment of disorders in humans, resulting from dysfunction of the polarization and conductivity of the cell membrane and preferably indicated for the treatment of ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, urinary incontinence and especially of erectile dysfunction in men, other disorders sensitive to the activity of BK channels.

According to another aspect, the invention includes pharmaceutical compositions containing at least one compound of formula I in combination with a pharmaceutical adjuvant, carrier or diluent.

According to another aspect of the present invention relates to a method of treatment or prevention of disorders responsive to opening of potassium channels in a mammal in need of such treatment or prevention, which includes the introduction of ukazani acceptable salt.

Therapeutic application of pharmacologically active compounds of the formula I is usually administered in the form of a pharmaceutical composition comprising as active substance at least one such compound in combination with a solid or liquid pharmaceutically acceptable carrier and, possibly, with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques.

Pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), bronchial or nasal administration. So, if you use solid media, the drug may be in the form of tablets placed in a hard gelatin capsule in powder or granular form or may be in the form of lozenges or candy. A solid carrier can contain conventional excipients such as binders, fillers, lubricating agents for tablets, disintegrant, wetting, etc., Tablet, if desired, may be covered with conventional film. If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule, sterile solution for injecti chodashim carrier before use. Liquid preparations can contain conventional additives, such as suspendresume agents, emulsifiers, wetting and non-aqueous media (including edible oils), stabilizers, as well as fragrances and/or dyes. For parenteral administration the carrier is usually a sterile water, at least in the most part, although you can also use saline solutions, glucose solutions. Suspension for injection can also be used, in this case, apply the usual suspendresume agents. Parenteral dosage forms may also be added to the usual stabilizers, buffering agents, etc., Especially useful for the introduction of compounds of formula I directly in parenteral drugs. Pharmaceutical compositions are prepared by conventional methods suitable to obtain the desired product containing appropriate quantities of the active substance, namely the compounds of formula I according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishig Company, Easton, PA, 17thedition, 1985.

The dose of the compounds of formula I to obtain a therapeutic effect depends not only on factors such as age, weight or sex of the patient and the method of introduction, but also on the desired degree of activity (CA) is FDI. The dose of specific compounds can be introduced in the form of a unit dosage forms, and that the unit dosage form is selected by a specialist in accordance with the relative level of activity. The decision about the specific dose (and the scheme of injection per day) is within the competence of the doctor, and they can vary depending on the specific circumstances, to obtain a desired therapeutic effect.

A suitable dose of a compound of formula I or pharmaceutical compositions based on it for a mammal, including humans, suffering and potential victims of any violations described here, is based on the active ingredient from about 0,01 µg/kg to 10 mg/kg weight of the patient, preferably from about 0.1 μg/kg to 5 mg/kg of patient's weight when administered orally. When parenteral dose may range from 0.1 μg/kg to 1 mg/kg weight of the patient in the case of intravenous administration. The active substance preferably in equal doses one to four times per day. However, usually give a small dose and gradually increase it until you determine the optimal dose for a given patient.

Compounds according to the invention can be entered separately or in combination with other itory cGMP PDE and particularly inhibitors of cGMP PDE V, for example sildenafil. Examples of therapeutic agents are inhibitors of PDE V is selected from imidazothiazoles (see WO 98/08848), carbazoles (see WO 97/03675, WO 97/03985 and WO 95/19978), imidazopyridine (see WO 97/19947), benzimidazole (see WO 97/24334), pyrazoloquinoline (see U.S. patent 5488055), derivatives of Anthranilic acid (see WO 95/18097), condensed heterocycles (see WO 98/07430) and thienopyrimidines (see DE 19632423).

The above-mentioned therapeutic agents when used in combination with the compounds according to the invention can be administered in amounts that are specified, for example, in Physician''s Desk Reference (PDR) or other amounts determined by the specialist.

However, it should be borne in mind that the number of connections that are entered in fact, determined by your physician based on the relevant circumstances, including the type of disease, the choice of input connections, method of administration, age, weight, and susceptibility of the patient and the severity of the patient's symptoms.

The following examples are given to illustrate the invention and not limit it, in the scope of the present invention are also many modifications of the invention.

Description of specific examples

In the following examples all temperatures are indicated in gradsects proton nuclear magnetic resonance (1H NMR) were recorded on a spectrometer Bruker AC 300. All spectra were measured in the indicated solvent and chemical shifts are given in units in a weak field compared to the internal standard tetramethylsilane was (TMS), constant spin interaction is specified in Hertz (Hz). The proton signals are indicated as follows: s, singlet; d, doublet; t, triplet; q, Quartet; m multiples; br broadened peak; dd, doublet of doublet; bd, broadened doublet; dt, doublet of triplet; bs, broadened singlet; dq, doublet of Quartet. Infrared (IR) spectra were measured on a spectrophotometer Perkin Elmer 781 at a wavelength of from 4000 to 400 cm-1calibrated wavelength 1601 cm-1characterizing the absorption of a polystyrene film, using potassium bromide (KBR), the spectral characteristics indicated in cm-1. Mass spectra of low-resolution (MS) and the apparent molecular weight (MN+) or (M-N)-was determined on the device Finnigan TSQ 7000. Elemental analysis indicated in percent by weight. If in the specific examples is not specified, the name specified compounds in which R2and R4denote N.

Example 1.

Methyl ester of 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinoline-carboxylic acid (3, R3

Pure mixture of 4-aminobenzotrifluoride (35 g, 0,218 mol) and (BOC)2On (52,4 g, 0.24 mol) with stirring, they were heated at 80°C for 2-3 hours as long as you do not stop the allocation of CO2. The mixture is allowed to cool and method rotary evaporation to remove tert-VION. The obtained white solid is recrystallized from a mixture of hexane/simple ether to obtain white needles (50.6 g, 89%) of N-(tert-butoxycarbonyl)-4-aminobenzotrifluoride.

To a cooled (-78°C) stirred solution of N-Boc-4-aminobenzotrifluoride (26,2 g, 0.1 mol) in dry THF (130 ml) in an argon atmosphere for 20 minutes add tert-uLi (130 ml and 0.22 mol, 1.7 M in cyclohexane). The resulting yellow solution was heated up to (-45) -(-40)°C and maintained for 2 hours. Received a heavy suspension of dianion yellow was cooled to (-78)°C and quickly added pure dry methyl-5-chloro-2-methoxybenzoate. The resulting solution was yellow-brown in color, they were heated to (-40)°C and maintained for 1 hour. The reaction mixture was diluted with ether (200 ml) and broke reaction of 1 N Hcl (250 ml), then gave the mixture to warm to room temperature. The organic layer was separated, washed with water, brine and then dried (Na2SO4). Cypriana, getting to 31.9 g of compound indicated in the title so pl. 148-150° C. IR (KBr, cm-1): 3280, 1725, 1640, 1530, 1320, 1250, 1150.

1H NMR (300 MHz, DMSO-d6): of 1.41 (9H, s), to 3.58 (3H, s), 7,19 (1H, d, J=8,9 Hz), 7,49 (1H, d, J=2.7 Hz), 7,58 (1H, d, J=2.6 Hz), 7,60 (1H, dd, J=8,9 and 2.7 Hz), to 7.93 (1H, dd, J=8.7 and 1.9 Hz), to 8.12 (1H, s), 8,15 (1H, m), 10,35 (1H, s). MS m/e 430 (MN+).

Calculated for C20H19ClF3NO4, %: 55,88; H OF 4.45; N 3,25.

Found, %: C 55,51; H To 4.38; N 3,26.

Stage C. 1-[2-Amino-5-(trifluoromethyl)phenyl]-1’-(5-chloro-2-methoxyphenyl)methanon (1, R3=CF3).

To a stirred solution of 1,1-dimethylethylene ester of N-[2-[5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]aminocarbonyl acid (19 g, 0,044 mol) in ethanol (300 ml) was added 3 N Hcl. The resulting suspension was heated under reflux for 3 hours. The progress of hydrolysis was monitored by TLC. The reaction mixture was cooled and poured into cold water (500 ml). The resulting product was extracted with ether (2× 200 ml) and combined ethereal extracts were washed with water, brine and then dried (Na2SO4). Evaporation of the ether led to a viscous oil Golden yellow color, which after soaking over night solidified with the formation of solid beige>): 3,68 (3H, s), 6,97 (1H, d, J=8,8 Hz), 7,19 (1H, d, J=8,9 Hz), 7,26 (1H, d, J=1.1 Hz), was 7.36 (1H, d, J=2.7 Hz), 7,53 (2H, m), 7,92 (2H, brd.s). MC m/e 330 (MN+).

Calculated for C15H11lF3NO2, %: 54,64; H 3,36; N 4,25.

Found, %: C 54,65; H 3,37; N 4,16.

Stage C. Methyl ester 3-[[2-[(5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-3-oxopropanoic acid (2, R3=CF3, Ra=CH2).

The solution methylmaleimide (1.3 ml, 12 mmol) in anhydrous CH2Cl2(10 ml) was added dropwise in a nitrogen atmosphere in a stirred cooled (0°C.) solution of 1-[2-amino-5-(trifluoromethyl)phenyl]-1’-(5-chloro-2-methoxyphenyl)methanone obtained at the stage In (3.3 g, 10 mmol), and anhydrous pyridine (0,97 ml, 12 mmol) in anhydrous CH2Cl2(30 ml). The resulting mixture was allowed to warm to room temperature and maintained for 1 hour. The reaction mixture was cooled to (0°C) and then broke reaction of 1 N HCl (1 ml). The organic layer was separated and sequentially washed with saturated Panso3, water, brine and then dried (MgSO4). Evaporation of CH2CL2results in solid beige color (4,28 g), which was used with ether, receiving the connection specified in the title, in the form of a solid is SS="ptx2">1H NMR (300 MHz, CDCl3): of 3.57 (2H, s), 3,66 (3H, s), 3,81 (3H, s), 6,92 (1H, d, J=8,8 Hz), 7,38 (1H, d, J=2.6 Hz), 7,47 (1H, dd, J=8.8 and 2.6 Hz), the 7.65 (1H, s), of 7.75 (1H, d, J=8,9 Hz), 8,84 (1H, d, J=8,8 Hz), 11,91 (1H, brd. s). MC m/e 428 (M-N)-.

Stage D: Methyl ester of 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinoline-carboxylic acid (3, R3=CF3, R3=CH3).

tert-Piperonyl potassium (0,63 g, 5.6 mmol) was added to a stirred solution of methyl ester 3-[[2-[(5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-3-oxopropanoic acid, obtained in stage C (2.0 g and 4.65 mmol) in anhydrous THF (30 ml) under nitrogen atmosphere. The resulting mixture was heated under reflux for 30 minutes the Reaction mixture was allowed to cool, diluted it with ether (30 ml) and then acidified using 1 N Hcl (20 ml). The organic layer was separated, washed with brine and then dried (Na2SO4). Evaporation of the solvent led to a solid beige color (1,94 g) which was recrystallized from a mixture of EtOAc/hexane, receiving the connection specified in the title, in the form of a white solid (1,82 g, 95%), so pl. 214-216°C. IR (KBR, cm-1): 1128, 1256,1322, 1662, 1742.

1H NMR (300 MHz, CDCl3): 3,68 (3H, s), 3,70 (3H, s), 6,97 (1H, d, J=8,8 Hz), 7,20 (1H, d, J=2.5 Hz), C19H13lF3NO4, %: TO 55.42; H 3,18; N 3,40.

Found, %: C 55,27; H 2,94; N 3,30.

Example 2.

4-(5-Chloro-2-methoxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline (4, R3=CF3).

The solution diisobutylaluminium (2,16 ml of 1 M solution in a mixture of hexanol, of 2.16 mmol) was added dropwise to a cooled (-78°C) stirred solution of the compound of example 1 (0,22 g, 0.54 mmol) in anhydrous THF (10 ml). The mixture was allowed to warm to room temperature and was stirred for 2-3 hours. The reaction mixture was cooled in an ice bath and then slowly broke reaction by adding dropwise 1 N HCl (10 ml). The reaction mixture was diluted tO (20 ml), the organic layer was separated, washed with water, brine and then dried (MgSO4). Evaporation of solvents yielded a white solid (263 mg), which was triturated with ether and received the connection specified in the header, in the form of a white solid (178 mg, 86%), so pl. 232-235°C. IR (KBr, cm-1): 1126, 1264, 1322, 1654, 3442.

1H NMR (300 MHz, CDCl3): 3,70 (3H, s) to 4.41 (1H, d, J=12,5 Hz), a 4.53 (1H, d, J=12,5 Hz), 7,01 (1H, d, J=8,8 Hz), to 7.15 (1H, d, J=2.6 Hz), 7,33 (1H, s), 7,47 (1H, dd, J=8.8 and 2.6 Hz), 7,52 (1H, d, J=8.6 Hz), 7,71 (1H, d, J=8.6 Hz), of 12.33 (1H, brd.s). MC m/e 384 (MN+).

Vicis">Example 3.

4-(5-Chloro-2-methoxyphenyl)-3-(hydroxymethyl)-7-(trifluoromethyl)-2(1H)-chinoline (4, R3=R4=H, R2=CF3).

According to the method described in examples 1 and 2, receive the connection specified in the header, so pl. 174-176°C; MC m/e 384 (MN+).

1H NMR (300 MHz, DMSO-d6): of 3.64 (3H, s), 3,88 (1H, d, J=11.0 in Hz), or 4.31 (1H, d, J=11,0 Hz), 4,70 (1H, brd.s), 7,05 (1H, d, J=8,4 Hz), 7.23 percent (1H, d, J=8,9 Hz), 7,29 (1H, d, J=2.4 Hz), was 7.36 (1H, d, J=8,4 Hz), 7,55 (1H, dd, J=8.7 and 2.4 Hz), the 7.65 (1H, s), 12,23 (1H, s).

Example 4.

4-(5-Chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium (5, R3=CF3).

To a stirred solution of the compound from example 2 (384 mg, 1 mmol) in anhydrous CH2Cl2(10 ml) was added manganese dioxide (0,44 g, 5 mmol). The resulting suspension was stirred under nitrogen atmosphere overnight. Added again Mno2(of 0.44 g, 5 mmol) and continued stirring the suspension until completion of the oxidation (2-3 days). The suspension was filtered through a layer of celite, washed with additional methylene chloride. After evaporation of solvent received the connection specified in the header, in the form of a pale yellow solid (206 mg, 54%), so pl. 238-240°C. IR (KBR, cm-1): 1120, 1268, 1320, 1678, 1707.

1H NMR (300 MHz, CDCl<53 (1H, brd. s). MS m/e 380 (M-N)-.

Example 5.

Ethyl ester of (E)-3-[4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-chinoline]-2-propanolol acid (6, R3=CF3).

To stir the cooled suspension of NaH (84 mg, 2.1 mmol, 60% in mineral oil) in anhydrous DMF (2 ml) under nitrogen atmosphere was added dropwise a solution of triethylphosphate (0,43 g of 1.95 mmol) in DMF (1 ml). The mixture was stirred 30 minutes and then added pure 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium (0,60 g of 1.62 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 3 hours. After TLC showed the absence of aldehyde and formation of isomeric mixture of esters. The reaction mixture was cooled in an ice bath and broke reaction of 1 N Hcl. The resulting product was extracted with 1:1 mixture of ether/EtOAc, washed with saturated Panso3, water, brine and then dried (Na2SO4). Evaporation of the solvent led to a solid beige color (0,765 g) which was recrystallized from a mixture of EtOAc/hexane, receiving of the connection specified in the header, in the form of pure TRANS (E)-isomer (0,497 g). The concentration of the uterine redkozemelnyh esters amounted to 0.62 g (86%). Characterization of the obtained compounds: I. pl. 270-273°C. IR (KBR, cm-1): 1126, 1284, 1322, 1664, 1713.

1H NMR (300 MHz, Dl3): of 1.28 (3H, t, J=7,1 Hz) 3,70 (3H, s), 4,20 (2H, q, J=7,1 Hz),? 7.04 baby mortality (1H, d, J=8,9 Hz), 7,11 (1H, d, J=2.6 Hz), 7.24 to 7,33 (2H, m), the 7.43 (1H, s), of 7.48-7,52 (2H, m), 7,76 (1H, d, J=8.6 Hz), 12,02 (1H, brd. s). MS m/e 450 (M-N)-.

Example 6.

(E)-4-(5-Chloro-2-methoxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline (7, R3=CF3).

To a stirred cooled (-78°C) solution of the ester from example 5 (0.3 g, 0.66 mmol) in anhydrous THF (9 ml) dropwise under nitrogen atmosphere was added a solution of Dibal-H in a mixture of hexanol (3 mmol, 3 ml of 1 M solution). The mixture was allowed to warm to room temperature and was stirred for 2 hours, the Reaction mixture was cooled in an ice bath and then slowly broke reaction of 1 N Hcl (10 ml). Added ethyl acetate (30 ml), separated layers, washed with water, brine and dried (MgSO4). Evaporation of the solvent led to a solid white color (0.29 grams), after trituration with ether got the connection specified in the header, in the form of alcohol (234 mg), so pl. 266-268°C.

1H NMR (300 MHz, DMSO-d6): to 3.67 (3H, s), of 3.96 (2H, m), was 4.76 (1 H, t, J=5.3 Hz), 6,11 (1H, d, J=15.7 Hz), 7,01 (1H, s), 7,18 (1H, dt, J=15.7 and 4.6 Hz), 7,27-7,31 (2H, m), 7,52 (1H, d, J=8.6 Hz), 7,60 (1H, 3NO3, %: 58,62; H 3,69; N 3,42.

Found, %: C 58,50; H 3,74; N 3,35.

Example 7.

Ethyl ester of 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-jinlinprovince acid (8, R3=CF3).

To a solution of the ester obtained according to example 5 in ethanol and anhydrous Hcl in the flask of ragg when shaken in an atmosphere of nitrogen was added tO2(5-10 wt.%). The resulting suspension was first made under the pressure of 60 F./inch2(413,7 kPa) during the night. The catalyst was filtered and the filtrate evaporated in a rotary evaporator, receiving the connection specified in the header, so pl. 193-195°C.

1H NMR (300 MHz, Dl3): of 1.16 (3H, m), 2,43 (2H, m), 2,65 (2H, m), the 3.65 (3H, s) to 4.01 (2H, m), of 6.96-7,01 (2H, m), 7,14 (1H, s), 7,25 (2H, s), 7,40-the 7.43 (2H, m), 7,60 (1H, brd. s). MS m/e 452 (M-N)-.

Example 8.

4-(5-Chloro-2-methoxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline (9, R3=CF3).

According to the method described in example 6, restore the connection according to example 7, when receiving the connection specified in the header: so pl. 200-202°C.

1H NMR (300 MHz, CDCl3): to 1.60 (2H, m), of 2.20 (3H, brd. m) a 3.50 (2H, m), 3,63 (3H, s), 6,97 (1H, d, J=8,8 Hz),? 7.04 baby mortality (1H, d, J=2.6 Hz), 7,16 (1H, s), 7,19 (1H, s), 7,41 (1H, dd, J=8.8 and 2.6 Hz), 7,49 (1H, d, J=8,3 Hz), the 7.65 (1H, J=of 7.36 Hz), 12,45 (1H, brd. s). MS m/e 412 (MN)+.=CF3).

Stage A. [2-Amino-5-(trifluoromethyl)phenyl](5-chloro-2-hydroxyphenyl)methanon (10, R3-=CF3).

To a cooled solution (-78°C) 1,1-dimethylethylene ester of N-[2-[5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]aminocarbonyl acid obtained according to example 1, stage A (7.0 g, of 21.2 mmol) in methylene chloride (60 ml) was added dropwise 1.0 M solution VVG3in methylene chloride (46,7 ml of 46.7 mmol). The resulting red solution was allowed to warm to room temperature and was stirred overnight. The reaction was interrupted with a saturated solution Panso3. The organic layer was separated, washed with water, brine and then dried (MgSO4). Evaporation of the solvent led to a solid yellow-red color, which after recrystallization from a mixture of CH2CL2/hexane became geltm (6,58 g, 98%).

Stage Century. Methyl ester 3-[[2-[5-chloro-2-hydroxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-3-oxopropanoic acid (11, R3=CF3).

To a solution of[2-amino-5-(trifluoromethyl)phenyl](5-chloro-2-hydroxyphenyl)methanone (0.5 g, was 1.58 mmol) and pyridine (0.25 ml, 3,17 mmol) in methylene chloride (15 ml) at 0°C was added dropwise a solution of methylmaleimide (0,34 ml, 3,17 mo for 2 hours. The reaction mixture was acidified using 1 N Hcl and the separated organic layer. Then it was washed twice with saturated NaHCO3, water, brine and dried (MgSO4). Evaporation of the solvent allowed to obtain specified in the title compound as yellowish oil.

Stage C. 2-Chloro-6,8-dihydro-11-(trifluoromethyl)-7H-[1]benzopyrano[3,4-C]quinoline-6,7-dione (12, R3=CF3).

The crude methyl ester 3-[[2-[5-chloro-2-hydroxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-3-oxopropanoic acid obtained in stage B, was dissolved in THF (15 ml) was added tert-piperonyl potassium (1 M in THF, of 1.74 mmol, 1,74 ml). The reaction mixture was heated for 15 minutes under reflux. Then it was acidified using 1 N Hcl and the separated organic layer. The organic layer was washed with water, brine and dried (MgSO4). Evaporation of the solvent was allowed to get a solid yellow color, which is rubbed with a mixture of ethyl acetate/hexane, getting mentioned in the title compound in the form of a solid yellow (0,48 g, 83%), so pl.>250°C. MS m/e 366 (MN+).

Calculated for C17H7ClF3NO3·0.5 N2O %: 54,49; H 2,15; N 3,74.

Found, %: C 54,10; H 1,85; N, 3.63.

1H NMR (VHI IS): 3479, 3074, 1761, 1652, 1630, 1577, 1368, 1325, 1141.

Stage D: 4-(5-Chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline (14, R3=CF3).

To a cooled suspension (-78°C) of 2-chloro-6,8-dihydro-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-6,7-dione obtained in stage C (1.0 g, 2,73 mmol) in methylene chloride (20 ml) was added dropwise a solution of Dibal-H (I M in methylene chloride, of 13.7 ml, 13.7 mmol). The reaction mixture was heated to 0°C and maintained for 3 hours. The reaction mixture was acidified using 1 N Hcl and was extracted twice with ethyl acetate. The organic layer was separated and washed with water, brine and then dried (MgSO4). After evaporation of the solvent and recrystallization of the crude product from a mixture of ethyl acetate/hexane received the connection specified in the header, in the form of a white solid (0.7 g, 69%), so pl.>250°C. MS m/e 368 (M-N-).

Calculated for C17H11lF3NO3, %: 55,23; H 3,00; N 3,79.

Found, %: C 56,59; H Was 4.02; N 3,36.

1H NMR (DMSO-d6): 3,90 (dd, J=10,9 Hz, 5.3 Hz, 1H), 4,36 (dd, J=10,9 Hz, 5.6 Hz, 1 H), 4,70 (t, J=5.4 Hz, 1H), 7,03 (d, J=8.7 Hz, IH), 7,17 (s, 1H), 7,26 (d, J=2.7 Hz, 1H), 7,39 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7,53 (d, J=8.6 Hz, 1H), 7,81 (dd, J=8,9 Hz, 1.9 Hz, 1H), 9,95 (s, 1H), 12,31 (s, 1H).

Example 10.

Ethyl ester of 3-[4-(5-P>

Stage A. 2-Chloro-6,8-dihydro-6-hydroxy-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-7-he (13, R3=CF3).

To a cooled (-78°C) solution of 2-chloro-6,8-dihydro-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-6,7-dione, obtained in example 9 at a stage S, (1,15 g and 3.15 mmol) in THF (30 ml) added dropwise a solution of Dibal-H (1 M in THF, 15.7 ml, 15.7 mmol). The reaction mixture was kept at -78°C for 4 hours. The reaction mixture was acidified using 1 N Hcl and was extracted twice with ethyl acetate. The organic layer was separated and washed with water, brine and then dried (MgSO4). Evaporation of the solvent with subsequent grinding of the crude product with ethyl acetate allowed to obtain specified in the title compound in the form of a solid white color (0.9 g, 78%), so pl.>260°C. MS m/e 366 (M-H)-.

Calculated for C17H9ClF3NO3·0,25 H2O %: 54,86; H TO 2.57; N 3,76.

Found, %: C 54,92; H 2,92; N 3.46 In.

1H NMR (DMSO-d6): 6,40 (d, J=6.2 Hz, 1H), 7,31 (d, J=8.7 Hz, 1H), 7,55-7,63 (t, 3H), 7,94 (d, J=8.7 Hz, 1H), 8,07 (d, J=2.4 Hz, 1H), scored 8.38 (s, 1H), to 12.44 (s, 1H). IR (KBR, cm-1): 3300, 1669, 1631, 1605, 1575, 1326, 1279, 1133.

Stage C. Ethyl ester 3-[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-chinoline]-2-propenol the al) in DMF (3 ml) was added dropwise triethylphosphate (0.1 ml, 0.5 mmol). The reaction mixture was stirred at 0°C for 0.5 hour and then was added a solution of 2-chloro-6,8-dihydro-6-hydroxy-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-7-she obtained in example 10 in stage A (0.15 g, 0.41 mmol), in DMF (5 ml). A mixture of red color was allowed to warm to room temperature and was stirred for 4 hours. The reaction was slowly cutting short 1 N Hcl solution and was extracted with ethyl acetate. The organic layer was separated and washed with saturated solution of Panso3, water, brine and dried (MgSO4). Evaporation of the solvent followed by recrystallization from a mixture of ethyl acetate/hexane allowed to obtain the connection specified in the header, in the form of a white solid (127 mg, 72%), so pl. 262-268°C (decomp.). MS m/e 436 (M-H-).

Calculated for C21H15ClF3NO4, %: 57,61; H OF 3.45; N 3,20.

Found, %: C 57,31; H Of 3.46; N 3,15.

1H NMR (DMSO-d6): of 1.18 (t, J=7,1 Hz, 3H), 4.09 to (q, J=7,0 Hz, 1H), was 7.08 (d, J=8,8 Hz, 1H), 7,16 (d, J=15.7 Hz, 1H), 7,20 (s, 1H), 7,29 (d, J=2.7 Hz, 1H), 7,34 (d, J=15.7 Hz, 1H), of 7.48 (dd, J=8.7 Hz and 2.7 Hz, 1H), EUR 7.57 (d, J=8.6 Hz, 1H), of 7.90 (dd, J=8,8 Hz and 1.8 Hz, 1 H), or 10.1 (s, 1H), and 12.6 (s, 1H). IR (KBR, cm-1): 3225, 1683, 1662, 1626, 1323, 1301, 1115.

Example 11.

3-[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hee is l) in EtOH (2 ml) was added 10 N NaOH (1 ml) and stirred at room temperature overnight. The reaction mixture was acidified using 1 N HCl and the separated precipitated solid yellow color that is specified in the header (34 mg, yield 91%), so pl. 258-261° C (decomp.). MS m/e 408 (M-N)-.

Calculated for C19H11ClF3NO4·0.5 H2O, %: 52,79; H 3,15; N 3,24.

Found, %: C 52,93; H 2,82; N 3,10.

1H NMR (DMSO-d6): 7,07-7,13 (m, 2H), 7,18 (s, 1H), 7,25-7,30 (m, 2H), 7,47 (dd, J=8.7 Hz and 2.7 Hz, 1 H), EUR 7.57 (d, J=8.7 Hz, 1H), 7,89 (dd, J=8.7 Hz and 1.7 Hz, 1H), 10,11 (s, 1H), 12,37 (s, br, 1H), 12,57 (s, 1H). IR (KBR, cm-1): 3144, 2996, 1676, 1628, 1323, 1270, 1252, 1130.

Example 12.

4-(5-Chloro-2-hydroxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline (17, R3=CF3).

To a chilled (-78°C.) suspension of the compound from example 10 (0.2 g, 0.46 mmol) in methylene chloride (10 ml) was added dropwise a solution of Dibal-H (1 M in methylene chloride, 2.3 ml, 2.3 mmol). The reaction mixture was heated to room temperature and was stirred for 4 hours. The reaction mixture was acidified using 1 N Hcl and was extracted twice with ethyl acetate. The organic layer was separated and washed with water, brine and dried (MgSO4). Evaporation of the solvent followed by recrystallization from a mixture of ethyl acetate/hexane allowed to obtain the connection specified in the header, in the form>9H13ClF3NO3·0.5 N2O %: 56,38; H 3,49; N 3.46 IN.

Found, %: C 56.35; H 3,72; N 3,29.

1H NMR (DMSO-d6): of 3.97 (dt, J=1.7 Hz and 4.9 Hz, 2H), 4,77 (t, J=5.3 Hz, 1H), 6,16 (dd, J=15,8 Hz and 1.9 Hz, 1 H), 7,05 (d, J=8.7 Hz, 1H), 7,10 (s, 1H), 7,16 (d, J=2.7 Hz, 1H), 7,21 (dt, J=15.7 Hz and 4.7 Hz, 1H), 7,41 (dd, J=8.7 Hz and 2.7 Hz, 1H), 7,51 (d, J=8.5 Hz, 1H), 7,78 (dd, J=8.7 Hz and 1.8 Hz, 1H), 9,90 (s, 1H), 12,32 (s, 1H). IR (KBR, cm-1): 3286, 1656, 1641, 1322, 1294, 1169, 1120, 1075.

Example 13.

Ethyl ester of 4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-jinlinprovince acid (18, R3=CF3).

To a solution of the compound from example 10 (0.4 g, of 0.91 mmol) in ethanol (20 ml) was added tO2(3 to 8 mg) and 3 drops of 1 N HCl. The mixture was first made in the Parr apparatus under a pressure of 50 lb/inch2(413,7 kPa) during the night. The catalyst was separated by filtration through celite and washed with ethanol. The filtrate is evaporated to dryness and the white residue was subjected to flash chromatrography (silica gel, 2:1 ethyl acetate/hexane) to obtain the compound indicated in the title, in the form of a solid white color (to 0.29 g, 72%), so pl. 241-245°C (decomp.). MS m/e 438 (M-N)-.

Calculated for C21H17ClF3NO4, %: 57,35; H 3,90; N 3,18.

Found, %: C 57,27; H Was 4.02; N, 2,99.

1H NMR (CD-1): 3353, 1698, 1656, 1626, 1376, 1311, 1270, 1167, 1128, 1074.

Example 14.

4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hinolinova acid (19, R3=CF3).

To a solution of the compound from example 13 (38 mg, 0,087 mmol) in tO (2 ml) was added 10 N NaOH (1 ml) and stirred the mixture at room temperature over night. The reaction mixture was acidified using 1 N model HC1 and the separated precipitate is white, representing the connection specified in the header (30 mg, 84%), so pl. 255-258°C. MS m/e 410 (M-N)-.

Calculated for C19H13ClF3NO4·0.5 N2O %: 54,24; H 3,35; 3,33 N.

Found, %: C 54,10; H 3,10; N 3,28.

1H NMR (DMSO-d6): 2,32-is 2.37 (m, 2H), 2,47 is 2.51 (m, 2H),? 7.04 baby mortality-7,07 (m, 2H), 7,25 (d, J=2.6 Hz, 1H), 7,40 (dd, J=8.7 Hz and 2.7 Hz, 1H), 7,52 (d, J=8.6 Hz, 1H), 7,79 (dd, J=8.7 Hz and 1.9 Hz, 1H), 9,98 (s, 1H), 12,10 (s, br, 1H), 12,31 (s, 1H). IR (KBR, cm-1): 3283, 3155, 1714, 1626, 1560, 1405, 1275, 1194, 1167, 1132.

Example 15.

4-(5-Chloro-2-hydroxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline (20, R3=CF3).

To a cooled suspension (-78°C.) of the compound from example 13 (0.2 g, 0.45 mmol) in methylene chloride (10 ml) was added dropwise a solution of Dibal-H (1 M in methylene chloride, 3,7 ml, 3,7 ü then acidified using 1 N model HC1 and was twice extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried (MgSO4). Evaporation of the solvent followed by recrystallization from a mixture of ethyl acetate/hexane led to the connection specified in the header, in the form of a white solid (145 mg, 80%), so pl. 257-259°C (decomp.). MS m/e 398 (MN+).

Calculated for C19H15lF3NO3·0,67 tO, %: 57,00; H 4,49; N 3,07.

Found, %: C 57,17; H To 4.62; N 2,88.

1H NMR (DMSO-d6): 1,5 (m, 2H), 2,3 (m, 2H), 3,25 (m, 2H), 4,35 (m, 1H), 7,02-7,07 (m, 2H), 7,21 (d, J=2.5 Hz, 1H), 7,39 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7,51 (d, J=8.5 Hz, 1H), to 7.77 (d, J=8.5 Hz, 1H), 9,90 (s, 1H), 12,24 (s, 1H). IR (KBr, cm-1): 3315, 1654, 1624, 1569, 1324, 1273, 1125, 1073.

Examples 16 and 17.

(E)- and (Z)-4-(5-Chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline (23, R3=CF3) and (25, R3=CF3).

Stage A. To the chilled suspensie (0°C) NaH (60% mineral oil, 68 mg, 1.7 mmol) in DMF (5 ml) was added triethyl-2-fluoro-2-phosphonate (0,165 ml, 0.82 mmol). The resulting mixture was stirred at 0°C for 0.5 hour and then was added a solution of 2-chloro-6,8-dihydro-6-hydroxy-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-7-she received on stage And in example 10 (0.25 g, of 0.68 mmol) in DMF (5 ml). The reaction is ivali 1 N HCl and then the mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated solution of Panso3, water, brine and then dried (MgSO4). Evaporation of the solvent allows to obtain a mixture of esters of the formula (21) (E:Z=1:2,5, 224 mg, 72%) as a colourless oil.

Stage C. To the cooled suspension (-78°C.) of the crude mixture of the ester from step A (210 mg, 0.46 mmol) in methylene chloride (10 ml) was added dropwise a solution of Dibal-H (1 M in methylene chloride, and 3.3 ml, 3.3 mmol). The reaction mixture was heated to room temperature and was stirred overnight. Then the reaction mixture was acidified using 1 N model HC1 and extracted twice with ethyl acetate. The organic layer was separated and washed with water, brine and then dried (MgSO4). Crude isomeric alcohols were purified by chromatography on a column (silica gel, 2:1, ethyl acetate/hexane) to receive individual E-isomer (E)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-Hinayana, example 16 (23, R3=CF3) and Z-isomer (Z)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-Hinayana, example 17 (25, R3=CF3). Physical characteristics (E)- and (Z)-isomers are described below.

Example 16. (E)-4-(5-Chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(triptime is but for C19H12lF3NO3·0,33 H2O %: 54,37; H 3.04 FROM; 3,34 N.

Found, %: C 54,72; H 3,11; N 3,18.

1H NMR (DMSO-d6): to 3.64 (m, 1H), 3,83 (m, 1H), 4,99 (m, 1H), 5,61 (d, J=19.6 Hz, 1H), 7,03 (d, J=8.7 Hz, 1H), 7,20-of 7.23 (m, 2H), 7,38 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7,54 (d, J=8.7 Hz, 1H). to 7.84 (d, J=8,9 Hz, 1H), to 10.09 (s, 1H), 12,42 (s, 1H).

Example 17. (Z)-4-(5-Chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-Hinayana (25, R3=CF3).

So pl. 242-245°C (decomp.). MS m/e 412 (M-N)-.

Calculated for C19H12lF3NO3·0,33 H2O %: 54,37; H 3.04 FROM; 3,34 N.

Found, %: C 54,62; H 3,27; N 3,11.

1H NMR (DMSO-d6): 3,81-3,86 (m, 2H), 5,35 (t, J=5,9 Hz, 1H), to 5.57 (d, J=40,3 Hz, 1H), 7,00 (d, J=8.7 Hz, 1H), 7,12 (d, J=2.6 Hz, 1H), 7,21 (s, 1H), 7,34 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7,51 (d, J=8.6 Hz, 1H), 7,81 (dd, J=8.6 Hz, 1.6 Hz, 1H), 9,90 (s, 1H), 12,32 (s, 1H).

Examples 18 and 19.

According to the methods described in examples 16 and 17 receive connection example 18 (24, R3=CF3) (E-isomer) and example 19 (26, R3=CF3) (Z-isomer) of the compounds of formula (5) obtained in example 4, as shown in reaction scheme 5. Physical characteristics (E)- and (Z)-isomers are described below.

Example 18. (E)-4-(5-Chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trift the NMR (Dl3): 3,68 (3H, s), 4,10 (2H, d, J=24,0 Hz) 5,54 (1H, d, J=18,0 Hz), 7,01 (1H, d, J=8,9 Hz),? 7.04 baby mortality (1H, d, J=2.4 Hz), 7,32 (1H, s), 7,46 (1H, dd, J=8,9 Hz and 2.3 Hz), 7,52 (1H, d, J=8.5 Hz), 7,73 (1H, d, J=7,6 Hz), 11,65 (1H, brd. s).

Example 19. (Z)-4-(5-Chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline (26, R3=CF3).

So pl. 230-232°C (decomp.). MS m/e 426 (M-N)-.

1H NMR (Dl3): of 3.69 (3H, s), 4.09 to (2H, d, J=10,7 Hz), 5,70 (1H, d, J=38,1 Hz), 6,98 (1H, d, J=8,8 Hz), to 7.09 (1H, s), 7,35 (1H, s), 7,41 (1H, d, J=8,8 Hz) to 7.50 (1H, m), to 7.67 (1H, brd. s), 11,75 (1H, brd.s).

Example 20.

4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (31a, R3=CF3, n=2).

Stage A. Methyl ester 4-[[2-[5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-4-oxobutanoic acid (27, R3=CF3, Rand=CH3, n=2).

Pure 3-carbomethoxyamino (4.8 ml, 0,039 mol) was added to a stirred cooled (0°C.) solution of aminobenzophenone, 1-[2-amino-5-(trifluoromethyl)phenyl]-1’-(5-chloro-2-methoxyphenyl)methanone obtained in example 1, stage (7.0 g, 0,021 mol) and anhydrous pyridine (4.8 ml, 0,059 mol) in anhydrous CH2Cl2(80 ml). The resulting mixture was allowed to warm to room temperature and was incubated for 12 hours. The reaction , water, brine and then dried (MgSO4). Evaporation CH2Cl2and kneading the obtained residue was allowed to get 7,71 g (82%) indicated in the title amide.

1H NMR (300, CDCl3): or 2.7 (4H, m), 3,06 (3H, s), 3,63 (3H, s), 6,85 (1H, d, J=8,9 Hz), 7,16 (1H, s), 7,30 (1H, d, J=2.6 Hz), 7,39 (1H, dd, J=8,8 Hz and 2.6 Hz), EUR 7.57 (1H, s), 7,66 (1H, dd, J=8,9 Hz and 1.9 Hz), 8,79 (1H, d, J=8,8 Hz). MS m/e 444 (MN+).

Stage Century. Methyl ester 4-(5-chloro-2-methoxyphenyl)-4-hydroxy-1,2,3,4-tetrahydro-2-oxo-6-(trifluoromethyl)-3-kinalimutan acid (28, R3=CF3, Ra=CH3, n=2).

A solution of bis(trimethylsilyl)amide potassium (0.5 M in toluene, 57 ml, 28.5 mmol) was added to a stirred cooled (-78°C) solution of methyl ester 4-[[2-[5-chloro-2-methoxyphenyl)carbonyl]-4-(trifluoromethyl)phenyl]amino]-4-oxobutanoic acid obtained in stage A (4,05 g, 9.1 mmol) in anhydrous THF (25 ml) and kept at -78°C for 3 hours. Acidification with 1 N Hcl and then extracted EtOAc allowed to get wet, specified in the header of the connection (of 4.05 g, 100%).

Stage C. 4-(5-Chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinata acid (29, R3=CF3, n=2).

Stir a suspension of the crude methyl ester of 4-(5-chloro-2-methoxyphenyl)-4-g in toluene (25 ml) was treated with a solution of 35% Nug in acetic acid (5 ml). The resulting mixture was heated at 85°C during the night. The reaction mixture is evaporated to dryness and distributed the balance between water and EtOAc. Extract into EtOAc was washed with brine, dried (MgSO4) and then evaporated, receiving the connection specified in the header (1.45 g, 78%).

Stage D. 4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinata acid (30, R3=CF3, n=2).

Pure mixture of crude 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-kinalimutan acid, obtained in stage C (1.45 g, 3.5 mmol), and pyridinecarboxamide (5 g, to 43.3 mmol) was heated at 185°C for 3 hours. The reaction mixture was allowed to cool, was added 1 N Hcl and was carried out by extraction with EtOAc receiving the connection specified in the header (1.20 g, 86%), so pl. 158-160°C.

1H NMR (300 MHz, CD3OD): 3,21 (1H, d, J=16,7 Hz), 3,60 (1H, d, J=16,7 Hz), 7,0 (1H, d, J=8,8 Hz), 7,13 (1H, d, J=2.6 Hz), 7,31 (1H, m), 7,37 (1H, dd, J=8,8 Hz, 2.6 Hz), 7,52 (1H, d, J=8.6 Hz), of 7.75 (1H, d, J=8.6 Hz). MS m/e 398 (MN+).

Stage E. 4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (31A, R3=CF3, n=2).

The solution of a complex of borane-metilsulfate (2 M in THF, 125 ml, 0.25 mol) for 20 minutes was added dropwise in a nitrogen atmosphere to peremehi acid, obtained in stage D (20 g, 0.05 mol) in anhydrous THF (125 ml). The obtained transparent reaction mixture was allowed to warm at room temperature and continued stirring for 2-3 days (IHVR shows the absence of starting material). The reaction mixture was cooled in an ice bath and then stop the reaction by adding dropwise 1 N NaOH (125 ml) until an alkaline reaction and then the mixture was acidified using 1 N Hcl. Added ether (250 ml) and the layers were separated, washed with water, brine and was then dried (Na2SO4). Evaporation of the solvent led to a solid brown color (21,4 g) which was recrystallized from EtOAc-Meon, obtaining 2.6 g of pure solid white color (the first portion). Rubbing the concentrated mother liquor with ether allowed to obtain 8.7 g of a white solid substance (the second portion). The second portion was recrystallized from tO-Meon and connected with the first portion, receiving 11.1 g specified in the connection header in the form of a solid white color, so pl. 255-256°C.

1H NMR (300 MHz, CD3D): 2,73 (2 H, m), of 3.64 (2H, t, J=7.4 Hz), 7,0 (1H, d, J=8,8 Hz), to 7.15 (1H, d, J=2.6 Hz), 7.23 percent (1H, broad s), of 7.36 (1H, dd, J=8,8 Hz, 2.6 Hz), of 7.48 (1H, d, J=8.6 Hz), 7,71 (1 H, dd, J=8.6 and 1.8 Hz). MS m/e 384 (MN+).

Example 21.

4-(5-Chloro-2-methoxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (31b, R3=CF3, n=2).

According to the method of example 20, step E, from the compound obtained in stage With example 20, get the connection specified in the header.

So pl. 219-221° C.

1H NMR (300 MHz, CDCl3): 7,71 (1H, d, J=8,4 Hz), 7,53-7,46 (2H, m), 7.23 percent (1H, s), 7,11 (1H, d, J=2.7 Hz), 7,02 (1H, d, J=8.7 Hz), with 3.79 (m, 2H), 3,70 (s, 1H), 3,79 (t, 2H). MS m/e 397 (MN+).

Calculated for C19H15lF3NO3, %: 57,37; H OF 3.80; N 3,52.

Found, %: C 57,31; H 3,94; N 3,38.

Examples 22 and 23.

A General method of preparing compounds of the formulas (34) and (35)

Stage A. Acylation of aminobenzophenone formula (1).

Pure acylchlorides (1.2 EQ.) was added to a stirred cooled (0°C.) solution of aminobenzophenone formula (1) (1 EQ.) and anhydrous pyridine (1.3 EQ.) in anhydrous CH2Cl2. The resulting mixture was allowed to warm to room temperature and kept for 2-3 hours. The reaction mixture was acidified using 1 N Hcl, the layers were separated and the organic layer was washed with a saturated solution Panso3, water, brine and then dried (MgSO4). Evaporation CH2Cl2led to sootvetstvuyuschimi)potassium amide (0.5 M in toluene, 3 EQ.) was added to a stirred cooled (-78°C) solution of amide of formula (32) (1 EQ.) in anhydrous THF and kept at -78°C for 3 hours. Acidification with 1 N Hcl and then extracted EtOAc led to a quinoline of formula (33).

Stage C. the de-hydration of the quinoline of formula (33).

Stir a suspension of crude compound of formula (33) in toluene was treated with a solution of 35% Nug in acetic acid. The resulting mixture was heated at 85°C during the night. The reaction mixture is evaporated to dryness and the residue was distributed between water and EtOAc. Extract into EtOAc was washed with brine and dried (MgSO4), and then the solvent evaporated to obtain Hinayana formula (34).

Stage D. Demethylation of compounds of formula (34).

Pure blend crude quinoline of formula (34) (1 EQ.) and pyridinylamino (5 EQ.) was heated at 185°C for 3 hours. The reaction mixture was allowed to cool, was added 1 N Hcl and then was carried out by extraction using EtOAc to obtain the corresponding hydroxycodone formula (35).

Example 22.

4-(5-Chloro-2-methoxyphenyl)-3-(4-methoxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline (34a, R3=CF3, R8=4-methoxyphenyl, n=0).

So pl. 130-135°C.

MC m/e 459 (MN+).

Calculated for C24H17lF3NO3, %: 62,69; H TO 3.73; N 3,05.

Found, %: C 62,74; H To 3.92; N 2,89.

Example 23.

4-(5-Chloro-2-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline (34b, R3=CF3, R8=4-methoxyphenyl, n=1).

So pl. 110-114°C.

1H NMR (300 MHz, Dl3): a 7.62 (1H, d, J=8.7 Hz), 7,47-the 7.43 (1H, dd, J=2.7 Hz and 8.7 Hz), 7,29 (1H, d, J=2.7 Hz), 7.23 percent (1H, s), 7,00-6,92 (3H, m), 6,70 (1H, d, J=8.7 Hz), of 3.78 (dd, 2H), and 3.72 (s, 3H), of 3.57 (s, 3H). MS m/e 473 (MH+).

Example 24.

4-(5-Chloro-2-methoxyphenyl)-3-(4-nitrophenyl)-6-(trifluoromethyl)-2(1H)-chinoline (34c, R3=CF3, R8=4-nitrophenyl, n=0).

So pl. 218-222°C.

1H NMR (300 MHz, Dl3): to 8.12 (2H, d, J=8.7 Hz), 7,72 (1H, d, J=8.7 Hz), 7,43 and 7.36 (4H, m), 7,33-7,29 (dd, 1H, J=2.7 and 8.7 Hz), to 6.95 (1H, d, J=2.7 Hz), PC 6.82 (1H, d, J=8.7 Hz). MS m/e 474 (MN+).

Calculated for C23H14ClF3N2O4, %: 58,18; H 2,97; N 5,90.

Found, %: C 57,70; H 3,20; N 5,65.

Example 25.

4-(5-Chloro-2-methoxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline (34d, R3=CF3, R8=4-AMINOPHENYL, n=0).

So pl. 287°C.

1H NMR (300 MHz, Dl3): a 7.62 (1H, d, J=8,4 Hz), 7,44 (1 is but23H16ClF3NO2, %: 62,10; H 3,63; N 6,30.

Found, %: C 61,89; H 3,81; N 6,06.

Example 26.

4-(5-Chloro-2-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2(1H)-chinoline (e, n=0, R8=Me, R3=CF3).

The solution of the corresponding compounds of formula (33) (5,63 mmol) of a 33% Nug in Asón (to 38.3 mmol) and 10 ml of Asón was heated to 75°C for 3 hours. The solution was cooled to room temperature and the reaction would stop H2About (50 ml), then stirred the mixture for 12 hours. The precipitate was filtered, washed with water and dried in vacuum. Solid pale brown recrystallized from a mixture of ethyl acetate/hexane, getting mentioned in the title compound in the form of a solid white color (0,550 g, yield 27%).

1H NMR (300 MHz, Dl3): 2,04 (s, 3H), and 3.72 (s, 3H), 7,03 (d, 1H, J=9.0 Hz), 7,12 (s, 1H), 7,44 (m, 3H), of 7.65 (d, 1H, J=8,4 Hz), of 10.93 (brs, 1H). MS m/e 368 (MH+).

Calculated for C18H13lF3NO2·0,33 H2O %: 58,79; H OF 3.56; N 3,81.

Found, %: C 58,89; H 3,82; N 3,53.

Example 27.

4-(5-Chloro-2-hydroxyphenyl)-3-(3,4-acid)-6-(trifluoromethyl)-2(1H)-chinoline (35A, R3=CF3, R8=3,4-acid, n=0).

So pl. 140-142°C.

1N I HAVE (1H, d, J=1,8 Hz), 3,85 (s, 3H), of 3.69 (s, 3H), 3,62 (s, 3H). MS m/e 489 (MH+).

Calculated for C25H19ClF3NO4,% 61,30; H 3,91; N 2,86.

Found, %: C 61,42; H To 3.89; N 2,75.

Example 28.

4-(5-Chloro-2-hydroxyphenyl)-3-(2,4-dihydroxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline (35b, R3=CF3, R8=2,4-dihydroxyphenyl, n=0).

So pl. 295°C (decomp.).

1H NMR (300 MHz, CD3D): 7,73 (1H, d, J=8.7 Hz), 7,49 (1H, d, J=8.7 Hz), 7,31-7,27 (2H, dd, J=2.7 Hz and 8.7 Hz), 7.03 is-7,00 (2H, m), 6.89 in (1H, d, J=8.7 Hz), 6,53-of 6.49 (2H, m). MS m/e 462 (MN+).

Calculated for C22H13lF3NO4, %: 59,01; H 2,93; N 3,13.

Found, %: C 58,38; H 3,15; N 2,96.

Example 29.

4-(5-Chloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline (35S, R3=CF3, R8=4-hydroxyphenyl, n=0).

So pl. 220-240°C.

1H NMR (300 MHz, Dl3): 7,53 (1H, d, J=8.7 Hz), 7,20 (1H, d, J=8.7 Hz), 7.24 to 7,17 (2H, m), 6,97-to 6.88 (4H, dd, J=8.7 Hz and 1.9 Hz), for 6.81 (1H, d, J=8.7 Hz), 6,77 (2H, d, J=8.7 Hz), of 3.77 (s, 3H), 3,62 (s, 3H). MS m/e 459 (MN+).

Example 30.

4-(5-Chloro-2-hydroxyphenyl)-3-[(4-hydroxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline (35d, R3=CF3, R8=4-hydroxyphenyl, n=1).

So pl. 242-250°C.

1H NMR (300 MHz, CD3dd, J=13,8 Hz and 14.7 Hz). MS m/e 445 (MN+).

Calculated for C23H15ClF3NO3·0.5 N2O %: 60,68; H 3,52; N IS 3.08.

Found, %: C 60,71; H 3,91; N 2,82.

Example 31.

4-(5-Chloro-2-hydroxyphenyl)-3-(4-acetamidophenyl)-6-(trifluoromethyl)-2(1H)-chinoline (e, R3=CF3, R8=4-acetamidophenyl, n=0).

So pl. 240-260°C.

1H NMR (300 MHz, CD3D): TO 7.77 (1H, d, J=8.7 Hz), 7,55 (1H, d, J=8.7 Hz), of 7.48-7,38 (m, 3H), 7,19-to 7.15 (m, 3H), 6.87 in-6,83 (m, 2H), 2,09 (s, 3H). MS m/e 472 (MN+).

Calculated for C24H16ClF3N3O3, %: 56,59; H 3,93; N 5,50.

Found, %: C 57,21; H To 3.73; N 5,28.

Example 32.

4-(5-Chloro-2-hydroxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline (35f, R3=CF3, R8=4-AMINOPHENYL, n=0).

So pl. 222-224°C.

1H NMR (300 MHz, CD3OD): 7,74 (1H, d, J=8,4 Hz), 7,53 (1H, d, J=8,4 Hz), was 7.36 (s, 1H), 7,15 (dd, 1H, J=2.7 Hz), of 6.99 (2H, d, J=8,4 Hz), 6,85-for 6.81 (m, 2H), return of 6.58 (1H, d, J=8,4 Hz). MS m/e 446,8 (MN+).

Calculated for C22H14lF3N2O3, %: 59,14; H 3,16; N 6,27.

Found, %: C 60,27; H 3,52; N 6,32.

Example 33.

4-(5-Chloro-2-hydroxyphenyl)-3-[2-(4-hydroxyphenyl)ethyl]-6-(trifluoromethyl)-2(1H)-chinoline (35g, R3=CF3, R8+).

Calculated for C24H17lF3NO3·1,5 H2O, %: 59,16; H 4,11; N 2,88.

Found, %: C 58,71; H Of 3.78; N 2,86.

Example 34.

4-(5-Chloro-2-hydroxyphenyl)-3-methyl-6-(trifluoromethyl)-2(1H)-chinoline (35h, n=0, R8=Me, R3=CF3).

MC m/z: 352 (MH-). IR (KBr): 3183, 1655,1321, 1263,1122 cm-1.

1H NMR (DMSO-d6): to 1.86 (3H, s),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7,12 (1H, s), 7,22 (1H, d, J=2.6 Hz), 7,39 (1H, dd, J=2,6 Hz, 8.7 Hz), 7,52 (1H, d, J=8.6 Hz), 7,78 (1H, d, J=8.7 Hz), 9,92 (1H, s), of 12.26 (1H, s).

Calculated for C17H11ClF3NO2·0.5 N2O %: 56.26 VERTICAL; H TO 3.33; N 3,86.

Found, %: 56,57; H And 3.16; N, 3.81.

Example 35.

3-[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]-Acrylonitrile (36A, R=H, X=CN, R3=CF3).

To a cooled (0°C.) suspension of NaH (60% mineral oil, 33 mg, 0.82 mmol) in DMF (5 ml) was added dropwise dieticiansupervised (63 μl, 0,39 mmol). The reaction mixture was stirred at 0°C for 0.5 hour and the solution was added 2-chloro-6,8-dihydro-6-hydroxy-11-(trifluoromethyl)-7H-[1]benzopyran[3,4-C]quinoline-7-she received on stage And in the second temperature and was stirred for 2 hours The reaction was interrupted 1 N Hcl and then the mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated Panso3, water, brine and then dried (MgS4). Evaporation of the solvent led to a yellowish oil, which was then purified by chromatography on a column (silica gel, 1:1 ethyl acetate/hexane) obtaining specified in the connection header in a solid yellow color (71 mg, 56%).

So pl.>265°C. MS m/e: 389 (M-N)-.

Calculated for C19H10lF3N2ABOUT2, %: 58,40; H 2,58; N 7,17.

Found, %: C 58,16; H 2,81; N 6,87.

1H NMR (DMSO-d6): 6,85 (1H, d, J=16.4 Hz), 7,10 (1H, d, J=8,8 Hz), 7,21 (1H, s), 7.23 percent (1H, d, J=16.4 Hz), 7,30 (1H, d, J=2.7 Hz), 7,49 (1H, dd, J=8,8 Hz, 2.7 Hz), to 7.59 (1H, d, J=8.6 Hz), to 7.93 (1H, dd, J=8.7 Hz, 1.7 Hz), 10,19 (1H, s) 12,70 (1H, s). IR (KBr, cm-1): 3333, 2224, 1656, 1625, 1585, 1321, 1265, 1118, 1073.

Example 36.

3-[4-(5-Chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]Acrylonitrile (36b, R=Me, X=CN, R3=CF3).

The connection specified in the header received from the compounds of formula (5) obtained in example 4 by the procedure described in example 35.

So pl.>250°C. MS m/e: 403 (M-N)-.

1H NMR (DMSO-d6): 3,71 (3H, s), 6,92 (1H, d, J=>P CLASS="ptx2">Example 37(a).

4-[4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]-3-butene-2-he (37A, R=H, X=Ac, R3=CF3).

Specified in the title compound was obtained from compound 13 obtained at the stage And in example 10, according to the method described in example 35.

So pl. 186-188°C. MS m/e): 406 (M-N)-.

IR (KBR, cm-1): 3185, 1656,1629,1322,1284, 1169,1125, 1076.

Calculated for C20H13lF3NO3, %: 58,91; H 3,21; N 3,43.

Found, %: C 58,64; H 3,05; N 3,23.

Example 37(b).

4-[4-(5-Chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]-3-butene-2-he (37b, R=Me, X=Ac, R3=CF3).

The connection specified in the header received from compound 5 obtained in example 4 by the procedure described in example 5.

So pl. 232-234°C. MS m/e): 422 (MH+).

IR (KBr, cm-1): 2844, 1686, 1625, 1656, 1588, 1320.

Calculated for C21H15lF3NO3, %: 59,80; H TO 3.58; N 3,32.

Found, %: 59,60; H Of 3.56; N 3,22.

Example 38.

4-(5-Chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinoline-carboxaldehyde (38A, R=H, R3=CF3).

To a suspension of 2-chloro-6,8-dihydro-6-hydroxy-11-(trifluoromethyl)-7H-[1] the reed hydroxylamine (9,3 mg, 0.13 mmol) and triethylamine (0,038 ml, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. Evaporated THF and added water. Collected precipitate a light yellow color and dried it on the air, getting mentioned in the title compound (36 mg, 85%), so pl. 195-198°C (decomp.).

MS m/e: 383 (MN+).

Calculated for C17H10lF3NO3, %: 53,35; H 2,63; N 7,32.

Found, %: C 53,18; H 4,55; N, 6.87.

1H NMR (DMSO-d6): 6,98 (d, J=8,8 Hz, 1H), 7,19-720 (m, 2H), 7,34 (m, 1H), 7,54 (d, J=8.6 Hz, 1H), a 7.85 (m, 1H), 7,95 (s, 1H), 9,87 (s, br, 1H), 11,30 (s, 1H), 12,46 (s, br, 1H). IR (KBr, cm-1): 3247, 1661, 1629, 1322, 1265, 1168, 1121, 1076.

Example 39.

4-(5-Chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium (38b, R=Me, R3=CF3).

Stir a suspension of the compound obtained in example 4 (80 mg, 0.21 mmol), Na2OH· HCl (18 mg, 0.25 mmol) and anhydrous NaOAc (20 mg, 0.25 mmol) in absolute ethanol (2 ml) was heated under reflux for 1 hour. The ethanol is evaporated in a rotary evaporator and distributed the residue between EtOAc and water. Layer in EtOAc was separated and washed with water, brine and then dried (Na2SO4). Evaporation of EtOAc followed by rubbing raw product (56 mg), so pl. 255-258°C. IR (KBR, cm-1): 3207, 1669, 1323, 1267, 1122.

1H NMR (DMSO-d6): 3,66 (3H, s), was 7.08 (1H, s), 7,22 (1H, d, J=8,9 Hz), 7,28 (1H, d, J=2.6 Hz), 7,53 (2H, dd, J=8,9 and 2.8 Hz), the 7.85 (1H, dd, J=8.7 and 1.7 Hz), of 7.97 (1H, s), of 11.29 (1H, s), 12,50 (1H, brd s). MS 397 (MH+).

Example 40.

Methyl ester of 4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-kinalimutan acid (30b, Ra=Me, R3=CF3).

Stage A. 2-Chloro-7,9-dihydro-12-(trifluoromethyl)-[1]benzocaine[4,5-C]quinoline-6,8-dione (39, R3=CF3).

Stir a mixture of carboxylic acids of formula 30A (Ra=N, R3=CF3) (1.20 g, 3.0 mmol) and catalytic amount of p-TsOH was heated under reflux in toluene for 4 hours. The solvent was removed in a rotary evaporator. The residue was treated with saturated sodium bicarbonate solution and was extracted with EtOAc. The organic extracts were dried over MgSO4and concentrated to obtain the compound indicated in heading (783 mg, 69%).

1H NMR (300 MHz, DMSO-d6): 3,23 (1H, d, J=13.3 Hz), 4.26 deaths (1H, d, J=13.3 Hz), 7,52 (1H, d, J=8,8 Hz), 7,60 (1H, m), 7,76 (1H, dd, J=8.8 and 2.6 Hz), 7,87 (1H, d, J=2.6 Hz), 7,92 (2H, m), br12.62 (1H, brd). MS m/e 380 (MN+).

Stage Century. Methyl ester 4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(t is the PR-7,9-dihydro-12-(trifluoromethyl)-[1]benzocaine[4,5-C]-quinoline-6,8-dione, obtained at the stage And, by chromatography on a column of silica gel using a mixture of CH2Cl2- Meon as eluent was obtained ether specified in the header.

1H NMR (300 MHz, DMSO-d6): 3,17 (1H, d, J=16.4 Hz), 3,47 (1H, d, J=16.4 Hz), 3,53 (3H, s), 7,05 (1H, d, J=8.7 Hz), 7,11 (1H, d, J=2.7 Hz), 7,18 (1H, m), 7,42 (1H, dd, J=8.7 and 2.7 Hz), 7,55 (1H, d, J=8.5 Hz), to 7.84 (1H, dd, J=8.7 and 2.7 Hz), and 10.0 (1H, s), and 12.4 (1H, brd s). MS m/e 412 (MN+).

Example 41.

4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-2(1H)-chinoline (40, R=R1=Me, R3=CF3).

The solution metallyte (1M in THF, 1.6 ml, 1.6 mmol) was added to a cooled (-78°C) stirred solution of 2-chloro-7,9-dihydro-12-(trifluoromethyl)-[1]benzocaine[4,5-C]quinoline-6,8-dione, obtained in example 40, step A (16 mg, 0.3 mmol) in anhydrous THF (3 ml) under nitrogen atmosphere. After stirring for 1 hour at -78°C. remove the cooling bath and continued to stir for 16 hours. The reaction was interrupted 1 N Hcl and was carried out by EtOAc extraction. The crude product was purified flash chromatography (silica gel, 19:1 CH2CL2/Meon) obtaining specified in the title compound (21 mg) as a solid beige color.

MS m/z: 412 (MN+).

1H NMR 2.

4-(5-Chloro-2-hydroxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (43, R3=CF3).

Stage A. 4-(5-Chloro-2-hydroxyphenyl)-3-(2-triisopropylsilyl)-6-(trifluoromethyl)-2(1H)-chinoline (41, R3=CF3).

Pure triisopropylsilane (0,293 ml, 1.37 mmol, of 1.05 equiv.) was added to a stirred solution of the compound from example 2 and imidazole (0,134 g, 1.97 mmol, 1.5 EQ.) in anhydrous DMF (10 ml). After holding at room temperature for 12 hours the mixture was poured into aqueous 1 N Hcl solution (50 ml). The aqueous layer was extracted with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified on a chromatographic column with silica gel (3:1-2:1 hexane/ethyl acetate) to obtain the 0,357 g of a transparent viscous oil (yield 50%). An analytical sample of the connection specified in the header, obtained by crystallization from a mixture of ethyl acetate/hexane, so pl. 209-210°C.

1H NMR (300 MHz, DMSO-d6): 0,91 (N, s), 2,58 (2H, m), 3,63 (2H, m),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7,06 (1H, s), 7.23 percent (1H, d, J=2.6 Hz), 7,40 (1H, dd, J=8.7 and 2.3 Hz), 7,51 (1H, d, J=8.6 Hz), 7,78 (1H, dd, J=8.6 and 1.7 Hz), 9,92 (1H, s), of 12.26 (1H, s). MS m/e 540 (MN+).

Study the SUB>3).

To a stirred solution of Hinayana from the stage And (0,244 g, 0,453 mmol) in THF at -78°C was added n-utility (0,593 ml, 0,950 mmol, 2.1 EQ., 1.6 M/hexane). After 15 minutes, was added pure itmean and gave the mixture to warm to room temperature. After stirring for 12 hours the reaction was interrupted aqueous 1 N Hcl (10 ml) and the resulting mixture was poured into water (50 ml). Was carried out by extraction of the aqueous layer with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified on a column of silica gel (4:1-3:1 hexane/ethyl acetate) to obtain the 0,202 g of compound indicated in the heading in the form of a solid white color (yield 81%).

1H NMR (300 MHz, DMSO-d6): 0,92 (N, s), 2.63 in (2H, m), 3,66 (2H, t, J=7,4 Hz in), 3.75 (3H, s), 7,05 (1H, d, J=8,8 Hz), to 7.15 (1H, s), 7,24 (1H, d, J=2.7 Hz), 7,41 (1H, dd, J=8.7 and 2.6 Hz), 7,78 (1H, d, J=8,9 Hz), to $ 7.91 (1H, dd, J=9.0 and 1.9 Hz), for 9.95 (1H, s).

Stage C. 4-(5-Chloro-2-hydroxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (43, R3=CF3).

Tetrabutylammonium (0,380 ml, 0,308 mmol, 2 EQ., 1.0 M/THF) was added to a stirred solution of Hinayana from the stage (0,105 g, 0,190 mmol) in THF (10 ml). Cher the United States organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified by chromatography on a column (silica gel, 2.5% methanol/chloroform) to give 74 mg of solid white. This substance was recrystallized from a mixture of ethyl acetate/hexane and obtained 0,064 g (yield 86%) specified in the connection header, so pl. 229-230°C.

1H NMR (300 MHz, DMSO-d6): of 2.56 (2H, m), 3,40 (2H, m in), 3.75 (3H, s), of 4.57 (1H, m), 7,05 (1H, d, J=8,8 Hz), 7,14 (1H, s), 7,25 (1H, d, J=2.6 Hz), 7,41 (1H, dd, J=8.7 and 2.7 Hz), to 7.77 (1H, d, J=8,8 Hz), 7,89 (1H, dd, J=8.8 and 2.0 Hz), to 9.91 (1H, s). MS m/e 398 (MN+).

Calculated for C19H15lF3NO3, %: 57,37; H OF 3.80; N 3,52.

Found, %: C 57,69; H 3,88; N 3,28.

Example 43.

4-(5-Chloro-2-methoxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (44, R3=CF3).

A mixture of Hinayana obtained in example 42, step B (0,202 g, 0,365 mmol), dimethylsulfate (0,038 ml, 0,402 mmol, 1.1 EQ.) and potassium carbonate (0,056 g, 0,402 mmol, 1.1 EQ.) in acetone was heated under reflux for 3 hours. The resulting mixture was poured into water (25 ml). Then was carried out by extraction of the aqueous layer with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filter cleaning or determine its characteristics. To mix the solution similarbank of Hinayana (0,228 g, 0,401 mmol) in THF (10 ml) was added tetrabutylammonium (0,802 ml, 0,802 mmol, 2 EQ., 1.0 M/THF). After 12 hours the crude reaction mixture was poured into water (50 ml). The aqueous layer was extracted with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified using chromatography on a column (silica gel, 1:1-1:2 hexane/ethyl acetate) to obtain the 0,148 g solid white. This substance was recrystallized from a mixture of ethyl acetate/hexane, getting 0,139 g (yield 84%) specified in the connection header, so pl. 175-176°C.

1H NMR (300 MHz, DMSO-d6): 2,48 (2H, m), 3,37 (2H, m) to 3.67 (3H, s in), 3.75 (3H, s), of 4.57 (1H, t, 5,4), 7,06 (1H, s), 7,29 (1H, d, J=9.0 Hz), 7,35 (1H, d, J=1.3 Hz), to 7.61 (1H, dd, J=8.8 and 2.7 Hz), to 7.77 (1H, d, J=8,8 Hz), 7,89 (1H, dd, J=8.8 and 1.9 Hz). MS m/e 412 (MN+).

Calculated for C20H17lF3NO3, %: WITH 58.33; H 4,16; N 3,40.

Found, %: C 58,30; H 4,07; N 3,18.

Example 44.

4-(5-Chloro-2-hydroxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (43, R3=CF3).

Stage A. 4-(5-Chloro-2-hydroxyphenyl)-3-(2-triisopropylsilyl)-6-(triptime the 5 EQ.) was added to the mixed solution quinolone 31A, obtained in example 20 and imidazole (0,134 g, 1.97 mmol, 1.5 EQ.) in anhydrous DMF (10 ml). After soaking for 12 hours at room temperature the mixture was poured into aqueous 1 N HCl (50 ml). The aqueous layer was extracted with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified on a column of silica gel (3:1-2:1 hexane/ethyl acetate) to obtain the 0,357 g of a transparent viscous oil (yield 50%). An analytical sample was obtained by crystallization from a mixture of ethyl acetate/hexane, so pl. 209-210°C.

1H NMR (300 MHz, DMSO-d6): 0,91 (N, s), 2,58 (2H, m), 3,63 (2H, m),? 7.04 baby mortality (1H, d, J=8,8 Hz), 7,06 (1H, s), 7.23 percent (1H, d, J=2.6 Hz), 7,40 (1H, dd, J=8.7 and 2.3 Hz), 7,51 (1H, d, J=8.6 Hz), 7,78 (1H, dd, J=8.6 and 1.7 Hz), 9,92 (1H, s), of 12.26 (1H, s). MS m/e 540 (MH+).

Stage C. 4-(5-Chloro-2-hydroxyphenyl)-1-methyl-3-(2-triisopropylsilyl)-6-(trifluoromethyl)-2(1H)-chinoline (42, R3=CF3).

n-Utility (0,593 ml, 0,950 mmol, 2.1 EQ., 1.6 M/hexane) was added to a stirred solution of Hinayana 41 (0,244 g, 0,453 mmol) obtained in stage A, in THF at -78°C. After 15 minutes was added to the pure logmean and gave the mixture to warm to room temperature. After peremeshivaniem (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified using a column of silica gel (4:1-3:1 hexane/ethyl acetate) to obtain the 0,202 g specified in the connection header in the form of a solid white color (yield 81%).

1H NMR (300 MHz, DMSO-d6): 0,92 (N, s), 2.63 in (2H, m), 3,66 (2H, t, J=7,4 Hz in), 3.75 (3H, s), 7,05 (1H, d, J=8,8 Hz), to 7.15 (1H, s), 7,24 (1H, d, J=2.7 Hz), 7,41 (1H, dd, J=8.7 and 2.6 Hz), 7,78 (1H, d, J=8,9 Hz), to $ 7.91 (1H, dd, J=9.0 and 1.9 Hz), for 9.95 (1H, s).

Stage C. 4-(5-Chloro-2-hydroxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (43, R3=CF3).

Tetrabutylammonium (0,380 ml, 0,308 mmol, 2 EQ., 1.0 M/THF) was added to a stirred solution of Hinayana (0,105 g, 0,190 mmol) obtained in stage b In THF (10 ml). After 12 hours the crude reaction mixture was poured into water (50 ml). The aqueous layer was extracted with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. The crude residue was purified through column chromatography (silica gel, 2.5% methanol/chloroform) to give 74 mg of solid white. This substance was recrystallized from a mixture of ethyl acetate/exams-d6): of 2.56 (2H, m), 3,40 (2H, m in), 3.75 (3H, s), of 4.57 (1H, m), 7,05 (1H, d, J=8,8 Hz), 7,14 (1H, s), 7,25 (1H, d, J=2.6 Hz), 7,41 (1H, dd, J=8.7 and 2.7 Hz), to 7.77 (1H, d, J=8,8 Hz), 7,89 (1H, dd, J=8.8 and 2.0 Hz), to 9.91 (1H, s). MS m/e 398 (MN+).

Calculated for C19H15lF3NO3, %: 57,37; H, 3.80; N 3,52.

Found, %: C 57,69; H 3,88; N 3,28.

Example 45.

4-(5-Chloro-2-methoxyphenyl)-1-methyl-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (44, R3=CF3).

A mixture of Hinayana 42 obtained in example 44, step B (0,202 g, 0,365 mmol), dimethylsulfate (0,038 ml, 0,402 mmol, 1.1 EQ.) and potassium carbonate (0,056 g, 0,402 mmol, 1.1 EQ.) in acetone (15 ml) was heated under reflux for 3 hours. The resulting mixture was poured into water (25 ml). The aqueous layer was extracted with ethyl acetate (3× 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4), filtered and concentrated in vacuum. Raw, chinoline (0,228 g) were used to conduct the subsequent reaction without purification or determine its characteristics.

Tetrabutylammonium (0,802 ml, 0,802 mmol, 2 EQ., 1.0 M/THF) was added to a stirred solution of Hinayana obtained above (0,228 g, 0,401 mmol) in THF (10 ml). After 12 hours the crude reaction mixture was poured into water (50 ml). The aqueous layer of extras what was intervali and concentrated in vacuum. The crude residue was purified on column (silica gel, 1:1-1:2 hexane/ethyl acetate) to obtain the 0,148 g of a white solid. This substance was recrystallized from a mixture of ethyl acetate/hexane, getting 0,139 g (yield 84%) specified in the connection header, so pl. 175-176°C.

1H NMR (300 MHz, DMSO-d6): 2,48 (2H, m), 3,37 (2H, m) to 3.67 (3H, s in), 3.75 (3H, s), of 4.57 (1H, t, 5,4), 7,06 (1H, s), 7,29 (1H, d, J=9.0 Hz), 7,35 (1H, d, J=1.3 Hz), to 7.61 (1H, dd, J=8.8 and 2.7 Hz), to 7.77 (1H, d, J=8,8 Hz), 7,89 (1H, dd, J=8.8 and 1.9 Hz). MS m/e 412 (MN+).

Calculated for C20H17lF3NO3, %: WITH 58.33; H 4,16; N 3,40.

Found, %: C 58,30; H 4,07; N 3,18.

Example 46. 4-(5-Chloro-2-methoxyphenyl)-3-methyl-6-(trifluoromethyl)-2(1H)-chinoline.

A solution of compound 33 (R3=CF3, R8=N, n=1) (5,63 mmol), 33% Nug in Asón (to 38.3 mmol) and 10 ml of Asón was heated to 75°C for 3 hours. The solution was cooled to room temperature, broke reaction with water (50 ml) and then stirred for 12 hours. The precipitate was filtered off, washed with N2O and dried in vacuum. The substance is light brown recrystallized from a mixture of ethyl acetate/hexane. The connection specified in the header, was isolated as white matter (0,550 g, yield 27%).

1H NMR (30

Calculated for C18H13ClF3NO2·0,33 H2O %: 58,79; H OF 3.56; N 3,81.

Found, %: C 58,89; H 3,82; N 3,53.

Example 47.

4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (31a, R3=CF3, n=2).

Stage A. 3-(2-Hydroxyethyl)-4-hydroxy-6-chlorocoumarin (45).

To a solution-butyrolactone (15.5 g, 178,0 mmol) in THF (100 ml) at -78°C was added 1.0 M solution of LiHMDS in tetrahydrofuran (356 ml, 356 mmol) and stirred the mixture at -78°C for 1.5 hours. Solution was added methyl ester 5-chlorosalicylic acid (16.6 g, purity 98%, 89,0 mmol) in THF (95 ml). After stirring for 1 hour at 0°C. the mixture was heated to room temperature overnight to complete the reaction. After cooling to 0°C was added concentrated Hcl (12 N, 150 ml) to bring the pH to 1. The reaction solution was stirred up until GHUR showed no intermediate keeeper. To the mixture was added 400 ml of CH2CL2and 300 ml of N2About; separating the organic phase and the aqueous layer was extracted CH2Cl2(100 ml). The organic layers were combined and dried over anhydrous Na2SO4was then removed under reduced pressure, dissolve the lisali product. After cooling to 0-5°C for about 3 hours the product was isolated by filtration and washed with heptane. After drying in vacuum has been obtained in whole of 13.9 g (yield 66%) of the compound indicated in the title, in the form of white crystals, so pl. 185-186°C. MS m/z 240.

1H NMR (DMSO, 300 MHz): to 7.84 (d, 1H, J=2.4 Hz), to 7.61 (dd, 1H, J=2.4 and 8.8 Hz), 7,38 (d, 1H, J=8,8 Hz), of 3.56 (t, 2H, J=6.6 Hz), 2,73 (t, 2H, J=6.6 Hz). 13C NMR (DMSO, 75 MHz): 162,6, 159,9, 150,5, 131,4, 127,9, 122,4, 118,2, 117,8, 103,2, 59,4, 27,6. IR (cm-1): 3247,2, 2945,1, 2458,6, 1664,9, 1623,9. 1572,7, 1311,5, 1378,1, 1070,8, 825,0.

Stage C. 2,3-Dihydro-8-chloro-4H-paramenters-4-one (46).

To a solution of 3-(2-hydroxyethyl)-4-hydroxy-6-chlorocoumarin (45) (8 g, 33.3 mmol) in toluene (360 ml) at room temperature was added p-TSA (0.95 g, 5.0 mmol) and the resulting solution was heated under reflux while removing water trapped in a Dean-stark. The reaction mixture was cooled to room temperature and washed twice with a saturated solution of sodium bicarbonate. The toluene was removed by distillation at atmospheric pressure to obtain a final volume of 32 ml After cooling to 70°C, the product began to crystallize. The suspension of crystals kept at 55-65°C for 30 minutes and then cooled to 0-5°C. the Product was isolated by filtration, washed with cold tLOW, so pl. 144-146°C. MS m/z 223 (M+H).

1H NMR (Dl3, 300 MHz): 7,58 (d, 1H, J=2.5 Hz), 7,49 (dd, 1H, J=2,3 and 8.8 Hz), 7,30 (d, 1H, J=8,9 Hz), the 4.90 (t, 2H, J=9,3 Hz), 3,21 (t, 2H, J=9.5 Hz). 13With NMR (CDCl3, 75 MHz): 166,4, 160,3, 153,4, 132,6, 129,6, 122,4, 118,6, 113,8. 103,6, 74,9. 27,1. IR (cm-1): 3073,1, 2975,8, 1721,2, 1644,4, 1490,8, 1403,7, 1270,6, 1111,8, 1040,1.

Stage C. 4-(4’-Triftormetilfullerenov)-5-(2-hydroxy-5-chloro)-2,3-dihydrofuran (47).

To a solution of 2,3-dihydro-8-chloro-4H-paramenters-4-it (46) (1,02 g, 4,58 mmol) and 4-(trifluoromethyl)aniline (0.74 g, 4,58 mmol) in THF (50 ml) at -15°C was added LiHMDS (10.5 ml, 10.5 mmol, 1.0 M solution in THF). Transparent red color solution was stirred at -15°C up until GHUR showed less than 1% of the remaining compounds (46) (about 30 minutes). The reaction was interrupted by adding an aqueous solution of NaH2PO4(50 ml, 10% wt. in H2O). After adding MTBE (25 ml), the layers were separated and enriched organic phase was washed sequentially NaH2PO4(50 ml, 10% wt. in N2About), and saturated brine. After drying over Na2SO4the solution was concentrated to obtain specified in the connection header in the form of a clear orange oil (1,76 g, yield 100%), which crystallized upon cooling. Add dichloromethane (20 ml) privale to obtain 1.6 g of the compound, specified in the header (90% yield), so pl. 180-180,5°C. MS m/z 384 (M+H).

1H NMR (DMSO, 300 MHz): 9,76 (s, 1H), 9,34 (s, 1H), 7,76 (d, 2H, J=8,5 Hz), 7,60 (d, 2H, J=8.7 Hz), 7,26 (s, 1H), 7,24 (dd, 1H, J=2.2 and 7.0 Hz), 6,83 (dd, 1H, J=2.4 and 7.1 Hz), to 4.52 (t, 2H, J=9.6 Hz), and 3.16 (t, 2H, J=9.6 Hz).13With NMR (DMSO, 75 MHz): 165,5, 159,7, 155,9, 144,7, 132,0, 131,3, 127,3, 123,7, 121,7, 121,2, 119,5, 110,1, 71,5, 32,9; IR (cm-1): 3303,6, 2950,2, 1654,6, 1608,5, 1531,7, 1408,8,1326,9, 1116,9,1065,7, 840,4.

Stage D. 4-(5-Chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline (31a, R3=CF3, n=2).

A solution of 4-(4’-triftormetilfullerenov)-5-(2-hydroxy-5-chloro)-2,3-dihydrofuran (47) obtained in stage (1,76 g, 4,58 mmol), Meon (500 ml) was flushed with nitrogen and irradiated with a Hanovia lamp power 450 W at 30-40°C With up until GHUR not showed the presence of less than 1% of the remaining compounds (47). Then Meon was concentrated in vacuo and dissolved in dichloromethane (50 ml) of the oil obtained. Crystals formed after stirring for 1 hour at room temperature. After cooling the suspension to 0°C. the crystals were isolated by filtration and subjected to the drying. Was obtained 0.54 g (yield 30%) of the compound indicated in the title, in the form of a crystalline solid purity (IHVR) equal to 97%, physical characteristics to the SS="ptx2">where R and R1each independently represents hydrogen or methyl;

R2, R3and R4each independently represents hydrogen or trifluoromethyl, provided that R2, R3and R4are not both hydrogen;

R5denotes bromine or chlorine;

R6denotes hydrogen or fluorine;

n denotes an integer from 0 to 6;

m denotes an integer of 0 or 1;

R7denotes CH3, CRR1OH, SNO, C=NOH, PINES3or aryl, possibly substituted by one or two substituents selected from the group consisting of hydroxy, methoxy, amino, acetylamino,

or their non-toxic pharmaceutically acceptable salt.

2. Connection on p. 1, characterized in that it has the formula

where R denotes hydrogen or methyl;

R2, R3and R4each independently represents hydrogen or trifluoromethyl, provided that R2, R3and R4are not both hydrogen;

R5denotes chlorine;

R6denotes hydrogen or fluorine;

n denotes an integer from 0 to 3;

m denotes an integer of 0 or 1;

Rwhat with hydroxy, methoxy, amino, acetylamino,

or its non-toxic pharmaceutically acceptable salt.

3. Connection on p. 2, wherein R3represents trifluoromethyl, R2and R4represent hydrogen and R7denotes CH2IT; or its non-toxic pharmaceutically acceptable salt.

4. Connection on p. 2, wherein R3represents trifluoromethyl, R2and R4denote hydrogen, R7denotes aryl, possibly substituted by one or two substituents selected from the group comprising hydroxy, methoxy, amino and acetylamino; or a nontoxic pharmaceutically acceptable salt.

5. Connection on p. 1, characterized in that it is selected from the group including:

4-(5-chloro-2-methoxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(hydroxymethyl)-7-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-chinainternational;

4-(5-chloro-2-methoxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(hydroxyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(E)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(Z)-4-(5-chloro-2-hydroxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(E)-4-(5-chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

(Z)-4-(5-chloro-2-methoxyphenyl)-3-(2-fluoro-3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(4-methoxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3,4-acid)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(2,4-dihydroxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-[(4-hydroxyphenyl)Methenolone;

4-(5-chloro-2-hydroxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-[2-(4-hydroxyphenyl)ethyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-methyl-6-(trifluoromethyl)-2(1H)-chinoline;

4-[4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)quinoline-3-yl]-3-butene-2-he;

4-(5-chloro-2-hydroxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium;

4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-hyalinobatrachium;

4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxy-2-methylpropyl)-6-(trifluoromethyl)-2(1H)-chinoline.

6. Connection on p. 5, characterized in that it is selected from the group including:

4-(5-chloro-2-methoxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-methoxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(hydroxymethyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3-hydroxy-1-propenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(3-hydroxypropyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trift the LASS="ptx2">4-(5-chloro-2-hydroxyphenyl)-3-(4-hydroxyphenyl)-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-[(4-hydroxyphenyl)methyl]-6-(trifluoromethyl)-2(1H)-chinoline;

4-(5-chloro-2-hydroxyphenyl)-3-(4-AMINOPHENYL)-6-(trifluoromethyl)-2(1H)-chinoline.

7. Connection on p. 1, characterized in that it is a 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline.

8. Connection on p. 1, characterized in that it is a 4-(5-chloro-2-methoxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-2(1H)-chinoline.



 

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