Derivatives of phenyl-3-aminomethylquinolone-2 as inhibitors of no-synthase, method for their preparing, biologically active compounds and pharmaceutical composition based on thereof

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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

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

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

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

32 cl, 1 tbl, 132 ex

 

The invention relates to organic chemistry and medicine, and is intended to produce compounds that inhibit NO-synthase, biologically active compounds and pharmaceutical compositions based on them.

NO synthase is the enzyme responsible for the catalytic conversion of L-arginine into nitric oxide (II) (NO). This process was first discovered in the late 80-ies, and from then until the present time discover new functions of NO in the body. Accordingly, the significance of NO-synthetase to regulate various body functions constantly increases, and hence, the importance of the various inhibitors and modulators of this enzyme for the treatment of diseases associated with disorders of these functions. In General we can say that the nitric oxide (II) is involved:

1) in the regulation of the tone of smooth muscles, which leads to the relaxation / contraction and, consequently, to the expansion / compression of the blood vessels (cardiovascular disease, as well as various violations of functioning of the sexual organs) and intestines (gastrointestinal disease);

2) in the functioning of all faguoqitirute cells, which are necessary for the body's fight against bacteria and foreign bodies. NO mediates inflammatory processes and is necessary for the formation of all related replies;

3) it is peredacha (when the signal transmission between neurons, including some brain structures). The impact on this process leads to the possibility to relieve the severity of epileptic seizures and the effects of strokes, to regulate the perception of pain, sleep duration, etc.

The proposed substance, new derivatives of quinolone-2, namely, amino - and hydroxy-derivatives of phenyl-3-aminomethyl-quinolone-2, are positioned as inhibitors of the so-called inducible form of NO-synthetase responsible for the generation of NO mainly in faguoqitirute cells. Created on the basis of these substances, medicines can be used to treat diseases such as rheumatoid arthritis, asthma and the like. There are medicines used in these diseases, including action-based inhibitors of NO-synthetase. However, most of the existing inhibitors of this enzyme distinguished by a lack of selectivity in relation to its different isoforms, which leads to the development of various side effects in the use of drugs based on them.

In the present application describes methods for the synthesis of the claimed structures, taking into account the peculiarities of the structure of the final compounds. Structural analogues of the proposed substances are described in the scientific and patent literature. For example, in US patent No. 5874472 side chain of arg is Nina modified by including a five - or six-membered aromatic or heteroaromatic cycles (thiophene, benzene, pyridine, etc.). The data on activity in respect of NO-synthetase isolated from different sources, show activity at the level of Ki of 0.5 to 50 nm. Data on toxicity are not available.

Among other proprietary compounds exhibiting activity towards NO-synthetase without its specific values, it should be noted application JP No. 10-120654, which describes derivatives of 4-methyl-3,4-degidro-2-aminopiperidine.

Data on activity occurring among the derivatives of quinolone-2: immunosuppressants, anti-inflammatory and anti-allergic drugs [US patent No. 6509352]; substances used for the treatment of hypertension, ischemia, myocardial infarction, angina and other [patent RU No. 2167874]; anti-allergic and anti-asthmatic substances [application JP No. 58-225065]; substances used for the treatment of various forms of epilepsy, Alzheimer's disease, schizophrenia and multiple sclerosis [US patents No. 5536709, 5646132], anticonvulsants and similar substances [application RU # 95109098]. In US patents No. 6509352 and 6605616 described derivatives of quinoline, representing amides of 4-oxo-China-2-one-3-carboxylic acid to aromatic amines have had, necessarily containing nitrogen atom, methyl Deputy. The compounds claimed in the present invention represent secondary amines, while the compounds described in the decree is the R patents, are tertiary inorganic salts. This fundamental difference leads to a difference of methods of synthesis and physico-chemical properties of the obtained compounds. In addition, the claimed compounds the substituent in position 4 hinolinova ring is N. in contrast to Aloxe-Deputy (OR4in this position the known compounds described in the above patents. Known compounds were investigated as inhibitors of acute experimental autoimmune encephalomyelitis. In these patents there is no mention of activity described in these compounds as inhibitors of NO-synthetase. Thus, we can conclude that the proposed connection and found to have a high biological activity against NO-synthetase from scientific, technical and patent literature is not known.

Task to be solved by the present invention is directed, is to obtain amino - and hydroxy-derivatives of phenyl-3-aminomethyl-quinolone-2, with a significantly higher activity (IC501-10 nm), and higher selectivity to the corresponding isoforms of the enzyme NO synthetase), little toxic for the human body with no identified side effects.

Based on the foregoing, the present invention offers a novel inhibitors of arginine website is inducible NO-synthetase, not affect endothelial her form in a physiologically acceptable concentration range. In the description of the present application presents a method of inhibiting the conversion of arginine to nitric oxide under the action of the inducible form of NO-synthetase, that is, the concentration of the following inhibitors, sufficient for effective inhibition of the enzyme under physiological conditions, the conditions of their administration, as well as methods of inhibiting excessive conversion of arginine to nitric oxide under such conditions as pathologically low blood pressure, septic shock or autoimmune disorders, methods of their administration and the doses of these inhibitors sufficient to achieve a therapeutic effect.

The problem is solved in that the proposed amino-derivatives of phenyl-3-aminomethyl-quinolone-2 have the General formula (I):

where:

R1, R2, R3, R4 are independently the same or different, and

R1 is selected from H, Alk, OAlk, Cl, Br, NO2, NH2;

R2 is selected from H, Alk, OAlk, F, OCF3OS6H5;

R3 is selected from H, Alk, OAlk, SCH3;

R4 is selected from H, Alk, OAlk, Cl, Br, CH2C6H5, NO2,

or

R3, R4 are selected from (CH2)3The co2Oh, och2CH2About;

R5=H or Alk;

R6, R7, R9 are H;

R8 is selected from H or from the following substituents:

The task is also solved by the fact that the hydroxy-derivatives of phenyl-3-aminomethyl-quinolone-2 have the General formula (2):

where:

R1, R2, R3, R4 are independently the same or different, and

R1 is selected from H, Alk, OAlk, Cl, Br, NO2, NH2;

R2 is selected from H, Alk, OAlk, F, OCF3OC6H5;

R3 is selected from H, Alk, OAlk, SCH3;

R4 is selected from H, Alk, OAlk, Cl, Br, CH2With6H5, NO2;

or

R3, R4 are selected from (CH2)3The co2Oh, och2CH2About;

R5=H or Alk:

at least one of the

R6, R7, R8 or R9 is IT, while the rest represent N.

The problem is solved by the methods of obtaining the proposed amino - and hydroxy-derivatives of phenyl-3-aminomethyl-quinolone-2 having the above General formula, as well as biologically active compounds and pharmaceutical composition based on them.

The proposed synthesis of compounds having the General formula (1), carried out by reacting the corresponding substituted 2-chinolin-3-carbaldehydes with the appropriate substituted p-phenylenediamine, followed by reduction of the resulting Schiff bases. The proposed synthesis of compounds having the General formula (2), carried out by reacting the corresponding substituted 2-chinolin-3-carbaldehydes with Anis is dynamic, recovery of the resulting Schiff bases with education alilovic esters such recovery and subsequent cleavage of Lewis acids.

In more detail, the synthesis of the corresponding substituted 2-chinolin-3-carbaldehyde carried out in several stages according to the following scheme:

First of anilines (to simplify the substituents not shown) synthesize the corresponding substituted acetanilide. Then the obtained acetanilide add to formuliruya mixture of Vilsmeier resulting from the addition POCl3to dimethylformamide. Two modes are available at this stage: with cooling of the reaction mixture (example 1) or by heating to 50° (example 3). As acetanilide by the given method is suitable compounds containing electrondonor substituents in the benzene ring or weak electron-withdrawing substituents (the output in this case is greatly reduced). The course of the reaction in the case of meta-substituted acetanilides is regioselective with the formation of almost one isomer (7-substituted quinoline). The reaction mixture was kept, and then gradually raise the temperature to 90-100°C. the reaction Time ranges from 8 to 24 hours. The selection of the reaction products of 2-chloro-quinoline-3-carbaldehyde is carried out by hydrolysis of the reaction is Messi in a large excess of finely crushed ice (100 ml reaction mixture is not less than 1 kg of ice). Drawn by the hydrolysis of the reaction products is mostly used without further purification, but if necessary they can be recrystallized from acetone, chloroform or of ethyl acetate.

The final stage of synthesis of substituted 2-chinolin-3-carbaldehyde is the hydrolysis of the corresponding 2-chloro-quinoline-3-carbaldehydes by boiling in aqueous acetic acid (about 80-90%) (example 2). The reaction time ranges from 4 to 12 hours. The reaction product often appears as a reaction (either by cooling the reaction mixture). If necessary, the resulting products can be cleaned by recrystallization from acetic acid or dimethylformamide.

The corresponding substituted p-phenylenediamine get in two stages according to the following scheme:

As the starting compound used is 4-chloronitrobenzene. At the first stage in the reaction of nucleophilic substitution receive the corresponding N,N-disubstituted p-nitrobenzene at 80-100°With (example 43). The reaction is usually performed with an excess of the appropriate amine and the secondary amine or in the medium of dimethylformamide (example 61) or other solvent (acetonitrile, dioxane and others) in the presence of inorganic bases (potash, soda, and other). Clearance obtained nitrosodi the surveillance carried out by recrystallization or by column chromatography on silica gel.

In the second stage restore nitro-derivatives obtained using any suitable reducing reagents (catalytic hydrogenolysis (example 44), the recovery of hydrazine hydrate in the presence of Raney Nickel (example 72), iron in hydrochloric acid, tin chloride, and others). The obtained amine or recrystallized, or cleaned by column chromatography on silica gel. Such amines are often not stable and rapidly oxidized by the oxygen in the air. Therefore, a careful conditions of storage or use them in further syntheses immediately after receipt.

Target products - amino-derivatives of phenyl-3-aminomethyl-quinolone-2 receive according to the following scheme:

As starting compounds using the appropriate substituted 2-chinolin-3-carbaldehyde and p-phenylenediamine obtained in the above schemes (I) and (II).

Schiff bases and their respective hydroxylamine as one of the possible intermediates formed in the reaction, restore obtaining the desired products. Possible interim allocation of Schiff bases. In this case, the reaction is often carried out either in dioxane or dimethylformamide at a temperature of about 100°C. the resulting Schiff base without further purification restore Borg is dream sodium in alcohol (methanol, ethanol).

In the case of the synthesis without intermediate allocation Schiff's base reaction is carried out in an inert solvent (acetonitrile, dichloroethane, and others). Initially for some time (about 1 hour) conduct the reaction between the aldehyde and the primary amine at low heat. Later in the reaction mass portions with efficient stirring, triacetoxyborohydride sodium or Lamborgini sodium (example 73). If necessary add a small amount of acetic acid. After the reaction mixture is diluted with an aqueous solution of sodium carbonate (potash). The organic layer is separated, dried. Received target products is recrystallized or cleaned by the method of column chromatography on silica gel.

Synthesis of intermediate selection Schiff bases or without their allocation is determined only from the point of view of convenience and expediency. For example, if the resulting Schiff's base is unstable, then, obviously, their separation is impractical. On the other hand, if for the further synthesis of the required additional cleaning of Schiff bases and their selection is desirable.

Target products - hydroxy-derivatives of phenyl-3-aminomethyl-quinolone-2 receive according to the following scheme:

In this case, as the source the compounds using the appropriate substituted 2-chinolin-3-carbaldehyde, received the instructions above, and anisidine. In the recovery of Schiff bases do not get the target product and the corresponding alkalemia esters, which decompose Lewis acids to obtain the desired product containing free hydroxyl group in the benzene ring. Depending on the source of anisidine possible to obtain the target product with multiple hydroxyl groups in positions 6, 7, 8, 9. For synthesis, you can use anisidine synthesized by known methods or commercially available. As the Lewis acid used tribromide boron (example 128). The reaction is carried out at strongly negative temperatures (˜-50° (C) in an inert solvent as methylene chloride. Upon termination of the reaction mixture to decompose the absolutized methanol. The obtained substances often recrystallized from a suitable solvent.

The invention is demonstrated in the following examples.

In the examples 1-42 retrieves various carbaldehyde in accordance with the scheme (I). These examples differ in the use of different reagents for different target products corresponding to General formula (1).

Example 1.

Synthesis of 2-chloro-6-methylinosine-3-carbaldehyde (I).

To formuliruya mixture of Vilsmeier obtained through prokopiv the deposits with simultaneous cooling 170 ml (1.75 mol) POCl 3to 60 ml (0.75 mol) of dimethylformamide, are added in small portions with simultaneous vigorous stirring and cooling 37.3 g (0.25 mol) of N-para-tolylacetylene. The reaction mixture was kept at room temperature for 1 hour and then slowly raise the temperature of the reaction mixture up to 90-100°C and maintained for 8 hours. Next, the reaction mixture is cooled and poured onto 1.5 kg of finely crushed ice. At the end of hydrolysis (at least 2-3 hours) the resulting suspension is filtered, the precipitate washed with water until slightly acid or neutral reaction (pH>5). Get 38 g (75%) of product (I). Analytically pure sample emit by recrystallization from acetone or chloroform. TPL 127-128°C (lit. 124-125°s With ethyl acetate, [9]).

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s), 7.8 (1H, d, J=8.5 Hz), 7.9 (1H, d, J=8.5 Hz), 8.0 (1H, d, J=3.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 2.

Synthesis of 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (II).

2-Chloro-6-methylinosine-3-carbaldehyde (38 g, 0.185 mol)obtained in example 1 are dissolved in 250 ml of a mixture of acetic acid - water (10:1 ratio), heated to boiling and boiled for 3-4 hours.

Upon completion of the reaction from the boiling solution begins to fall buildup (II). The reaction mixture is cooled, the precipitate filtered, washed with a mixture of alcohol-water, then with water to remove residual acetic key is lots. Produce 22 g (65%) product (II). Analytically pure sample is obtained by recrystallization from dimethylformamide. TPL 310-312°C (lit. 275°acetic acid, [10]).

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 7.2 (1H, d, J=8.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.6 (1H, d, J=3.5 Hz), 8.5 (1H, s), 10.1 (1H, s), 12.0 (1H, broadened peak).

Example 3.

Synthesis of 2-chloro-8-methylinosine-3-carbaldehyde (III).

Formilitary the mixture is prepared according to example 1 and at a temperature of about 50°add small portions of 37.3 g (0.25 mol) of N-ortho-tolylacetylene. The reaction mixture is maintained at the same temperature for 1 hour, then slowly raise the temperature of the reaction mixture up to 90-100°and incubated for 24 hours. Next, the reaction mixture is cooled and poured onto 1.5 kg of finely crushed ice. At the end of hydrolysis (at least 2-3 hours) the resulting suspension is filtered, washed with water until slightly acid or neutral reaction (pH>5). Allocate 28 g (54%) of product (III). Analytically pure sample is obtained by recrystallization from acetone or chloroform. TPL 134-136°C (lit. 137-138°s With ethyl acetate, [9]).

H1NMR spectrum (δ, DMSO-d6): 2.6 (3H, s), 7.6 (1H, t, J=8.5 Hz), 7.9 (1H, d, J=8.5 Hz), 8.0 (1H, d, J=8.5 Hz), 8.9 (1H, s), 10.2 (1H, s).

Example 4.

Synthesis of 8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (IV).

Conducted according to the technique prevedeno the example 2, with the use of the product (III). Obtain 26.5 g (74%) of product (IV). MP 299-300°C.

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s); 7.1 (1H, t, J=8.5 Hz); 7.5 (1H, d, J=8.5 Hz); 7.7 (1H, d, J=8.5 Hz); 8.5 (1H, s); 10.1 (1H, s); 11.0 (1H, broadened peak).

Example 5.

Synthesis of 2-chloro-7-methylinosine-3-carbaldehyde (V).

Conducted according to the technique described in example 1. Get 42 g (82%) of product (V). TPL 143-144°C (lit. 144-145°s With ethyl acetate, [9]).

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s), 7.6 (1H, d, J=8.5 Hz), 7.7 (1H, d, J=3.5 Hz), 8.2 (1H, d, J=8.5 Hz), 8.9 (1H, s), 10.4 (1H, s).

Example 6.

Synthesis of 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (VI).

Conducted according to the methodology described in example 2. Obtain 24.5 g (78%) of the desired product. TPL 296-297°C.

H1NMR spectrum (δ, DMSO-d6): 2.2 (3H, s); 6.9 (1H, d, J=8.5 Hz); 7.1 (1H, s); 7.7 (1H, d, J=8.5 Hz); 8.2 (1H, s); 10.1 (1H, s); 12.0 (1H, broadened peak).

Example 7.

Synthesis of 2-chloro-6-ethoxyquinoline-3-carbaldehyde (VII).

Conducted according to the technique shown in example 3. Get 36 g (60%) of the desired product. TPL 168-170°C.

H1NMR spectrum (δ, DMSO-d6): 1.3 (3H, t, J=7.5 Hz), 4.2 (2H, q, J=7.5 Hz), 7.6 (3H, m), 7.9 (1H, d, J=8.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 8.

Synthesis of 6-ethoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (VIII).

Conducted according to the methodology described in example 2, using the product (VII). Get 25 g (73%) of the product (VIII). TPL 298-300°C (With decomp.).

H 1NMR spectrum (δ, DMSO-d6): 1.1 (3H, t, J=7.5 Hz); 4.0 (2H, q, J=7.5 Hz); 7.2 (2H, m); 7.4 (1H, s); 8.4 (1H, s); 10.1 (1H, s); 12.0 (1H, broadened peak).

Example 9.

Synthesis of 2-chloro-5,8-dimethylindoline-3-carbaldehyde (IX).

Conducted according to the technique shown in example 3. Get 30 g (55%) of the desired product. TPL 184-185°C.

H1NMR spectrum (δ, DMSO-d6): 2.6 (3H, s), 2.7 (3H, s), 7.4 (1H, d, J=8.5 Hz), 7.7 (1H, d, J=8.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 10.

Synthesis of 5,8-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (X).

Conducted according to the methodology described in example 2, using the product (IX). Obtain 26.5 g (74%) of product (X). TPL 297-298°C.

H1NMR spectrum (δ, DMSO-d6): 2.2 (3H, s); 2.5 (3H, s); 6.9 (1H, d, J=8.5 Hz); 7.2 (1H, d, J=8.5 Hz); 8.5 (1H, s); 10.1 (1H, s); 11.1 (1H, broadened peak).

Example 11.

Synthesis of 2-chloro-7-methoxyquinoline-3-carbaldehyde (XI).

Conducted according to the technique described in example 1. Yield 45 g (81%). TPL 187-189°C (lit. 197-198°s With ethyl acetate, [9]).

H1NMR spectrum (δ, DMSO-d6): 3.8 (3H, s), 7.3 (3H, m), 8.1 (1H, d, J=8.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 12.

Synthesis of 7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XII).

Conducted according to the methodology described in example 2, using the product (XI). Get 22 g (64%) of the product (XII). TPL 286-288°C.

H1NMR spectrum (δ, DMSO-d6): 3.8 (3H, s), 6.7 (1H, d, J=3.5 Hz), 6.8 (1H. d/d, J=8.5 Hz / 3.5 Hz), 7.8 (1H, d, J=8.5 Hz), 8.4 (1H, s), 10. (1H, s), 12.0 (1H, broadened peak).

Example 13.

Synthesis of 2-chloro-6-atelinae-3-carbaldehyde (XIII).

Conducted according to the technique described in example 1. Get 40 g (78%) of the product (XIII). TPL 95-97°C.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 2.9 (2H, q, J=7.5 Hz); 7.85 (1H, d, J=8.5 Hz / J=3.5 Hz); 7.95 (1H, d, J=8.5 Hz); 8.05 (1H, d, J=3.5 Hz); 8.9 (1H, s); 10.2 (1H, s).

Example 14.

Synthesis of 6-ethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XIV).

Conducted according to the methodology described in example 2, using the product (XIII). Obtain 24.5 g (78%) of the product (XIV). TPL 240-241°C.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 2.65 (2H, q, J=7.5 Hz); 7.3 (1H, d, J=8.5 Hz); 7.5 (1H, d, J=8.5 Hz / J=3.5 Hz); 7.7 (1H, d, J=3.5 Hz); 8.3 (1H, s); 10.2 (1H. s); 12.0 (1H, broadened peak).

Example 15.

Synthesis of 2-chloro-7,8-dimethylindoline-3-carbaldehyde (XV).

Conducted according to the technique described in example 1. Get 40 g (75%) of the product (XV). TPL 124-126°C.

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s), 2.6 (3H, s), 7.5 (1H, d, J=8.5 Hz), 8.0 (1H, d, J=8.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 16.

Synthesis of 7,8-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XVI).

Conducted according to the methodology described in example 2, using the product (XV). Obtain 26.5 g (74%) of the product (XVI). TPL >330°C.

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s); 2.6 (3H, s); 7.2 (1H, d, J=8.5 Hz); 7.6 (1H, d, J=8.5 Hz); 8.3 (1H, s), 10.3 (1H, s); 11.6 (1H, broadened peak).

Primer.

Synthesis of 2-chloro-6,7-dimethylindoline-3-carbaldehyde (XVII).

Conducted according to the technique described in example 1. Get 39 g (70%) of the product (XVII). TPL 164-166°C.

H1NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 2.4 (3H, s), 7.6 (1H, s), 7.9 (1H, s), 8.7 (1H, s), 10.4 (1H, s).

Example 18.

Synthesis of 6,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XVIII).

Conducted according to the methodology described in example 2, using the product (XVII). Obtain 26.5 g (74%) of product (XVIII). TPL 236-238°C.

H1NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 2.4 (3H, s), 7.1 (1H, s), 7.5 (1H, s), 8.2 (1H, s), 10.2 (1H, s), 12.0 (1H, broadened peak).

Example 19.

Synthesis of 6-chloro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (XIX).

Conducted according to the technique described in example 1. Get 40 g (72%) of product (XIX). TPL 188-190°C.

H1NMR spectrum (δ, DMSO-d6): 6.3 (2H, s), 7.4 (1H, s), 7.6 (1H, s), 8.7 (1H, s), 10.4 (1H, s).

Example 20.

Synthesis of 6-oxo-5,6-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (XX).

Conducted according to the methodology described in example 2, using the product (XIX). Obtain 28 g (80%) of the product (XX). TPL >300°C.

H1NMR spectrum (δ, DMSO-d6): 6.1 (2H, s), 6.6 (1H, s), 7.6 (1H, s), 8.6 (1H, s), 10.2 (1H, s), 12.0 (1H, broadened peak).

Example 21.

Synthesis of 7-chloro-2,3-dihydro-[1,4]like[2,3-g]quinoline-8-carbaldehyde (XXI).

Conducted according to the technique described in example 1. Get 42 grams (73%) of product (XXI). TPL-228° C.

H1NMR spectrum (δ, DMSO-d6): 4.1 (4H, s), 7.5 (1H, s), 8.0 (1H, s), 8.5 (1H, s), 10.5 (1H, s).

Example 22.

Synthesis of 7-oxo-6,7-dihydro-[1,4]like[2,3-g]quinoline-8-carbaldehyde (XXII).

Conducted according to the methodology described in example 2, using the product (XXI). Obtain 28 g (80%) of the product (XXII). TPL >300°C.

H1NMR spectrum (δ, DMSO-d6): 6.1 (2H, s), 6.6 (1H, s), 7.6 (1H, s), 8.6 (1H, s), 10.2 (1H, s), 12.0 (1H, broadened peak).

Example 23.

Synthesis of 2-chloro-6,8-dimethylindoline-3-carbaldehyde (XXIII).

Conducted according to the technique shown in example 3. Get 35 g (65%) of product (XXIII). TPL 107-108°C (lit. 110-111°, [12]).

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s), 2.6 (3H, s), 7.6 (1H, s), 7.7 (1H, s), 8.7 (1H, s), 10.4 (1H, s).

Example 24.

Synthesis of 6,8-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXIV).

Conducted according to the methodology described in example 2, using the product (XXIII). Obtain 24.5 g (78%) of product (XXIV). TPL 299-301°C.

H1NMR spectrum (δ, DMSO-d6): 2.2 (3H, s); 2.4 (3H, s); 7.2 (1H, s); 7.5 (1H, s); 8.4 (1H, s); 10.1 (1H, s); 11.2 (1H, broadened peak).

Example 25.

Synthesis of 2-chloro-7-ethoxyquinoline-3-carbaldehyde (XXV).

Conducted according to the technique shown in example 3. Get 36 g (60%) of the product (XXV). TPL 166-167°C.

H1NMR spectrum (δ, DMSO-d6): 1.4 (3H, t, J=7.5 Hz); 4.25 (2H, q, J=7.5 Hz); 7.2 (1H, d, J=8.5/3.5 Hz); 7.4 (1H, d, J=3.5 Hz); 8.1 (1H, d, J=8.5 Hz); 8.9 (1H, s); 10.1 (1 is, C).

Example 26.

Synthesis of 7-ethoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXVI).

Conducted according to the methodology described in example 2, using the product (XXV). Get 22 g (64%). TPL 288-290°C.

H1NMR spectrum (δ, DMSO-d6): 1.35 (3H, t, J=7.5 Hz); 4.1 (2H, q, J=7.5 Hz); 6.8 (1H, d, J=3.5 Hz); 6.9 (1H, d, J=8.5/3.5 Hz); 7.8 (1H, d, J=8.5 Hz); 8.2 (1H, s); 10.1 (1H, s); 12.0 (1H, broadened peak).

Example 27.

Synthesis of 2-chloro-5,7-dimethylindoline-3-carbaldehyde (XXVII).

Conducted according to the technique described in example 1. Get 44 g (78%) of product (XXVII). TPL 96-98°C.

H1NMR spectrum (δ, DMSO-d6): 2.5 (3H, s), 2.7 (3H, s), 7.4 (1H, s), 7.6 (1H, s), 8.8 (1H, s), 10.4 (1H, s).

Example 28.

Synthesis of 5,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXVIII).

Conducted according to the methodology described in example 2, using the product (XXVII). Obtain 24.5 g (78%) of product (XXVIII). TPL 253-254°C.

H1NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 6.9 (1H, s), 7.0 (1H, s), 8.45 (1H, s), 10.2 (1H, s), 12.0 (1H, broadened peak).

Example 29.

Synthesis of 2-chloro-quinoline-3-carbaldehyde (XXIX).

Conducted according to the technique described in example 1. Get 37 g (78%) of product (XXIX). TPL 178-180°C.

H1NMR spectrum (δ, DMSO-d6): 7.4 (1H, t, J=8.5 Hz); 7.6 (1H, d, J=8.5 Hz); 7.8 (1H, t, J=8.5 Hz); 8.9 (1H, s); 10.2 (1H, s).

Example 30.

Synthesis of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXX).

Conducted according to the methodology described in note is d 2, with the use of the product (XXIX). Obtain 24.5 g (78%) of product (XXX). TPL 307-310°C.

H1NMR spectrum (δ, DMSO-d6): 7.1 (1H, t, J=8.5 Hz); 7.3 (1H, d, J=8.5 Hz); 7.6 (1H, t, J=8.5 Hz); 8.5 (1H, s); 10.0 (1H, s); 12.0 (1H, broadened peak).

Example 31.

Synthesis of 2-chloro-6-isopropylindole-3-carbaldehyde (XXXI).

Conducted according to the technique described in example 1. Get 40 g (68%) of product (XXXI). TPL 125-126°C.

H1NMR spectrum (δ, DMSO-d6): 1.35 (6N, d, J=7.5 Hz), 3.06 (1H, m), 7.77 (1H, d, J=8.5 Hz), 7.89 (1H, d, J=8.5 Hz), 8.02 (1H, d, J=3.5 Hz), 8.76 (1H, s), 10.55 (1H, s).

Example 32.

Synthesis of 6-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXXII).

Conducted according to the methodology described in example 2, using the product (XXXI). Obtain 24.5 g (78%) of product (XXXII). TPL 221-222°C.

H1NMR spectrum (δ, DMSO-d6): 1.2 (6N, d, J=8.5 Hz); 2.95 (1H, Sep, J=7.5 Hz); 7.2 (1H, d, J=8.5 Hz); 7.5 (1H, d, J=8.5/3.5 Hz); 7.9 (1H, d, J=3.5 Hz); 8.4 (1H, s); 10.2 (1H, s); 12.0 (1H, broadened peak).

Example 33.

Synthesis of 2-chloro-5,6,7-trimethoxyaniline-3-carbaldehyde (XXXIII).

Conducted according to the technique described in example 1. Get 44 g (78%) of product (XXXIII). TPL 114-116°C.

H1NMR spectrum (δ, DMSO-d6): 3.9 (3H, s); 4.0 (3H, s); 4.1 (3H, s); 7.3 (1H, s); 8.75 (1H, s); 10.3 (1H, s).

Example 34.

Synthesis of 5,6,7-trimetoksi-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXXIV).

Conducted according to the methodology described in example 2, using the product (XXXIII) Obtain 24.5 g (78%) of product (XXXIV). TPL 268-270° (Razlog.).

H1NMR spectrum (δ, DMSO-d6): 3.7 (3H, s); 3.8 (3H, s); 3.9 (3H, s); 6.7 (1H, s); 8.4 (1H, s); 10.2 (1H, s); 12.0 (1H, broadened peak).

Example 35.

Synthesis of 2-chloro-6-tertbutylphenol-3-carbaldehyde (XXXV).

Conducted according to the technique described in example 1. Get 38 g (62%) of product (XXXV). TPL-102°C.

H1NMR spectrum (δ, DMSO-d6): 1.36 (S, s), 7.59 (1H, d, J=8.5 Hz), 7.92 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=3.5 Hz), 8.95 (1H, s), 10.55 (1H, s).

Example 36.

Synthesis of 6-tertbutyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXXVI).

Conducted according to the methodology described in example 2, using the product (XXXV). Obtain 26.5 g (67%) of the desired product. TPL 228-230°C.

H1NMR spectrum (δ, DMSO-d6): 1.25 (M, s); 7.2 (1H, d, J=8.5 Hz); 7.5 (1H, d, J=8.5 Hz); 7.95 (1H, d, J=3.5 Hz); 8.5 (1H, s); 10.2 (1H, s); 12.0 (1H, broadened peak).

Example 37.

Synthesis of 2-chloro-6-propilinian-3-carbaldehyde (XXXVII).

Conducted according to the technique described in example 1. Get 40 g (68%) of product (XXXVII). TPL 105-106°C.

H1NMR spectrum (δ, DMSO-d6): 0.9 (3H, t, J=7.5 Hz); 1.6 (2H, q, J=7.5 Hz); 2.6 (2H, t, J=7.5 Hz); 7.4 (1H, d, J=8.5 Hz); 7.8 (1H, d, J=8.5 Hz); 8.2 (1H, s); 8.8 (1H, s); 10.3 (1H, s).

Example 38.

Synthesis of 6-propyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXXVIII).

Conducted according to the methodology described in example 2, using the product (XXXVII). Get 25 g (68%) of product (XXXVIII). TPL 213-215°C.

H1YAM the range (δ , DMSO-d6): 0.9 (3H, t, J=7.5 Hz); 1.6 (2H, q, J=7.5 Hz); 2.5 (2H, t, J=7.5 Hz); 7.1 (1H, d, J=8.5 Hz); 7.5 (1H, d, J=8.5 Hz); 7.8 (1H, s); 8.4 (1H, s); 10.1 (1H, s); 12.0 (1H, broadened peak).

Example 39.

Synthesis of 2-chloro-7,8-dihydro-6N-cyclopent[g]quinoline-3-carbaldehyde(IXL).

Conducted according to the technique described in example 1. Get 40 g (68%) of product (IXL). TPL-140°C.

H1NMR spectrum (δ, DMSO-d6): 2.1 (2H, m, J=7.5 Hz); 3.05 (2H, m, J=7.5 Hz); 3.15 (2H, m, J=7.5 Hz); 7.8 (1H, s); 8.05 (1H, s); 8.8 (1H, s); 10.4 (1H, s).

Example 40.

Synthesis of 2-oxo-2,6,7,8-tetrahydro-1H-cyclopent[g]quinoline-3-carbaldehyde (XL).

Conducted according to the methodology described in example 2, using the product (IXL). Get 40 g (68%) of product (XL). TPL >310°C.

H-NMR spectrum (δ, DMSO-d6): 2.0 (2H, m, J=7.5 Hz); 2.9 (2H, m, J=7.5 Hz); 3.0 (2H, m, J=7.5 Hz); 7.1 (1H, s); 7.6 (1H, s); 8.2 (1H, s); 10.1 (1H, s); 12.0 (1H, broadened peak).

Example 41.

Synthesis of 2-chloro-6-methoxy-3-carbaldehyde (XLI).

Conducted according to the technique shown in example 3. Get 40 g (68%) of product (XLI).TPL 158-159°C.

H1NMR spectrum (δ, DMSO-d6): 3.8 (3H, s); 7.9 (1H, d, J=8.5 Hz/3.5 Hz); 8.1 (1H, d, J=8.5 Hz); 8.2 (1H, d, J=3.5 Hz); 9.0 (1H, s); 10.2 (1H, s).

Example 42.

Synthesis of 6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XLII).

Conducted according to the methodology described in example 2, using the product (XLI). Get 25 g (68%) of product (XLII). TPL 282-284°C.

H1NMR spectrum (δ, DMSO-d6

In the examples 43-82 retrieves various substituted p-phenylenediamine in accordance with the scheme (II). These examples are using different amines.

Example 43.

Synthesis of 1-(4-nitrophenyl)-pyrrolidine (XLIII).

A mixture of 4-chloronitrobenzene (16 g, 0.1 mol) and 30 ml of pyrrolidine (25.5 g, 0.36 mol) is heated with stirring under reflux at a temperature of about 80-85°C. Upon completion the reaction mixture is diluted with water (200-300 ml). The formed product in the form of a thick oil RUB clean before hardening and separated by filtration. Thus obtained product was then purified by passing through a layer of silica gel (CSC, 60100 μm) in the system hexane-ether. The fractions containing the product was concentrated in vacuo. Obtain 13.6 g (71%) of product XLIII.

LC-Mass (M+N)+: 193

Example 44.

Synthesis of 4-pyrrolidin-1-yl-aniline (XLIV).

Obtained in the previous example, 1-(4-nitrophenyl)-pyrrolidin (13.6 g, 0.07 mol) is dissolved in 100 ml of pure methanol and hydronaut in the presence of palladium on charcoal (10% wt., 1.5 g., 1.4 mmol) in 2-2 .5 ATM and a temperature of not more than 20°With the installation Parr Instruments (USA). Upon completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. Obtain 8.1 g (70%) of product XLIV.

LC-Mass (M+N)+: 163

<> Example 45.

Synthesis of 1-(4-nitrophenyl)-piperidine (XLV).

Conducted according to the technique shown in example 43, using instead of pyrrolidine piperidine. Obtain 17.6 g (85%) of product XLV.

LC-Mass (M+H)+: 207

Example 46.

Synthesis of 4-piperidine-1-yl-aniline (XLVI).

Conducted according to the methodology described in example 44, using the product (XLV). Get 12 g (80%) of product XLVI.

LC-Mass (M+N)+: 177.

Example 47.

Synthesis of 4-methyl-1-(4-nitrophenyl)-piperidine (XLVII).

Conducted according to the technique shown in example 43, using instead of pyrrolidine 4 methylpiperidin. Obtain 17.1 g (77%) of product XLVII.

LC-Mass (M+H)+: 221.

Example 48.

Synthesis of 4-(4-methylpiperidin-1-yl)-aniline (XLVIII).

Conducted according to the methodology described in example 44, using the product (XLVII) Obtain 12 g (80%) of product XLVIII.

LC-Mass (M+H)+: 191

Example 49.

Synthesis of 3-methyl-1-(4-nitrophenyl)-piperidine (IL).

Conducted according to the technique shown in example 43, using instead of pyrrolidine 3 methylpiperidin. Obtain 16.2 g (73%) of product IL.

LC-Mass (M+N)+: 221.

Example 50.

Synthesis of 4-(3-methylpiperidin-1-yl)-aniline (L).

Conducted according to the methodology described in example 44, using the product (IL) Obtain 10.5 g (77%) of product L.

LC-Mass (M+N)+: 191

Example 51.

Synthesis of 3,5-dimethyl-1-(4-nitrophenyl)-piperidine (LI).

Conducted according to the technique shown in example 43, and the through instead of pyrrolidine 3,5-dimethylpiperidin. Obtain 17.8 g (76%) of product LI.

LC-Mass (M+N)+: 235.

Example 52.

Synthesis of 4-(3,5-dimethylpiperidin-1-yl)-aniline (LII).

Conducted according to the methodology described in example 44, using the product (LI) Obtain 11.2 g (72%) of product LII.

LC-Mass (M+H)+: 205.

Example 53.

Synthesis of 4-hydroxy-1-(4-nitrophenyl)-piperidine (LIII).

Conducted according to the technique shown in example 43, using instead of pyrrolidine 4-hydroxypiperidine. Obtain 16.7 g (75%) of the product LIII.

LC-Mass (M+N)+: 223.

Example 54.

Synthesis of 4-(4-hydroxypiperidine-1-yl)-aniline (LIV).

Conducted according to the methodology described in example 44, using the product (LIII). Obtain 12.1 g (84%) of product LIV.

LC-Mass (M+N)+: 193.

Example 55.

Synthesis of 3-hydroxy-1-(4-nitrophenyl)-piperidine (LV).

Conducted according to the technique shown in example 43, using instead of pyrrolidine 3-hydroxypiperidine. Obtain 15.2 g (69%) of product LV.

LC-Mass (M+H)+: 223.

Example 56.

Synthesis of 4-(3-hydroxypiperidine-1-yl)-aniline (lvis).

Conducted according to the methodology described in example 44, using the product (LV) Obtain 11.2 g (79%) of product LVI.

LC-Mass (M+H)+: 193.

Example 57.

Synthesis of 1-(4-nitrophenyl)-piperidine-4-ethylcarboxylate (LVII).

Conducted according to the technique shown in example 43, using instead of pyrrolidine utilizedabated. Obtain 20.7 g (74%) of product LVII.

LC-Mass (M+N)+: 279.

the example 58.

Synthesis of 4-(4-carbomethoxybiphenyl-1-yl)-aniline (LVIII).

Conducted according to the methodology described in example 44, using the product (LVII) Obtain 15.2 g (83%) of product LVIII.

LC-Mass (M+H)+: 249.

Example 59.

Synthesis of 1-(4-nitrophenyl)-piperidine-3-ethylcarboxylate (LIX).

Conducted according to the technique shown in example 43, using instead of pyrrolidine utilipath. Obtain 18.6 g (67%) of product LIX.

LC-Mass (M+N)+: 279.

Example 60.

Synthesis of 4-(3-carbomethoxybiphenyl-1-yl)-aniline (LX).

Conducted according to the methodology described in example 44, using the product (LIX) Obtain 13.1 g (79%) of the product LX.

LC-Mass (M+H)+: 249.

Example 61.

Synthesis of 1-(4-nitrophenyl)-piperidine-4-carbamide (LXI).

A mixture of 4-chloronitrobenzene (16 g, 0.1 mol) and isonipecotamide (27.5 g, 0.22 mol) in 50 ml of dimethylformamide is heated with stirring under reflux at a temperature of about 100°C. Upon completion the reaction mixture is diluted with water (200-300 ml). The formed product in the form of a thick oil RUB clean before hardening and separated by filtration. Thus obtained product was then purified by passing through a layer of silica gel (CSC, 60/100 µm) in the system hexane-ethyl acetate. The fractions containing the product was concentrated in vacuo. Obtain 15.8 g (63%) of product LXI.

LC-Mass (M+N)+: 250.

Example 62.

Synthesis of 4-(4-carbamoylpiperidino-1-yl)-aniline (LXII).

The wire is t by the method, shown in example 44, using the product (LXI). Obtain 10.1 g (76%) of product LXII.

LC-Mass (M+H)+: 220.

Example 63.

Synthesis of cyclohexyl-methyl-(4-nitrophenyl)-amine (LXIII).

Conducted according to the technique shown in example 43, using instead of pyrrolidine N-methylcyclohexylamine. Obtain 14.2 g (60%) of product LXIII.

LC-Mass (M+N)+: 235.

Example 64.

Synthesis of N-cyclohexyl-N-methyl-para-phenylenediamine (LXIX).

Conducted according to the methodology described in example 44, using the product (LXIII). Obtain 8.7 g (71%) of product LXIX.

LC-Mass (M+N)+: 205.

Example 65.

Synthesis of 1-methyl-4(4-nitrophenyl)-piperazine (LXV).

Conducted according to the technique shown in example 43, using instead of pyrrolidine N-methylpiperazin. Obtain 15.3 g (69%) of product LXV.

LC-Mass (M+H)+: 222.

Example 66.

Synthesis of 4-(4-methyl-piperazin-1-yl)-aniline (LXVI).

Conducted according to the methodology described in example 44, using the product (LXV). Obtain 9.6 g (72%) of product LXVI.

LC-Mass (M+N)+: 192.

Example 67.

Synthesis of 1-[4-(4-nitrophenyl)-piperazine-1-yl]-ndimethylacetamide (LXVII).

Conducted according to the methodology described in example 61, using instead of isonipecotamide N-acetylpiperidine. Obtain 19.1 g (77%) of product LXVII.

LC-Mass (M+H)+: 250.

Example 68.

Synthesis of 1-[4-(4-AMINOPHENYL)-piperazine-1-yl]-ndimethylacetamide (LXVIII).

Conducted according to the methodology described in example 44, using the-W product (LXVII). Obtain 11.6 g (79%) of product LXVIII.

LC-Mass (M+H)+: 220.

Example 69.

Synthesis of furan-2-yl-[4-(4-nitrophenyl)-piperazine-1-yl]-amide (LXIX).

Conducted according to the methodology described in example 61, using instead of isonipecotamide N-sharperson. Obtain 19.8 g (66%) of product LXIX.

LC-Mass (M+N)+: 302.

Example 70.

Synthesis of furan-2-yl-[4-(4-AMINOPHENYL)-piperazine-1-yl]-amide (LXX).

Conducted according to the methodology described in example 44, using the product (LXIX). Obtain 15.3 g (86%) of product LXX.

LC-Mass (M+N)+: 272.

Example 71.

Synthesis of 1-benzyl-4(4-nitrophenyl)-piperazine (LXXI).

Conducted according to the technique shown in example 43, using instead of pyrrolidine N-benzylpiperazine. Obtain 17.3 g (58%) of product LXXI.

LC-Mass (M+N)+: 298.

Example 72.

Synthesis of 4-(4-benzyl-piperazin-1-yl)-aniline (LXXII).

Obtained in the previous example, 1-benzyl-4(4-nitrophenyl)-piperazine (17.3 g, 0.06 mol) is dissolved in 150 ml of methanol, bring the temperature of the reaction mixture up to 40-45°and then contribute hydrazine hydrate (80%, 10 ml, 0.15 mol) and further portions (supporting uniform boiling and gas development) freshly prepared Raney-Nickel. As the reaction temperature in the reaction mass support in the region of 45-55°C. Upon completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. Thus obtained product cleaned the Ute pass through a layer of silica gel (KSK, 60100 μm) in the system chloroform-methanol. The fractions containing the product was concentrated in vacuo. Obtain 9.1 g (58%) of product LXXII.

LC-Mass (M+N)+: 268.

Example 73.

Synthesis of 1-(4-nitrophenyl)-4-phenyl-piperazine (LXXIII).

Conducted according to the technique shown in example 43, using instead of pyrrolidine N-phenylpiperazin. Obtain 16.3 g (58%) of product LXXIII.

LC-Mass (M+H)+: 284.

Example 74.

Synthesis of 4-(4-phenyl-piperazine-1-yl)-aniline (LXXIV).

Conducted according to the methodology described in example 44, using the product (LXXIII). Obtain 10.3 g (70%) of product LXXIV.

LC-Mass (M+N)+: 254.

Example 75.

Synthesis of 2-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (LXXV).

Conducted according to the technique shown in example 43, using instead of pyrrolidine tetrahydroisoquinoline. Obtain 16.3 g (65%) of product LXXV.

LC-Mass (M+H)+: 255.

Example 76.

Synthesis of 4-(3,4-dihydro-1H-isoquinoline-2-yl)-aniline (LXXVI).

Conducted according to the methodology described in example 44, using the product (LXXV). Obtain 9.5 g (66%) of product LXXVI.

LC-Mass (M+N)+: 225.

Example 77.

Synthesis of 1-(4-nitrophenyl)-4-pyrid-2-yl-piperazine (LXXVII).

Conducted according to the methodology described in example 61, using instead of isonipecotamide 2-pyridineboronic. Obtain 15.6 g (55%) of product LXXVII.

LC-Mass (M+H)+: 285.

Example 78.

Synthesis of 4-(4-pyrid-2-yl-piperaz-1-yl)-aniline (LXXVIII).

Conducted according to the technique, which can be found in example 44, with the use of the product (LXXVII). Obtain 9.8 g (70%) of product LXXVIII.

LC-Mass (M+H)+: 255.

Example 79.

Synthesis of 2-[4-(4-nitrophenyl)-piperazine-1-yl]-pyrimidine (LXXIX).

Conducted according to the methodology described in example 61, using instead of isonipecotamide 2-pyrimidinylpiperazine. Obtain 16.8 g (59%) of product LXXIX.

LC-Mass (M+N)+: 286.

Example 80.

Synthesis of 4-(4-pyrimid-2-yl-piperaz-1-yl)-aniline (LXXX).

Conducted according to the methodology described in example 44, using the product (LXXIX). Obtain 10.7 g (71%) of product LXXX.

LC-Mass (M+N)+: 256.

Example 81.

Synthesis of 2-[benzyl-(4-nitrophenyl)-amino]-ethanol (LXXXI).

Conducted according to the technique shown in example 43, using instead of pyrrolidine N-benzylethanolamine. Obtain 14.8 g (54%) of product LXXXI.

LC-Mass (M+N)+: 273.

Example 82.

Synthesis of 2-[benzyl-(4-AMINOPHENYL)-amino]-ethanol (LXXXII).

Conducted according to the technique shown in example 72, using the product (LXXXI). Obtain 9.2 g (70%) of product LXXXII.

LC-Mass (M+H)+: 243.

In the examples 83-127 retrieves the target compounds, having the General formula (1), in accordance with the scheme (III).

Example 83.

Synthesis of 3-[(4-dimethylamino-phenylamino)-methyl]-5,6,7-trimetoksi-1H-quinoline-2-it (LXXXIII).

The mixture of substances XXXIV (2.63 g, 10 mmol) and N,N-dimethyl-para-phenylenediamine (1.5 g, 11 mmol) is dissolved in 50 ml of dry dichloroethane. The reaction mixture was stirred with n is grebanier at a temperature of ˜ 70°C for 1 hour and further contribute portions with vigorous stirring triacetoxyborohydride sodium (3.5 g, 16.5 mmol). Upon completion of the reaction (control - TLC, chloroform-methanol) and the mixture is cooled, diluted with water and soda solution, the layers separated, the organic layer is dried over anhydrous sodium sulfate (magnesium) and concentrate under reduced pressure. The selected product is recrystallized from ethyl acetate. Obtain 1.87 g (49%) of product LXXXIII. TPL 193-194.

LC-Mass (M+N)+: 384.

H1NMR spectrum (δ, DMSO-d6): 2.8 (3H, s); 3.6 (3H, s); 3.7 (3H, s); 3.75 (3H, s); 4.0 (2H, d, J=5 Hz); 5.2 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 6.7 (1H. s); 7.6 (1H, s); 11.6 (1H, broadened).

Example 84.

Synthesis of 3-[(4-dimethylamino-phenylamino)-methyl]-6-ethyl-1H-quinoline-2-it (LXXXIV).

Conducted according to the technique shown in example 83, using the XIV instead XXXIV. Obtain 1.44 g (45%) of product LXXXIV. TPL 228-229°C.

LC-Mass (M+H)+: 322.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.3 Hz); 2.6 (2H, q, J=7.3 Hz); 2.7 (6N, s); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J-8.5 Hz); 6.65 (2H, d, J=8.5 Hz); 7.2 (1H, d, J=8.5 Hz); 7.3 (1H, d, J=8.5 Hz); 7.4 (1H, d, J=3.0 Hz); 7.7 (1H, s); 11.6 (1H, broadened peak).

Example 85.

Synthesis of 6-ethoxy-3[(4-pyrrolidin-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LXXXV).

Conducted according to the technique shown in example 83, using compounds VIII and XLIV as initial reagents. The floor is with 1.58 g (43%) of product LXXXV. TPL 248-250°C.

LC-Mass (M+H)+: 364.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 1.8 (4H, m); 3.0 (4H, m), 4.0 (4H, superposition of quadruplet with J=7.5 Hz) and a doublet with J=5 Hz); 5.2 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 6.7 (1H, d, J=8.5/3.25 Hz); 6.8 (1H, d, J=3.25 Hz); 7.4 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.4 (1H, broadened peak).

Example 86.

Synthesis of 7-methoxy-3[(4-piperidine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LXXXVI).

Conducted according to the technique shown in example 83, using compounds XII and XLVI as initial reagents. Obtain 1.98 g (55%) of product LXXXVI. TPL 240-242°C.

LC-Mass (M+N)+: 364.

H1NMR spectrum (δ, DMSO-d6): 1.4 (2H, m); 1.6 (4H, m); 2.8 (4H, m); 3.7 (3H, s); 4.0 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.6 (3H, m); 6.8 (1H, s); 7.4 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 87.

Synthesis of 7-ethoxy-3[(4-piperidine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LXXXVII).

Conducted according to the technique shown in example 83, using compounds XXVI and XLVI as initial reagents. Obtain 1.92 g (51%) of product LXXXVII. TPL 258-260°C.

LC-Mass (M+N)+: 378.

H1NMR spectrum (δ, DMSO-d6): 1.3 (3H, t, J=7.5 Hz); 1.5 (2H, m); 1.6 (4H, m); 2.9 (4H, m); 4.1 (4H, superposition of quadruplet with J=7.3 Hz) and a doublet with J=5 Hz); 5.4 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (3H, the superposition of the 2N - d with J=8.5 Hz, 1H, j with J=8.5 Hz); 6.8 (1H, d, J=3 Hz); 7.4 (1H, d, J=8.5 Hz); 7.65 (1H, s); 11.4 (1H, broadened peak).

Example 88.

inches 7-methyl-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LXXXVIII).

Conducted according to the technique shown in example 83, using the compound VI and 4-morpholine-4-yl-aniline as starting reagents. Obtain 1.77 g (51%) of product LXXXVIII. TPL 263-265°C.

LC-Mass (M+N)+: 350.

H1NMR spectrum (δ, DMSO-d6): 2.39 (3H, s); 2.8 (4H, m); 3.6 (4H, m); 4.0 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 7.0 (1H, d, J=8.5 Hz); 7.1 (1H, s); 7.4 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 89.

Synthesis of 6-ethoxy-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LXXXIX).

Conducted according to the technique shown in example 83, using the compound VIII and 4-morpholine-4-yl-aniline as starting reagents. Obtain 1.94 g (51%) of product LXXXIX. TPL 228-229°C.

LC-Mass (M+N)+: 380.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 2.8 (4H, m); 3.6 (4H, m); 3.9 (2H, q, J=7.5 Hz); 4.0 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H. d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.0 (3H, m); 7.2 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 90.

Synthesis of 6-isopropyl-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it (LDL).

Conducted according to the technique shown in example 83, using the connection XXXII and 4-morpholine-4-yl-aniline as starting reagents. Obtain 1.52 g (40%) of the product XC. TPL 258-259°C.

LC-Mass (M+N)+: 378.

H1NMR spectrum (δ, DMSO-d6): 1.2 (6N, d, J=7.3 Hz); 2.9 (4H, m); 3.6 (4H, m); 4.1 (2H, d, J=5 Hz); 5.4 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 7.2(1H, d, J=8.5 Hz); 7.3 (1H, d, J=8.5 Hz); 7.4 (1H, d, J=3.0 Hz); 7.7 (1H, s); 11.6 (1H, broadened peak).

Example 91.

Synthesis of 7[(4-morpholine-1-yl-phenylamino)-m-ethyl-5H-[1,3]dioxolo[4.5]quinoline-6-she (XIC).

Conducted according to the technique shown in example 83, using the connection XX and 4-morpholine-4-yl-aniline as starting reagents. Obtain 1.45 g (38%) of product XIC. TPL 270-274°C (decomp).

LC-Mass (M+N)+: 380.

H1NMR spectrum (δ, DMSO-d6): 2.9 (4H, m); 3.7 (4H, m); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.0 (2H, s); 6.5 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 6.9 (1H, s); 7.1 (1H, s); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 92.

Synthesis of 6-methyl-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XIIC).

Conducted according to the technique shown in example 83, using compound II and XLVIII as initial reagents. Obtain 1.76 g (49%) of product XIIC. TPL 256-258°C.

LC-Mass (M+N)+: 362.

H1NMR spectrum (δ, DMSO-d6): 1.0 (3H, d, J=7.5 Hz); 1.3 (3H, m); 1.7 (2H, m); 2.2 (3H, s); 2.5 (2H, m); 3.2 (2H, m); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.2 (2H, m); 7.4 (1H, s); 11.5 (1H, broadened peak).

Example 93.

Synthesis of 7-methoxy-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XIIIC).

Conducted according to the technique shown in example 83, using compounds XII and XLVIII as initial reagents. Obtain 1.88 g (50%) of the product XIIIC. TPL 242-243°C.

LC-Mass (M+H)+: 378.

H1NMR spectrum of the (δ , DMSO-d6): 0.9 (3H, d, J=7.5 Hz); 1.2 (2H, m); 1.4 (1H, m); 1.6 (2H, m); 2.5 (2H, m); 3.3 (2H, m); 3.9 (3H, s); 4.1 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (3H, m); 6.8 (1H, s); 7.5 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.5 (1H, broadened peak).

Example 94.

Synthesis of 7-methyl-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XIVC).

Conducted according to the technique shown in example 83, using compounds VI and XLVIII as initial reagents. Obtain 1.91 g (53%) of product XIVC. TPL 254-255°C.

LC-Mass (M+N)+: 362.

H1NMR spectrum (δ, DMSO-d6): 1.09 (3H, d, J=7.5 Hz); 1.3 (3H, m); 1.6 (2H, m); 2,4 (3H, s); 2.5 (2H, m); 3.4 (2H, m); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.0 (1H, d, J=3 Hz); 7.45 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.5 (1H, broadened peak).

Example 95.

Synthesis of 6-methyl-3{[4-(3-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XVC).

Conducted according to the technique shown in example 83, using the compound (II) and XLV as initial reagents. Obtain 1.56 g (43%) of product XVC. TPL 233-234°C.

LC-Mass (M+H)+362.

H1NMR spectrum (δ, DMSO-d6): 0.8 (4H, m); 1.6 (4H, m); 2.0 (1H, m); 2.3 (3H, s); 2.4 (1H, m); 3.2 (2H, m, overlapped with a signal of H2O); 4.0 (2H. d, J=5 Hz); 5.4 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 7.2 (2H, m); 7.3 (1H, s); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 96.

Synthesis of 5,6,7-trimetoksi-3{[4-(3-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (NEKRESI).

Hold on is eodice, shown in example 83, using compounds XXXIV and XLV as initial reagents. Obtain 1.94 g (44%) of product NEKRESI. TPL 179-180°C.

LC-Mass (M+N)+: 438.

H1NMR spectrum (δ, DMSO-d6): 0.9 (4H, m); 1.7 (4H, m); 2.1 (1H, m); 2.4 (1H, m); 3.7 (3H, s); 3.8 (3H, s); 3.84 (3H, s); 4.1 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (1H, s); 6.75 (2H, d, J=8.5 Hz); 7.8 (1H, s); 11.5 (1H, broadened peak).

Example 97.

Synthesis of 6-ethoxy-3{[4-(3,5-dimethyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XVIIC).

Conducted according to the technique shown in example 83, using compounds VIII and LII as initial reagents. Obtain 1.88 g (46%) of product XVIIC. TPL 179-180°C.

LC-Mass (M+H)+: 406.

H1NMR spectrum (δ, DMSO-d6): 0.8-1.0 (3H, d, J=7.5 Hz); 1.3 (3H, t, J=7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 3.0-3.4 (2H, m); 3.9 (2H, q, J=7.5 Hz); 4.1 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.1 (3H, m); 7.2 (1H,d, J=8.5 Hz); 7.7 (1H, s); 11.5 (1H, broadened peak).

Example 98.

Synthesis of 3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (XVIIIC).

Conducted according to the technique shown in example 83, using the connection XXX and LIV as initial reagents. Obtain 1.88 g (46%) of product XVIIIC. TPL 226-227 of the°C.

LC-Mass (M+H)+: 350.

H1NMR spectrum (δ, DMSO-d6): 1.5 (2H, m); 1.8 (2H, m); 2.5 (2H, m); 3.2 (2H, m); 3.6 (1H, m); 4.1 (2H, d, J=5 Hz); 4.4 (1H, d, J=4.0 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.1 (1H, t, J=8.5 Hz); 7.3 (1H, is, J=8.5 Hz); 7.45 (1H, t, J=8.5 Hz); 7.6 (1H, d, J=8.5 Hz); 7.8 (1H, s); 12.0 (1H, broadened peak).

Example 99.

Synthesis of 3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-8-methyl-1H-quinoline-2-she (IC).

Conducted according to the technique shown in example 83, using the connection XXX and LIV as initial reagents. Obtain 1.49 g (41%) of product IC. TPL 208-209°C.

LC-Mass (M+N)+: 364.

H1NMR spectrum (δ, DMSO-d6): 1.5 (2H, m); 1.65 (2H, m); 2.3 (3H, s); 2.6 (2H, m), 3.19 (2H, m); 3.60 (1H, m); 4.1 (2H, d, J=5 Hz); 4.4 (1H, d, J=4.5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.0 (1H, t, J=8.5 Hz); 7.25 (1H, d, J=8.5 Hz); 7.4 (1H, d, J=8.5 Hz); 7.7 (1H, s); 10.8 (1H, broadened peak).

Example 100.

Synthesis of 3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7,8-dimethyl-1H-quinoline-2-she (C).

Conducted according to the technique shown in example 83, using compounds XVI and LIV as initial reagents. Obtain 1.67 g (44%) of product C. TPL 208-209°C.

LC-Mass (M+N)+: 378.

H1NMR spectrum (δ, DMSO-d6): 1.55 (2H, m); 1.65 (2H, m); 2.3 (6N, s); 2.45 (2H, m); 3.20 (2H, m); 3.50 (1H, m); 4.0 (2H, d, J=5 Hz); 4.4 (1H, d, J=4.5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 6.95 (1H, d, J=8.5 Hz); 7.20 (1H, d, J=8.5 Hz); 7.65 (1H, s); 10.8 (1H, broadened peak).

Example 101.

Synthesis of 8-{[4-(4-hydroxypiperidine-1-yl)-phenylamino]-methyl}-2,3-dihydro-6N-[1,4]like[2,3-g]-quinoline-7-she (CI).

Conducted according to the technique shown in example 83, using compounds XXII and LIV as the source is of agentov. Obtain 1.95 g (48%) of the product CI. TPL 257-259°C.

LC-Mass (M+N)+: 408.

H1NMR spectrum (δ, DMSO-d6): 1.3 (2H, m); 1.6 (2H, m); 2.45 (2H, s); 3.15 (2H, m); 3.4 (1H, m); 4.0 (2H, d, J=5 Hz); 4.3 (4H, m); 4.4 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 6.85 (1H, s); 7.0 (1H, s); 7.5 (1H, s); 11.6 (1H, broadened peak).

Example 102.

Synthesis of 7-{[4-(4-hydroxypiperidine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-she(CII).

Conducted according to the technique shown in example 83, using compounds XXII and LIV as initial reagents. Obtain 1.79 g (46%) of product CII. TPL 234-235°C(decomp).

LC-Mass (M+N)+: 394.

H1NMR spectrum (δ, DMSO-d6): 1.4 (2H, m); 1.7 (2H, m); 2.5 (2H, m); 3.0 (2H, m); 3.5 (1H, m); 4.0 (2H, d, J=5 Hz); 4.5 (1H, broadened); 5.5 (1H, t, J=5 Hz); 6.0 (2H, s); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.8 (1H, s); 7.0 (1H, s); 7.5 (1H, s); 11.0 (1H, broadened peak).

Example 103.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it (CIII).

Conducted according to the technique shown in example 83, using compounds VI and LVI as initial reagents. Obtain 1.97 g (54%) of product III. TPL 214-216°C.

LC-Mass (M+N)+: 364.

H1NMR spectrum (δ, DMSO-d6): 1.1 (1H, m); 1.4 (1H, m); 1.6 (1H, m); 1.9 (1H, m); 2.2 (3H, s); 2.49 (2H, m); 3.3 (2H, m); 4.0 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H. so J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.0 (1H, d, 1=3.0 Hz); 7.45 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.6 (1H, broadened the IR).

Example 104.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-ethyl-1H-quinoline-2-it (CIV).

Conducted according to the technique shown in example 83, using compounds XIV and LVI as initial reagents. Obtain 1.65 g (44%) of product CIV. TPL 213-214°C.

LC-Mass (M+N)+: 378.

H1NMR spectrum (δ, DMSO-d6): 1.1 (4H, m); 1.4 (1H, m); 1.6 (1H, m); 1.9 (1H, m); 2.2 (2H, m); 2.49 (2H, m); 3.3 (2H, m); 4.0 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.2 (2H, m); 7.4 (1H, s); 7.6 (1H, s); 11.5 (1H, broadened peak).

Example 105.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-propyl-1H-quinoline-2-she (CV).

Conducted according to the technique shown in example 83, using compounds XXXVIII and LVI as initial reagents. Obtain 1.27 g (32%) of the product CV. TPL 217-218°C.

LC-Mass (M+H)+: 392.

H1NMR spectrum (δ, DMSO-d6): 0.9 (3H, t, J=7.5 Hz); 1.0-1.9 (6N, m); 2.4 (1H, m); 2.5 (1H, m); 2.65 (2H, t, J=7.5 Hz); 3.0 (4H, m); 3.5 (1H, m); 4.0 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.25 (2H, m); 7.4 (1H. C); 7.70 (1H, s); 11.5 (1H, broadened peak).

Example 106.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-isopropyl-1H-quinoline-2-it (CVI).

Conducted according to the technique shown in example 83, using compound XXXII and LVI as initial reagents. Obtain 1.43 g (37%) of product CVI. TPL 219-220°C.

LC-Mass (M+N)+: 392.

H1YAM the range (δ , DMSO-d6): 1.0 (7H, m); 1.4 (1H, m); 1.7 (1H, m); 1.9 (1H, m); 2.2 (1H, m); 2.9 (1H, m); 3.1 (1H, m); 3.5 (1H, m); 4.0 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 7.1 (2H, d, J=8.5 Hz); 7.3 (2H, d, J=8.5 Hz); 7.4 (1H, s); 7.6 (1H, s); 11.5 (1H, broadened peak).

Example 107.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-tertbutyl-1H-quinoline-2-it (CVII).

Conducted according to the technique shown in example 83, using compounds XXXVI and LVI as initial reagents. Obtain 1.75 g (43%) of product CVII. TPL 243-245°C.

LC-Mass (M+N)+: 406.

H1NMR spectrum (δ, DMSO-d6): 1.2 (10H, m); 1.5 (1H, m); 1.7 (1H, m); 1.9 (1H, m); 2.3 (1H, m); 2.5 (1H, m); 3.2 (1H, m); 3.6 (1H, m); 4.1 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.2 (2H, d, J=8.5 Hz); 7.5 (2H, m); 7.7 (1H, s); 11.5 (1H, broadened peak).

Example 108.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6,7-dimethyl-1H-quinoline-2-she (VIII).

Conducted according to the technique shown in example 83, using compounds XVIII and LVI as initial reagents. Obtain 2.05 g (54%) of product VIII. TPL 260-262°C(decomp.).

LC-Mass (M+N)+: 378.

H1NMR spectrum (δ, DMSO-d6): 1.2 (1H, m); 1.5 (1H, m); 1.7 (1H, m); 1.9 (1H, m); 2.2 (3H, s); 2.25 (3H, s); 2.45 (2H, m); 3.1 (1H, m); 3.2 (1H, m); 3.5 (1H, m); 4.0 (2H, q, j 1=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, 1=8.5 Hz); 7.0 (1H, s); 7.35 (1H, m); 7.6 (1H, s); 11.5 (1H, broadened peak).

Example 109.

Synthesis of 3-{[4-(3-guide the hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7-methoxy-1H-quinoline-2-it (CIX).

Conducted according to the technique shown in example 83, using compounds XII and LVI as initial reagents. Obtain 1.91 g (50%) of the product CIX. TPL 239-241°C.

LC-Mass (M+N)+: 380.

H1NMR spectrum (δ, DMSO-d6): 1.1 (1H, m); 1.5 (1H, m); 1.7 (1H, m); 1.9 (1H, m); 2.3 (1H, t, J=7.5 Hz); 2.5 (1H, t, J=7.5 Hz); 3.2 (2H, m); 3.6 (1H, m); 3.8 (3H, s); 4.0 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.8 (1H, d, J=8.5 Hz); 6.9 (1H, s); 7.5 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.5 (1H, broadened peak).

Example 110.

Synthesis of 3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-5,6,7-trimetoksi-1H-quinoline-2-she (AU).

Conducted according to the technique shown in example 83, using compounds XXXIV and LVI as initial reagents. Obtain 2.12 g (48%) of the product SH. TPL 209-210°C.

LC-Mass (M+H)+: 440.

H1NMR spectrum (δ, DMSO-d6): 1.1 (1H, m); 1.5 (1H, m); 1.7 (1H, m); 1.9 (1H, m); 2.3 (1H, t, J=7.5 Hz); 2.4 (1H, t, J=7.5 Hz); 3.2 (2H, m); 3.5 (1H, m); 3.7 (3H, s); 3.8 (6N, s); 4.1 (2H, d, J=5 Hz); 4.5 (1H, d, J=4.5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (3H, m); 7.8 (1H, s); 11.5 (1H, broadened peak).

Example 111.

Synthesis of 7-{[4-(3-hydroxypiperidine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-she (CXI).

Conducted according to the technique shown in example 83, using compounds XX and LVI as initial reagents. Obtain 1.91 g (49%) of product XI. TPL 264-267°C(decomp).

LC-Mass (M+H)+: 394.

H1NMR spectrum (δ, DMSO-d6): 1.1 (1H, m); 1.5 (1H. m); 1.7 (1H,m); 1.9 (1H, m); 2.3 (1H, t, J=7.5 Hz); 2.4 (1H, t, J=7.5 Hz); 3.0 (2H, m); 3.6 (1H, m); 4.1 (2H, d, J=5 Hz); 4.6 (1H, d, J=4.5 Hz); 5.4 (1H, t, J=5 Hz); 6.0 (2H, s); 6.3 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz): 6.65 (1H. s); 7.1 (1H, s); 7.7 (1H, s); 11.4 (1H, broadened peak).

Example 112.

Synthesis of 8-{[4-(3-hydroxypiperidine-1-yl)-phenylamino]-methyl}-2,3-dihydro-6N-[1,4]like[2,3-g]-quinoline-7-it (CXII).

Conducted according to the technique shown in example 83, using compounds XXII and LIV as initial reagents. Obtain 2.12 g (52%) of product CXII. TPL 270-272°C.

LC-Mass (M+H)+: 408.

H1NMR spectrum (δ, DMSO-d6): 1.1 (1H, m); 1.5 (1H, m); 1.7 (1H, m); 1.9 (1H. m); 2.3 (1H, t, J=7.5 Hz); 2.4 (1H, t, J=7.5 Hz); 3.1 (1H, m); 3.4 (1H, m); 3.5 (1H, m); 4.0 (2H, d, J=5 Hz); 4.25 (4H, m); 4.5 (1H, d, J=4.0 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.8 (1H, s); 7.0 (1H, s); 7.5 (1H, s); 11.5 (1H, broadened peak).

Example 113.

Synthesis of 3-{[4-(4-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it (CXIII).

Conducted according to the technique shown in example 83, using compounds VI and LVIII as initial reagents. Obtain 2.01 g (48%) of product CXIII. TPL 234-236°C.

LC-Mass (M+H)+: 420.

H1NMR spectrum (δ, DMSO-d6): 1.1 (3H, t, J=7.5 Hz); 1.65 (2H, m); 1.90 (2H, m); 2.4 (4H, superposition 3H/1H/m); 2.5 (2H, m); 3.4 (2H, m), 4.0 (4H, superposition kV/J=7.5 Hz and d/J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.0 (1H, d, J=8.5 Hz); 7.1 (1H, d, J=8.5 Hz); 7.4(1H, d, J=8.5 Hz); 7.7 (1H, c); 11.5 (1H, broadened peak).

Example 114.

Sin is ez 3-{[4-(4-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-8-methyl-1H-quinoline-2-it (CXIV).

Conducted according to the technique shown in example 83, using compounds IV and LVIII as initial reagents. Obtain 2.08 g (50%) of the product CXIV. TPL 178-179°C.

LC-Mass (M+H)+: 420.

H1NMR spectrum (δ, DMSO-d6): 1.0 (3H, t, J=7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 2.4 (4H, superposition 3H/1H/m); 2.6 (2H, m); 3.4 (2H, m), 4.0 (4H, superposition kV/J=7.5 Hz and d/J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.1 (1H, T. J=8.5 Hz); 7.25 (1H, d, J=8.5 Hz); 7.5 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.0 (1H, broadened peak).

Example 115.

Synthesis of 3-{[4-(3-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-6-methoxy-1H-quinoline-2-it (CXV).

Conducted according to the technique shown in example 83, using compounds XLII and LX as initial reagents. Obtain 2.10 g (48%) of product CXV. TPL 171-172°C.

LC-Mass (M+N)+: 436.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 1.6 (2H, m); 2.0 (2H. m); 2.55 (2H, m); 2.8 (1H, m); 3.30 (2H, m); 3.60 (3H, s); 4.0 (4H, superposition kV/J=7.5 Hz and d/J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 7.1 (2H, superposition of 1H/1H/d with J=8.5 Hz); 7.25 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.0 (1H, broadened peak).

Example 116.

Synthesis of 3-{[4-(3-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-7-methoxy-1H-quinoline-2-it (CXVI).

Conducted according to the technique shown in example 83, using compounds XII and LX as initial reagents. Obtain 1.93 g (44%) of product CXVI. TPL 193-194°C.

LC-Mass (M+N)+: 436.

H1-Alspector (δ , DMSO-d6): 1.1 (3H, t, J=7.5 Hz); 1.6 (2H, m); 2.0 (2H, m); 2.6 (2H, m); 2.7 (1H, m); 3.40 (2H, m); 3.75 (3H, s); 4.0 (4H, superposition kV/J=7.5 Hz and d/J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (3H, m); 6.8 (1H, s); 7.5 (1H, d, J=8.5 Hz); 7.7 (1H, s); 11.0 (1H, broadened peak).

Example 117.

Synthesis of 3-{[4-(cyclohexyl-methyl-amino)-phenylamino]-methyl}-5,8-dimethyl-1H-quinoline-2-it (CXVII).

Conducted according to the technique shown in example 83, using compound X and LXIV as initial reagents. Obtain 1.77 g (46%) of product CXVII. TPL 195-196°C.

LC-Mass (M+N)+: 390.

H1NMR spectrum (δ, DMSO-d6): 1.0-1.8 (6N, s); 2.3 (3H, s); 2.35 (3H, s); 2.5 (3H, s); 3.2 (1H, m, overlapping with H2O); 4.1 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.15(1H, d, J=8.5 Hz); 8.0 (1H, s); 10.5 (1H, broadened peak).

Example 118.

Synthesis of 7-{[4-(cyclohexyl-methyl-amino)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-she (CXVIII).

Conducted according to the technique shown in example 83, using compounds XX and LXIV as initial reagents. Obtain 2.23 g (55%) of product CXVIII. TPL 209-210°C.

LC-Mass (M+N)+: 406.

H1NMR spectrum (δ, DMSO-d6): 1.0-1.9 (6N, s); 2.55 (3H, s); 3.2 (1H, m, overlapping with H2O); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.0 (2H, s); 6.5 (2H, d, J=8.5 Hz); 6.65 (2H, d, J=8.5 Hz); 6.8 (1H, s); 7.1 (1H, s); 10.5 (1H, broadened peak).

Example 119.

Synthesis of 6-methyl-3-{[4-(4-methyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it(CXIX).

About the W ill result on the method shown in example 83, using compound II and LXVI as initial reagents. Obtain 2.27 g (63%) of product CXIX. TPL 275-277°C.

LC-Mass (M+H)+: 363.

H1NMR spectrum (δ, DMSO-d6): 2.1 (3H, s); 2.3 (3H, s); 2.35 (4H, m); 2.8 (4H, m); 4.1 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.6 (2H, d, J=8.5 Hz); 7.2 (2H, m); 7.25 (1H, s); 7.6 (1H, s); 11.6 (1H, broadened peak).

Example 120.

Synthesis of 5,8-dimethyl-3-{[4-(4-methyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (SHH).

Conducted according to the technique shown in example 83, using compound X and LXVI as initial reagents. Get 1.99 g (53%) of product SHH. TPL 225-226°C.

LC-Mass (M+N)+: 377.

H1NMR spectrum (δ, DMSO-d6): 2.1 (3H, s); 2.4 (10H, m); 2.9 (4H, m); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.2 (1H, d, J=8.5 Hz); 8.0 (1H, ); 10.6 (1H, broadened peak).

Example 121.

Synthesis of 3-{[4-(4-acetyl-piperazine-1-yl)-phenylamino]-methyl}-7-ethoxy-1H-quinoline-2-it (CXXI).

Conducted according to the technique shown in example 83, using compounds XXVI and LXVIII as initial reagents. Obtain 2.05 g (49%) of product CXXI. TPL 266-267°C.

LC-Mass (M+N)+: 421.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=8.5 Hz); 2.0 (3H, s); 2.8 (4H, m); 3.6 (4H, m), 4.0 (4H, superposition kV/J=8.5 Hz and d/J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.8 (4H, m); 7.4 (1H, d, J=8.5 Hz); 7.6 (1H); 11.6 (1H, broadened peak).

Example 122.

Synthesis of 7-[4-(4-acetyl-piperazine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-she (CXXII).

Conducted according to the technique shown in example 83, using compounds XX and LXVIII as initial reagents. Obtain 1.97 g (47%) of product CXXII. TPL 280°C(decomp).

LC-Mass (M+N)+: 421.

H1NMR spectrum (δ, DMSO-d6): 1.9 (3H, s); 2.9 (4H. m); 3.6 (4H, m); 4.0 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.0 (2H, s); 6.5 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.9 (1H, s); 7.1 (1H, s); 7.8 (1H, s); 11.6 (1H, broadened peak).

Example 123.

Synthesis of 3-({4-[4-(furan-2-carbonyl)-piperazine-1-yl]-phenylamino}-methyl)-5,7-dimethyl-1H-quinoline-2-it (CXXIII).

Conducted according to the technique shown in example 83, using compounds XXVIII and LXX as initial reagents. Obtain 2.12 g (46%) of product CXXIII. TPL 203-204°C.

LC-Mass (M+H)+: 457.

H1NMR spectrum (δ, DMSO-d6): 2.25 (3H, s); 2.35 (3H. s); 3.0 (4H, m); 3.75 (4H, m); 4.05 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.6 (3H, m); 6.8 (3H, m); 7.0 (2H, m); 7.8 (1H, s); 7.9 (1H, s); 11.6 (1H, broadened peak).

Example 124.

Synthesis of 3-({4-[4-(furan-2-carbonyl)-piperazine-1-yl]-phenylamino}-methyl)-5,8-dimethyl-1H-quinoline-2-it (CXXIV),

Conducted according to the technique shown in example 83, using compound X and LXX as initial reagents. Obtain 1.94 g (42%) of product CXXIV. TPL 219-220°C.

LC-Mass (M+H)+: 457.

H1NMR spectrum (δ, DMSO-d6): 2.35 (3H, s); 2.4 (3H, s); 3.0 (4H, m); 3.75 (4H, m); 4.2 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.6 (3H, m); 6.75 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.0 (1H, d, J=3.5 Hz); 7.15 (1H, d, J=8.5 Hz); 7.8 (1H, s); 8.0 (1H, s); 11.6 (N. broadened peak).

Example 125.

Synthesis of 7-methyl-3-{[4-(4-benzyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (CXXV).

Conducted according to the technique shown in example 83, using soedineniya VI and LXXII as initial reagents. Obtain 2.27 g (63%) of product CXXV. TPL 236-237°C.

LC-Mass (M+N)+: 439.

H1NMR spectrum (δ, DMSO-d6): 2.3 (3H, s); 2.8 (4H, m); 3.2 (4H, overlapping with H2Oh); 3.45 (2H, s); 4.0 (2H, d, J=5 Hz); 5.6 (1H, t, J=5 Hz); 6.4 (2H, d, J=8.5 Hz); 6.7 (2H, d, J=8.5 Hz); 6.95 (1H, d, J=8.5 Hz); 7.1 (1H, s); 7.25 (4H, m); 7.4 (1H, d, J=8.5 Hz); 7.7 (1H, C); 11.6 (1H, broadened peak).

Example 126.

Synthesis of 5,6,7-trimetoksi-3-{[4-(4-phenyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it (CXXVI).

Conducted according to the technique shown in example 83, using compounds XXXIV and LXXIV as initial reagents. Obtain 2.63 g (53%) of product CXXVI. TPL 253-255°C.

LC-Mass (M+H)+: 501.

H1NMR spectrum (δ, DMSO-d6): 3.0 (4H, m); 3.7 (3H, s); 3.8 (3H, s); 3.85 (3H, s); 4.1 (2H, d, J=5 Hz); 5.5 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.6 (1H, s); 6.75 (3H, m); 6.9 (2H. d, J=8.5 Hz); 7.2 (2H, t, J=8.5 Hz); 7.8 (1H, s); 11.6 (1H, broadened peak).

Example 127.

Synthesis of 3-{[4-(3,4-dihydro-1H-isoquinoline-2-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it (CXXVII).

Conducted according to the technique shown in example 83, using compounds VI and LXXVI as initial reagents. Obtain 1.98 g (50%) of the product CXXVII. TPL 195-197°C(decomp.).

LC-Mass (M+N)+: 396.

H1-The Mr range (δ , DMSO-d6): 2.35 (3H, s); 2.8 (2H, t, J=7.5 Hz); 3.2 (2H, so J=7.5 Hz); 4.0 (2H, d, J=5 Hz); 4.1 (2H, s); 5.6 (1H, t, J=5 Hz); 6.5 (2H, d, J=8.5 Hz); 6.8 (2H, d, J=8.5 Hz); 6.9 (1H, d, J=8.5 Hz); 7.1 (5H, m); 7.4 (1H, d, J=8.5 Hz); 7.6 (1H, s); 11.6 (1H, broadened peak).

In the examples 128-131 retrieves the target compounds of General formula (2)having a free hydroxyl group and obtained by the scheme (IV).

Example 128.

Synthesis of 3-[(3,4-dihydroxy-phenylamino)-methyl]-5,7-dimethyl-1H-quinoline-2-it (CXXVIII).

A mixture of 2.0 g (10 mmol) of 5,7-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXVIII) and 1.8 g (12 mmol) of aminouracil (3,4-dimethoxyaniline) is heated in 6-8 ml of dimethylformamide at a temperature of 100-110°C for 20 minutes. The reaction mixture is cooled. The precipitation is filtered off, washed with ethanol (50 ml). The precipitate is suspended when heated in 100 ml of ethanol. To the resulting suspension is added in portions with heating and vigorous stirring 0.8 g (20 mmol) of sodium borohydride. The reaction mixture is refluxed for 1 hour (control - TLC, eluent: chloroform-methanol; 9-1). Upon termination of the reaction mixture is diluted with a small amount of water (20 ml), evaporated under reduced pressure to a volume of about 50 ml of the precipitation is filtered off, washed with water. The selected substance is thoroughly dried. The dried product (2.14 g, 6.3 mmol) is suspended in 100 ml of methylene chloride (freshly above the P 2O5) and cooled to -78°With outdoor bath: dry ice - acetone). To the mixture is added 15 ml of BBr3(15 mmol, 1M solution in methylene chloride). The reaction mixture was stirred at the same temperature for 1 hour, then slowly raise the temperature to room (for 1 hour) and incubated for 8 hours. Upon completion of the reaction, to the reaction mixture was added dropwise 10 dry methanol. The solvent is evaporated under reduced pressure and the resulting residue is recrystallized from ethanol with the addition of ether. Get 0,83 (27%) g of the product CXXVIII. TPL 261-264°C (decomp.).

H1NMR spectrum (δ, DMSO-d6): 2.3 (3H, s); 2.4 (3H, s); 4.4 (2H, broadened peak); 5.2 (broadened peak); 6.8 (3H, the superposition of the 1H/2H/d, J=8.5 Hz); 6.9 (2H, m); 7.0 (1H, s); 8.2 (1H, s); 9.6 (2H, broadened peak); 12.0 (1H, s).

Example 129.

Synthesis of 3-[(2,4-dihydroxy-phenylamino)-methyl]-6,7-dimethyl-1H-quinoline-2-it (CXXIX).

Carried out according to the method described in example 128, using the XVIII and 2,4-dimethoxyaniline as initial reagents. Obtain 0.97 g (31%) of product CXXIX. TPL 261-263°C (decomp.).

H1NMR spectrum (δ, DMSO-d6): 2.0 (3H, s); 2.1 (3H, s); 4.1 (2H, broadened peak); 6.2 (1H, d, J=8.5 Hz); 6.4 (1H, s); 7.0 (1H, d, J=8.5 Hz); 7.1 (1H, s); 7.3 (1H, s); 7.9 (1H, s); 9.5 (1H, broadened peak); 10.0 (1H, broadened peak); 10.5 (1H, broadened peak); 12.0 (1H, broadened peak).

Example 130.

Synthesis of 3-[(3,5-dihydroxy-penilai is about)-methyl]-6-methyl-1H-quinoline-2-it (SHHH).

Carried out according to the method described in example 128, using II and 3.5-dimethoxyaniline as initial reagents. Obtain 0.71 g (24%) of product SHHH. TPL 280-286°C (decomp.).

H1NMR spectrum (δ, DMSO-d6): 2.4 (3H, s); 4.1 (2H, broadened peak); 6.1 (3H, m); 7.2 (1H, d, J=8.5 Hz); 7.4 (1H, d, J=8.5 Hz); 7.45 (1H, d, J=3 Hz); 7.8 (1H, s); 8.5-10.5 (3H, broadened peak); 12.0 (1H, broadened peak).

Example 131.

Synthesis of 3-[(2-hydroxy-phenylamino)-methyl]-6-ethyl-1H-quinoline-2-it(CXXXI).

Carried out according to the method described in example 128, using the XIV and 2-methoxyaniline as initial reagents. Get 1,11 g (37%) of product CXXXI. TPL 239-240°C.

H1NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz); 2.6 (2H, q, J=7.5 Hz); 4.4 (2H, broadened peak); 6.8 (1H, t, J=8.5 Hz); 6.95 (1H, d, J=8.5 Hz); 7.1 (2H, superposition of d/t, J=8.5 Hz); 7.3 (1H, d, J=8.5 Hz); 7.4 (2H, superposition of 1H d/J=8.5 Hz, 1H from); 7.9 (1H, s); 10-12 (2H, broadened peaks).

Example 132. The method of conducting biological tests.

For inhibition of NO synthetase uses the above-described substances in concentrations from 0.1 nm. Murine macrophages (cell line RAW 264.7) were grown in DMEM containing 10% (v/v) calf serum and 3 mm L-glutamine, at 37°C / 5% CO2. For the induction of NO-synthetase in the reaction mixture, containing 400,000 cells/ml, were added lipopolysaccharide (LPS) from Salmonella typhi at a concentration of 5 μg/ml After incubation for 16 hours p is the same temperature of the medium was replaced by phosphate buffer Krebs-ringer with or without added test compounds. Under these conditions, cells were incubated for 4 hours at 37°C / 5% CO2. To determine the concentration of NO at the end of the incubation, the incubation medium was added an equal volume of 6 nm solution of diamino-fluorescein diacetate in phosphate buffer Krebs-ringer with subsequent determination of the fluorescence of the solution. As a result, subsequent analysis was to determine the concentration of each test compound at which the observed 50% inhibition of NO generation (IC50). For standard commercially available inhibitor L-NG-monomethyl-arginine (used as control) IC50was defined equal to 37 μM At protected in this patent inhibitors the value of this parameter ranges from 0.5 nm to 100 μm

When screening for pure enzyme, allowing to determine the selectivity of the steps described above substances in relation to various forms of NO-synthetase, the enzyme (recombinant murine inducible or endothelial NO-synthase, Sigma) and study the substance was preincubating for 35 minutes, after which to start the reaction system was added L-arginine. The composition of the incubation medium was 0.25 μCi [3H] arginine/ml, 120μM NADPH, 1 μM FAD and FMN, 10 μM BH4, 100nM CaM, 100 mM Hepes, 2,4 mM CaCl2, 24μM L-arginine, ImM EDTA, ImM DTT, pH 7.4. Incubation continued for 45 minutes, after which the reaction OST who was aliwalas adding a special stop buffer part 100 mM Hepes, pH 5.5, 3 mM EDTA, 3 mM EGTA, and the resulting [+H]-citrulline was separated from unreacted substrate by an ion-exchange resin DOWEX 50 W X 8-400. Inhibition of NOS was determined by the formation of L-[3H]-citrulline of L-[3H]-arginine. Measured in this way, the IC50for inducible NO synthetase ranges from 25 nm to 7μm the Degree of binding to the protected compounds with endothelial NO-synthase ranges from 0 to 50%, indicating a high selectivity of the compounds.

For inhibition of excessive conversion of arginine to NO by different pathological conditions with subsequent therapeutic effect used dosages, depending on the specific condition and individual characteristics of the subject. In the General case, apply the dosage from 1 to 100 μmole of substance per kilogram of body weight of the subject, the substance is dissolved in water or physiological solution. The method of introducing substances - oral. If necessary, the introduction of substances can be repeated.

To test the ability of the protected patent substances to inhibit caused by excessive secretion of NO pathological effects studies performed on Wistar rats. Was used 249 males 5-7 weeks of age, weighing 180±15, the Animals were kept under standard conditions (ambient temperature 22�B1; 2°With synchronized change of the light period of day from 8:00 to 20:00, night from 20:00 to 8:00) in cells of 5 pieces on the ground cut from food grade paper. Animals received standard pelleted food and water in standard drinking bottles ad libitum. The day before the experiment the rats under anesthesia (ketamine + xylazine) was used catheters in the femoral artery for registration of blood pressure in the femoral vein for injection of LPS. After surgery and during the experiment the animals were kept in individual cages.

The test substance was administered into the stomach probe in suspension substances in distilled pyrogen-free water. The control group of animals instead of the test substance was administered only water. The volume of injection was 0.2 ml / 100 g body weight (2 ml/kg). Each substance was administered in four doses from 1 to 100 μmol/kg, and each dosage of each analyte was administered to three animals. For the induction of NO-synthetase LPS was diluted in 0.9% NaCl and injected intravenously at a dose of 4 mg/kg in a volume of 100 ál/kg Effect was determined by the degree of inhibition of hypotensive shock reactions to the introduction of animals LPS, and in the subsequent analysis determined the effective concentration of substance at which demonstrated 50% inhibition of the response to the introduction of LPS (EU50). We protected in this patent inhibitora the value of this parameter ranges from 1.5 to 400 μ mol/kg

Table 1

The results of biological tests.
No.ExampleIC50IC50ID50(in vivo),
(cell)(enzyme)mkmolkg
830.031
840.029
850.010.31
860.0720.282.5
870.0216
880.013
890.0145,3
900.0097
910.0056
920.0720.410
930.0530.29
940.095
950.061
960.06
970.11
980.0160.56
990.0131.8
1000.038
1010.001315.3
1020.008
1030.019
1040.0190.4
0.0093
1060.037
1070.042
1080.00423.4
1090.015
1100.0027
1110.0065
1120.0067
1130.029
1140.0081
1150.033
1160.021
1170.26
1180.140
1190.0120.0354
1200.0064
1210.016
1220.0062
1230.014
1240.018
1250,034
1260.016
1270.026
12811.000
129Of 10,000
1302.100
1310.0986.1
IC50(cell) Activity of a substance as an inhibitor of inducible NO-synthase, measured on cell cultures (µmol).

IC50(enzyme) Activity of a substance as an inhibitor of inducible NO-synthase, measured on the enzyme (µmol).

ID50(in vivo) - the Ability of a substance to inhibit in what are called LPS reduced pressure, for the remaining products were not investigated.

Thus, the new amino - and hydroxy phenyl-3-aminomethyl-quinolone-2 exhibit significantly higher activity and a higher selectivity for NO-synthetase compared to known inhibitors, with no identified side effects, so you can use them as an active ingredient in biologically active compounds and pharmaceutical compositions.

1. Amino phenyl-3-aminomethyl-quinolone-2 General formula (1)

where R1, R2, R3, R4 are independently the same or different, and

R1 is selected from H, Alk, OAlk;

R2 is selected from H, Alk, OAlk, OCF3;

R3 is selected from H, Alk, OAlk, SCH3;

R4 is selected from H, Alk, OAlk;

or R2, R3 is selected from (CH2)3, OCH2O, OCH2CH2O;

R5=H or Alk;

R6, R7, R9 are H;

R8 is independently selected from the following substituents:

where n=1, 2, 3;

Het represents a furan;

R represents hydrogen or alkyl.

2. Amino phenyl-3-aminomethyl-quinolone-2 according to claim 1, characterized in that they are selected from:

3-[(4-dimethylamino-phenylamino)-methyl]-5,6,7-trimetoksi-1H-quinoline-2-it;

6 ethoxy-3[(4-pyrrolidin-1-yl-phenylamino)-methyl]-1H-quinoline-2-it:

7-methoxy-3[(4-piperidine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it;

7 ethoxy-3[(4-piperidine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it;

7-methyl-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it:

6 ethoxy-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it;

6-isopropyl-3[(4-morpholine-1-yl-phenylamino)-methyl]-1H-quinoline-2-it;

7[(4-morpholine-1-yl-phenylamino)-m-ethyl-5H-[1,3]dioxolo[4,5g]quinoline-6-it;

6-methyl-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

7-methoxy-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

7-methyl-3{[4-(4-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

6-methyl-3{[4-(3-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

5,6,7-trimetoksi-3{[4-(3-methyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

6 ethoxy-3{[4-(3,5-dimethyl-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-8-methyl-1H-quinoline-2-it;

3-{[4-(4-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7,8-dimethyl-1H-quinoline-2-it;

8-{[4-(4-hydroxypiperidine-1-yl)-phenylamino]-m is Teal}-2,3-dihydro-6N-[1,4]like[2,3-g]-quinoline-7-it;

7-{[4-(4-hydroxypiperidine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-ethyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-propyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-isopropyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6-tertbutyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-6,7-dimethyl-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-7-methoxy-1H-quinoline-2-it;

3-{[4-(3-hydroxy-piperidine-1-yl)-phenylamino]-methyl}-5,6,7-trimetoksi-1H-quinoline-2-it;

7-{[4-(3-hydroxypiperidine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-it;

8-{[4-(3-hydroxypiperidine-1-yl)-phenylamino]-methyl}-2,3-dihydro-6N-[1,4]like[2,3-g]-quinoline-7-it;

3-{[4-(4-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it;

3-{[4-(4-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-8-methyl-1H-quinoline-2-it;

3-{[4-(3-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-6-methoxy-1H-quinoline-2-it;

3-{[4-(3-carboethoxy-piperidine-1-yl)-phenylamino]-methyl}-7-methoxy-1H-quinoline-2-it;

3-{[4-(cyclohexyl-methylamino)-phenylamino]-methyl}-5,8-dimethyl-1H-quinoline-2-it;

7-{[4-cyclohexyl-methyl-amino)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-it;

6-methyl-3-{[4-(4-methyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

5,8-dimethyl-3-{[4-(4-methyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

3-{[4-(4-acetyl-piperazine-1-yl)-phenylamino]-methyl}-7-ethoxy-1H-quinoline-2-it;

7-{[4-(4-acetyl-piperazine-1-yl)-phenylamino]-methyl}-5H-[1,3]dioxolo[4,5-g]-quinoline-6-it;

3-({4-[4-(furan-2-carbonyl)-piperazine-1-yl]-phenylamino}-methyl)-5,7-dimethyl-1H-quinoline-2-it;

3-({4-[4-(furan-2-carbonyl)-piperazine-1-yl]-phenylamino}-methyl)-5,8-dimethyl-1H-quinoline-2-it;

7-methyl-3-{[4-(4-benzyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

5,6,7-trimetoksi-3-{[4-(4-phenyl-piperazine-1-yl)-phenylamino]-methyl}-1H-quinoline-2-it;

3-{[4-(3,4-dihydro-1H-isoquinoline-2-yl)-phenylamino]-methyl}-7-methyl-1H-quinoline-2-it.

3. Hydroxy phenyl-3-aminomethyl-quinolone-2 General formula (2)

where R1, R2, R3, R4 are independently the same or different, and

R1 is selected from H, Alk, OAlk;

R2 is selected from H, Alk, OAlk, OCF3;

R3 is selected from H, Alk, OAlk, SCH3;

R4 is selected from H, Alk, OAlk;

R5=H or Alk;

at least one of the

R6, R7, R8 or R9 is IT, while the rest represent N.

4. Hydra is cypresstree phenyl-3-aminomethyl-quinolone-2 according to claim 3, characterized in that they are selected from:

3-[(3,4-dihydroxy-phenylamino)-methyl]-5,7-dimethyl-1H-quinoline-2-it;

3-[(2,4-dihydroxy-phenylamino)-methyl]-6,7-dimethyl-1H-quinoline-2-it;

3-[(3,5-dihydroxy-phenylamino)-methyl]-6-methyl-1H-quinoline-2-it;

3-[(2-hydroxy-phenylamino)-methyl]-6-ethyl-1H-quinoline-2-it.

5. The method of obtaining amino phenyl-3-aminomethyl-quinolone-2 according to claim 1, including the interaction of the corresponding substituted 2-chinolin-3-carbaldehydes with the appropriate substituted p-phenylenediamine and subsequent recovery of the resulting Schiff bases.

6. The method according to claim 5, characterized in that the corresponding substituted 2-chinolin-3-carbaldehyde obtained by hydrolysis of the corresponding 2-chloro-quinoline-3-carbaldehyde when they are boiling in 80-90%acetic acid for 4-12 h, followed by cooling the reaction mixture, separating and washing the precipitate.

7. The method according to claim 6, characterized in that the corresponding 2-chloro-quinoline-3-carbaldehyde produced by interaction of dimethylformamide and POCl3when cooled education formuliruya mixture of Vilsmeier, by adding thereto a substituted acetanilide, exposure to this reaction mixture at room temperature, heated to 90-100°and holding at that temperature for 8-24 h followed by hydrolysis in a large excess of finely izmelchennoe what about the ice.

8. The method according to claim 7, characterized in that substituted acetanilides use compounds containing electron-donating substituents in the benzene ring.

9. The method according to claim 7, characterized in that substituted acetanilides use compounds containing electron-withdrawing substituents in the benzene ring.

10. The method according to any of claims 7 to 9, characterized in that the substituted acetanilide add to the mixture of Vilsmeier in small portions under vigorous stirring and cooling.

11. The method according to any of claims 7 to 9, characterized in that the substituted acetanilide add to the mixture of Vilsmeier small portions at a temperature of about 50°C.

12. The method according to any of claims 7 to 11, characterized in that the corresponding 2-chloro-quinoline-3-carbaldehyde before hydrolysis purified by recrystallization from acetone, chloroform or ethyl acetate.

13. The method according to any of pp.5-12, characterized in that the corresponding substituted 2-chinolin-3-carbaldehyde purified by recrystallization from acetic acid or dimethylformamide.

14. The method according to claim 5, characterized in that the corresponding substituted p-phenylenediamine is obtained from the original 4-chloronitrobenzene with formation of the corresponding N,N-substituted p-nitrobenzene with their subsequent recovery.

15. The method according to 14, characterized in that adowanie corresponding N,N-substituted p-nitrobenzene is carried out in an excess of the appropriate amine, or in the environment of a secondary amine, or in the environment of dimethylformamide.

16. The method according to item 15, wherein the corresponding N,N-substituted p-nitrobenzene purified by recrystallization or column chromatography on silica gel.

17. The method according to any of p-16, characterized in that the recovery of the corresponding N,N-substituted p-nitrobenzene is carried out by hydrogenation in the presence of palladium on charcoal.

18. The method according to any of p-16, characterized in that the recovery of the corresponding N,N-substituted p-nitrobenzene spend hydrazine hydrate in the presence of Raney Nickel.

19. The method according to any of PP-18, characterized in that the corresponding substituted p-phenylenediamine purified by recrystallization or column chromatography on silica gel.

20. The method according to any of pp.5-19, characterized in that the Schiff bases restore, not separating from the reaction mixture.

21. The method of claim 20, wherein for repair use traceability sodium or cyanoborohydride sodium.

22. The method according to any of pp.5-19, characterized in that the Schiff's base before restoring separated from the reaction mixture.

23. The method according to item 22, wherein the selected Schiff bases restore with sodium borohydride in alcohol.

24. The method of obtaining hydroxy phenyl-3-amine the Teal-quinolone-2 according to claim 3, including the interaction of the corresponding substituted 2-chinolin-3-carbaldehydes with relevant anisidine, recovery of the resulting Schiff bases with the formation of appropriate alilovic esters and their subsequent cleavage of Lewis acids.

25. The method according to paragraph 24, wherein the splitting alilovic esters Lewis acids is carried out in inert solvents at temperatures below -50°C, followed by gradual heating to room temperature, holding at that temperature and processing absolutized alcohol.

26. The method according to any of PP and 25, characterized in that the Lewis acid used tribromide boron.

27. The method according to paragraph 24, wherein the corresponding substituted 2-chinolin-3-carbaldehyde obtained by hydrolysis of the corresponding 2-chloro-quinoline-3-carbaldehyde when they are boiling in 80-90%acetic acid for 4-12 h, followed by cooling the reaction mixture, separating and washing the precipitate.

28. The method according to item 27, wherein the corresponding 2-chloro-quinoline-3-carbaldehyde produced by interaction of dimethylformamide and POCl3when cooled education formuliruya mixture of Vilsmeier, by adding thereto a substituted acetanilide, exposure to this reaction mixture at room temperature, heated to 90-100°and exposure etc is this temperature for 8-24 h followed by hydrolysis in a large excess of crushed ice.

29. The method according to p, characterized in that as substituted acetanilides use compounds containing electron-donating substituents in the benzene ring.

30. The method according to p, characterized in that as substituted acetanilides use compounds containing electron-withdrawing substituents in the benzene ring.

31. The method according to any of PP-30, characterized in that the substituted acetanilide add to the mixture of Vilsmeier in small portions under vigorous stirring and cooling.

32. The method according to any of p-31, characterized in that the substituted acetanilide add to the mixture of Vilsmeier small portions at a temperature of about 50°C.

33. The method according to any of p-32, characterized in that the corresponding 2-chloro-quinoline-3-carbaldehyde before hydrolysis purified by recrystallization from acetone, chloroform or ethyl acetate.

34. The method according to any of PP-33, characterized in that the corresponding substituted 2-chinolin-3-carbaldehyde purified by recrystallization from acetic acid or dimethylformamide.

35. Biologically active compound, inhibition of NO-synthase, characterized in that it comprises as an active ingredient the compound according to claim 1 or 2, obtained by the method according to any of pp.5-25.

36. The pharmaceutical composition inhibiting NO-synthetase, ex is different, however, it contains as an active ingredient the compound according to claim 1 or 2, obtained by the method according to any of pp.5-25.



 

Same patents:

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

The invention relates to new substituted benzo/a/acridinium formula (II), where R1and R2are independently IT, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R1and R2together represent-OCH2O-; R3represents H; R5and R6are independently H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R5and R6together represent-co2O-; R7represents H or (C1-C8)alkyl, or R1, R2, R3, R5, R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R1and R2together represent-OCH2O-; R2and R3together represent-co2O-; R5and R6together represent-OCH2O-; R7represents H or (C1-C8)alkyl, provided that one of R1and R2is (C1-C8)alkoxy, or R1and R2together represent-co2O-, or R1, R5and R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R2

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them

The invention relates to a new process for the synthesis of some derivatives of dihydro-2,3-benzodiazepine and is particularly applicable to the process of obtaining these compounds with high enantiomeres purity and outputs

The invention relates to 3-substituted derivatives of 3H-2,3-benzodiazepine, method of production thereof and to pharmaceutical compositions based on them

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

FIELD: medicine, organic chemistry, pharmaceuticals.

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

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

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, chemical technology.

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

EFFECT: improved method of synthesis.

8 cl, 3 ex

FIELD: organic chemistry, medicine.

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

EFFECT: valuable pharmacological properties of derivatives.

3 cl, 1 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means phenyl or naphthyl comprising the following substitutes: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl (-CF3), phenyl or heteroaryl representing aromatic 5-membered ring that comprises sulfur atom; each among R2, R3, R4 and R6 and independently of one another means hydrogen atom, hydroxy-group, (lower)-alkenyl, halogen atom, (lower)-alkyl or (lower)-alkoxy-group wherein at least one radical among R2, R3, R4 and R6 doesn't mean hydrogen atom, or R3 and R4 are bound and also bound with carbon atoms to which they are bound and form ring, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-O-, -O-CH=CH-, -CH=CH-CH=CH-, -(CH2)3-5-, -O-(CH2)2-3 or -(CH2)2-3-O- wherein R2 and R6 have above given values; R5 means (lower)-alkoxy-, (lower)-alkenyloxy-group, or ; R7 means hydrogen atom or (lower)-alkyl; R8 means (lower)-alkyl; R9 means hydrogen atom; R10 means phenyl or naphthyl that can be mono- or poly-substituted with -CF3; n means 1, 2 or 3, and wherein the bond between Ca carbon atom and Cb carbon atom represents carbon-carbon single or double bond, and to their pharmaceutically acceptable salts and esters also. Indicated compounds can be used as therapeutically active substances in treatment and/or prophylaxis of diseases mediated by agonists of PPAR-α and/or PPAR-γ receptors, for example, in treatment of diabetes.

EFFECT: valuable medicinal properties of compounds.

24 cl, 167 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

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

15 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

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

15 cl, 14 tbl, 118 ex

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