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

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment 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.

19 cl, 1 tbl, 95 ex

 

The invention relates to organic chemistry and medicine, and is intended to produce compounds that inhibit NO-synthase, medicaments 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 regulating the tone of smooth muscles, which leads to the relaxation/contraction and, consequently, to the expansion and contraction of the blood vessels (cardiovascular disease, as well as various violations of functioning of the sexual organs) and intestines (gastrointestinal diseases).

2. In the operation 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 responses.

3. In neuropterida(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, namely, a new quinolone derivatives-2, are positioned as inhibitors of the so-called inducible form of NO-synthetase responsible for the generation of NO, mainly in faguoqitirute cells, and, therefore, participating in the NO action under the second paragraph of the above. Created on the basis of these substances lekarstvennye tools can be used to treat diseases associated with hyperactivity of this function, such as rheumatoid arthritis, asthma and the like. There are medicines used in these diseases, including action-based inhibitors of NO-synthetase. However, the effect on this enzyme substances with a structure like the one shown in this patent, previously described was not, as medicines are not enforced and are associated with NO-synthase they are much better than previously known inhibitors.

The present invention presents as a broad class of novel effective inhibitors of NO-synthetase. Suggests ways of synthesis of new derivatives of 3-aminomethylphenol-2, given the characteristics of the line the end of the connection.

The presence of NO in the body significantly affects many vital processes, for example: the tone of blood vessels, their permeability and many other conditions associated mainly with the circulatory and immune systems.

The synthesis of NO in the body is made from L-arginine. Currently there are three known isoforms of the enzyme that catalyzes the formation of nitric oxide from arginine, NO-synthetase. This:

1. the so-called endothelial NO-synthase, mediating the formation of NO in the endothelium smooth muscle and thus participating in the regulation of its tone and, consequently, blood pressure, intensity contractile activity of the intestines, etc.

2. inducible NO synthase, mediating the formation of NO in faguoqitirute the cells of the body, which leads to the development of inflammatory processes and associated side effects.

3. neuronal NO synthase, mediating the formation of NO in neurons of the Central nervous system and, therefore, participating in some of both physiological and pathological States (the latter should include, for example, stroke and epilepsy).

Among the analogues, inhibitors of NO-synthetase known various derivatives of arginine and related compounds (for example, D-arginine and so on).

However, most existing ing is beterov this enzyme differs insufficient selectivity to various isoforms that leads to the development of various side effects in the use of drugs based on them. For example, up to the present time unable to effectively block the inducible isoform of the enzyme that could find application, for example, in the treatment of arthritis or the effects of endotoxic shock associated with decreasing pressure, and not to affect endothelial, without breaking, thus, physiologically required the synthesis of nitric oxide.

Among the works carried out in the search for new effective inhibitors of NO-synthetase, there are such, which are modifications of the side chain of arginine molecules. For example in [1] a side chain of arginine is modified by including a 5 - or 6 - membered aromatic or heteroaromatic cycles (thiophene, benzene, pyridine and so on). 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 is necessary to note [2], which describes derivatives of 4-methyl-3,4-degidro-2-aminopiperidine.

Data on activity occurring among the derivatives of quinolone-2 the following: immunosuppressants, protivostala the global and antiallergic drugs [3]; substances used to treat hypertension, ischemia, myocardial infarction, angina, etc [4]; anti-allergic and anti-asthmatic substances [5]; substances used for the treatment of various forms of epilepsy, Alzheimer's disease, schizophrenia and multiple sclerosis [6, 7], anticonvulsants and similar substances [8].

Data on the possible activity of derivatives of 3-aminomethyl-2-quinolones against different isoforms of NO-synthetase in the scientific and patent literature is not found.

Task to be solved by the present invention is directed, is to obtain derivatives of 3-aminomethylphenol-2 with high activity against NO-synthetase, low-toxic for the human body if not detected the presence of side effects.

Based on the foregoing, the present invention offers a novel inhibitors of arginine website inducible NO synthetase that does not affect endothelial her form in a physiologically acceptable concentration range, as well as the way they are received. New inhibitors of arginine website inducible NO synthetase is derived 3-aminomethyl-2-quinolones and related compounds. 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, the concentration described in the above 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 NO by such conditions as pathologically low blood pressure, septic shock or autoimmune disorder, that is, the routes of administration and dosage of the above inhibitors sufficient to achieve a therapeutic effect.

The problem is solved in that the derivative C-aminomethyl-2-quinolones have the General formula (I):

in which R1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-och2O-; 3,4-CH2-; 2,3-(CH2)4-; 4-OCF3; -CONR1R2; -SO2NR1R2; 2-Ph; -OPh; -COOR; -NHCOR; 2-och3, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 4-och3; 5-iPr; all isomers of di-OAlk, di-Alk, di-Hal, Hal-Alk, Hal,-OAlk;

R3=N or CH3;

X is selected from H; 6-(C1-C3)Alk; 6-iPr; 6-iBu; 7-(C1-C2)Alk; 8-(C1-C2)Alk; 6,7-CH2-CH2-; 6-(C1-C2)OAlk; 6-OCF3; 6-OPh; 7-(C1-C2)OAlk; 7-SCH3; 6,7-och2O-; 6,7-och2CH2O-; 5,6,7-och3; 6-F.

The task is also solved by the fact that derivatives of C-aminomethyl-2-quinolones have the General formula (2):

in R 1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-och2O-; 3,4-CH2-; 2,3-(CH2)4-; 4-OCF3; -CONR1R2; -SO2NR1R2; 2-Ph; -OPh; -COOR; -NHCOR; 2-och3, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 4-och3; 5-iPr; all isomers of di-OAlk, di-Alk, di-Hal, Hal-Alk, Hal,-OAlk;

R3=H or CH3;

X and Y are the same or different and selected from 7,8-CH3, 6,8-CH3; 5,8-CH3; 5,7-CH3; 6,7-CH3; 6,7-och3; 6-CH3,7-Cl.

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

in which R1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-och2O-; 3,4-CH2-; 2,3-(CH2)4-; 4-OCF3; -CONR1R2; -SO2NR1R2; 2-Ph; -OPh; -COOR; -NHCOR; 2-och3, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 4-och3; 5-iPr; all isomers of di-OAlk, di-Alk, di-Hal, Hal-Alk, Hal,-OAlk;

R3=N or CH3.

The synthesis of these compounds is based on the 2-chlorhydrin-3-carbaldehyde in four stages:

1) synthesis of the above carbaldehydes of substituted acetanilides (Example 1). At this stage there are two possible modes of carrying out reactions between the original connections: cooling reagent is (Example 1) or up to 50° (Example 5). As the source acetanilides by the given method is suitable compounds containing electrondonor substituents in the benzene ring or weak electroncapture deputies (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 time ranges from 8 to 24 hours, the optimum temperature of the reaction mixture is 90-100°C. the Selection received at this stage of carbaldehydes is carried out by hydrolysis of the reaction mixture 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 product is used without further purification, but if necessary it can be recrystallized either from acetone, chloroform or from ethyl acetate;

2) the hydrolysis products obtained in the first stage, up to 2-chinolin-3-carbaldehyde. This is done by boiling 2-chloro-quinoline-3-carbaldehyde 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). It can be cleaned by recrystallization from acetic key is lots or from dimethylformamide;

3) synthesis of Schiff bases, necessary to obtain the final structures based on direct interaction carbaldehyde obtained in the second stage, with the primary amines (Example 3). Optimal conditions for short - time heat 1 EQ. aldehyde with a slight excess (˜1.5 EQ) of a primary amine in a medium of dimethylformamide. The use of the latter allows the reaction in a homogeneous medium and in a short time (less than 1 hour), which has a positive impact on the overall yield and purity of the reaction products. The output of Schiff bases obtained by the given method, is not less than 50%;

4) recovery of Schiff bases using reducing agents (Example 4). First of all, this recovery complex hydrides (sodium borohydride, Lamborgini and triacetoxyborohydride sodium, DIBORANE, and others), catalytic hydrogenation, etc. To obtain the target compounds were successfully used sodium borohydride in ethanol (methanol, isopropanol). The advantage of this method of synthesis is the low cost of reagents used, the ease of implementation of synthesis and ease of selection of the reaction products. Purification of the target compounds is quite simple and is simple recrystallization. If necessary, you can repeat this procedure with the label of another solvent.

Below are examples of the preparation of compounds of the General formula (1), (2) or (3).

Example 1.

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

To formuliruya mixture of Vilsmeier obtained by addition with simultaneous cooling 170 ml (1.75 mol) POCl3to 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 melkorazmernaja 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. So pl. 127-128°C (lit. 124-125°s With ethyl acetate, [9]).

H-NMR 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 (product I), dissolved in 250 ml of a mixture of the criminal code of Usna acid-water (10:1 ratio) and heated at boiling for 3-4 hours.

Upon completion of the reaction from the boiling solution begins to fall out of the target product. The reaction mixture is cooled, the precipitate filtered, washed with a mixture of alcohol-water, then with water to remove residual acetic acid. Get 22 g (65%) product (II). Analytically pure sample is obtained by recrystallization from dimethylformamide. So pl. 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, ush. peak).

Example 3.

Synthesis of 3-[(2,4-dimethoxyaniline)methyl]-6-methyl-1H-quinoline-2-she(III).

A solution of 1.9 g (0.01 mol) of 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde obtained in Example 2 (product II), and 2 g (0.014 mol) of 2,4-dimethoxyaniline heated in 5-7 ml of dimethylformamide at 110-120°C for 1 hour. Upon completion of the reaction the mixture is cooled, the precipitated precipitate is filtered off and washed with alcohol. Allocate 1.5 g (48%) of product (III). So pl. 290-292°C. thus Obtained substance is used further without additional purification.

Example 4.

Synthesis of 3-[(2,4-dimethoxyaniline)methyl]-6-methyl-1H-quinoline-2-she (IV).

In 50 ml of ethanol at 50°suspended 1.5 g (0,0048 mol) of 3-[(2,4-dimethoxyaniline)-methyl]-6-methyl-1H-quinoline-2-it is obtained in Example 3 (product III). Next, in small portions contribute 0.4 g (0.01 mol) sodium borohydride and reaction the second mixture is heated with stirring for 2 hours. Monitoring the reaction by TLC (chloroform:methanol 10:1). Upon termination of the reaction mixture is diluted with 5 ml of water, evaporated prior to the crystallization. The mixture is cooled, the precipitated precipitate is filtered off, washed with water alcohol, water. After recrystallization from ethanol obtain 0.96 g (60%) of target compound (product IV)corresponding to the General structural formula 1. So pl. 198-199°C.

H-NMR spectrum (δ, DMSO-d6): 2.25 (3H, s), 3.6 (3H, s), 3.8 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.0 (1H, t, J=7.5 Hz), 6.25 (1H, d, J=8.5Hz), 6.4 (1H, d, J=8.5 Hz), 6.5 (1H, d, J=3.5 Hz), 7.3 (2H, superposition of two d, J=8.5 Hz), 7.4 (1H, d, J=3.5 Hz), 7.65 (1H, s), 11.5 (1H, ush. peak).

Example 5.

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

Formilitary the mixture is prepared analogously to example 1, is heated and the temperature is about 50°add small portions of 37.3 g (0.25 mol) of N-orthotrichaceae. 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 melkorazmernaja 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). Obtain 28 g (54%) of product (V). Analytically pure sample is obtained by recrystallization from acetone or chlorine is form. So pl. 134-136°C (lit. 137-138°s With ethyl acetate, [9]).

H-NMR 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 6.

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

This example shows a variant embodiment of the invention in the case where R3=CH3.

Obtained according to example 2 of the aldehyde (II) in an amount of 5.2 g (0.025 mol) is dissolved by heating in 250 ml of methanol, then add a solution of KOH (2,875 g, 0.05 mol). To the resulting reaction mixture was added 7.5 ml of methyl iodide and refluxed for 5 hours. The reaction mixture is poured onto 300 g of finely crushed ice and acidified with hydrochloric acid. The precipitation is filtered off, washed with a large amount of dilute alkali (3-5%), then with water until neutral. After recrystallization from acetonitrile obtain 2.2 g (40%) of the product (VI). So pl. 195°C (lit. 198°C [11]).

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 3.6 (3H, s), 7.05 (1H, t, J=8.5 Hz), 7.15 (1H, d, J=3.5 Hz), 7.5 (1H, d, J=8.5 Hz/J=3.5 Hz), 8.4 (3H, s), 10.2 (3H, s).

Example 7.

Synthesis of 3-[(4-ethoxybenzylidene)-methyl]-1,6-dimethyl-1H-quinoline-2-she (VII).

This example shows the synthesis of Schiff bases, when R3=CH3.

A mixture of 2.2 g (0.01 mol) of the compound obtained in example 6 (product VI), and 2 g (0.014 mol) of para-phenetidine heated p and boiling in 10 ml of dioxane for 3 hours. Upon completion of the reaction, the solvent is evaporated in vacuo, the resulting material is recrystallized from ethanol, dried and produce 1.2 g (36%) of the product (VII). Thus obtained substance is used further without additional purification.

Example 8.

Synthesis of 3-[(4-ethoxybenzylidene)-methyl]-1,6-dimethyl-1H-quinoline-2-she (VIII).

This example shows the final step of the synthesis of the target product in the case when R3=CH3.

Get on the methodology described in example 4, but as the source reagent is used as a compound obtained according to example 7 (VII). Allocate 0.7 g (55%) of the target product (VIII). So pl. 116-117°C.

H-NMR spectrum (δ, DMSO-d6): 1.33 (3H, t, J=7.5 Hz), 2.21 (3H, s), 3.58 (3H, s), 3.89 (4H, m), 4.58 (1H, t, J=7.5 Hz), 6.67 (2H, d, J-8.5 Hz), 6.71 (2H, d, J=8.5 Hz), 6.92 (1H, d, J=8.5 Hz), 7.02 (1H, d, J=3.5 Hz), 7.12 (1H, ), 7.27 (1H, d, J=8.5 Hz).

Example 9.

Synthesis of 3-[1-(2,4-dimethoxyaniline)-ethyl]-6-methyl-1H-quinoline-2-she (IX).

This example shows the final step of the synthesis of the target product using other reducing agent.

To a suspension of 0.93 g (of 0.003 mol) of the product (III)obtained according to the method described in example 3 in 50 ml of dry toluene prikapivatsya solution metalmilitia (to 0.007 mol) in ether (30 ml). The temperature of the reaction mixture increases and bring to the boiling point of toluene. As the reaction suspension is dissolved. Next, actionnow mixture was poured into a cooled saturated solution of ammonium chloride. The target product is extracted with dichloromethane (2×50 ml), dried and concentrated under reduced pressure. The resulting residue is separated by flash chromatography using as eluent a mixture of hexane-ethyl acetate. Fraction, which contains the target product concentrate. The residue is recrystallized from a mixture of ether-hexane (1:1) and obtain 0.25 g (24%) of the target product (IX). So pl. 187-188°C.

H-NMR spectrum (δ, DMSO-d6): 1.39 (3H, s), 2.21 (3H, s), 3.72 (3H, s), 3.77 (3H, s), 4.22 (1H, m), 6.05 (1H, d, J=8.5 Hz), 6.19 (1H, d, J=3.5 Hz), 6.2 (1H, d, J=8.5 Hz), 6.55 (1H, d, J=7.5 Hz), 6.91 (1H, d, J=3.5 Hz), 6.98 (1H, d, J=3.5 Hz), 7.09 (1H, d, J=8.5 Hz), 7.43 (1H, d, J=8.5 Hz), 10.5 (1H, ush. peak).

In the examples 10-26 shows for various carbaldehydes that corresponds to the first stage of the synthesis. These examples differ in the use of different reagents for different substituents in the target products, the corresponding structural formula 1. Modes in examples 10-17, 20, 22, 24-26 as in example 1, that is, cooling the mixture, in examples 18, 19, 21, 23 as in example 5, that is, by heating the initial mixture.

Example 10.

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

Get 42 g (82%) of product X. So pl. 143-144°C (lit. 144-145°s With ethyl acetate, [9]).

H-NMR 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 11.

Synthesis of 2-chloro-6-atelinae-3-kerbal is Devida (XI).

Get 35 g (64%) of product XI. So pl. 84-86°C.

H-NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz), 2.8 (2H, q, J=7.5 Hz), 7.85 (1H, d/d, J=8.5/J=3.5 Hz), 7.95 (1H, d, J=8.5 Hz), 8.95 (1H, s), 10.4 (1H, s).

Example 12.

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

Get 40 g (68%) of the product (XII). So pl. 110-112°C.

H-NMR 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 13.

Synthesis of 2-chloro-6-tertbutylphenol-carbaldehyde (XIII).

Get 38 g (62%) of product XIII. So pl. 132-134°C.

H-NMR 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 14.

Synthesis of 2-chloro-7-atelinae-3-carbaldehyde (XIV).

Get 40 g (78%) of product XIV. So pl. 121-123°C.

H-NMR spectrum (δ, DMSO-d6): 1.3 (3H, t, J=7.5 Hz), 2.8 (2H, K, J=7.5 Hz), 7.5 (1H, d, J=3.5 Hz), 7.6 (1H, d, J=8.5 Hz/J=3.5 Hz), 8.4 (1H, d, J=8.5 Hz), 10.6 (1H, s).

Example 15.

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

Get 39 g (70%) of the product XV. So pl. 164-166°C.

H-NMR 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 16.

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

Get 44 g (78%) of product XVI. So pl. 116-118°C.

H-NMR 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 17.

Synthesis of 2-chloro-7,8-dimetilan the Lin-3-carbaldehyde (XVII).

Get 40 g (75%) of the product XVII. So pl. 106-108°C.

H-NMR 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 18.

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

Get 30 g (55%) of product XVIII. So pl. 172-174°C.

H-NMR 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 19.

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

Get 35 g (65%) of product XIX. So pl. 107-108°C (lit. 110-111°, [12]).

H-NMR 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 20.

Synthesis of 2-chloro-7-methylsulfonylamino-3-carbaldehyde (XX).

Get 47 g (80%) of product XX. So pl. 195-197°C (lit. 195-196°s With ethyl acetate, [9]).

H-NMR spectrum (δ, DMSO-d6): 2.5 (3H, s), 7.7 (1H, d, J=8.5 Hz/J=3.5 Hz), 8.35 (1H, d, J=3.5 Hz), 8.75 (1H, s), 10.6 (1H, s).

Example 21.

Synthesis of 2-chloro-6-methoxyquinoline-3-carbaldehyde (XXI).

Get 40 g (72%) of product XXI. So pl. 143-144°C (lit. 146-147°s With ethyl acetate, [9]).

H-NMR spectrum (δ, DMSO-d6): 3.9 (3H, s), 7.55 (1H, d, J=8.5 Hz/J=3.5 Hz), 7.9 (1H, d, J=8.5 Hz), 8.8 (1H, s), 10.4 (1H, s).

Example 22.

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

Get 45 g (81%) of product XXII. So pl. 187-189°C (lit. 197-198°s With ethyl acetate, [9]).

H-NMR 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 23.

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

Get 36 g (60%) of product XXIII. So pl. 168-170°C.

H-NMR 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 24.

Synthesis of 2-chloro-6,7-dimethoxyquinazolin-3-carbaldehyde (XXIV).

Get 45 g (75%) of the product XXIV. So pl. 214-216°C (lit. 213-215°s With ethyl acetate, [9]).

H-NMR spectrum (δ, DMSO-d6): 3.8 (3H, s), 3.9 (3H, s), 7.4 (1H, s), 7.6 (1H, s), 8.7 (1H, s), 10.4 (1H, s).

Example 25.

Synthesis of 6-chloro-[1,3]O-Cu2-O dioxolo[4,5-g]quinoline-7-carbaldehyde (XXV).

Get 40 g (72%) of product XXV. So pl. 188-190°C.

H-NMR 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 26.

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

Get 42 grams (73%) of product XXVI. So PL-228°C.

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

Examples 27-34 illustrate the second stage of the synthesis using different reagents, obtained in the first stage. The modes are identical to those given in example 2.

Example 27.

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

As a source of reagent is used, the product XXII. Get 22 g (64%) of product XXVII. So pl. 286-288°C.

H-NMR spectrum (δ, DMSO-d6): 3.8 (3H, s), 6.7 (1H, d, J=3.5 Hz), 6.8 (1H, d/d, J=8.5Hz/3.5 Hz), 7.8 (1H, d, J 8.5Hz), 8.4 (1H, s), 10.2 (1H, s), 12.0 (1H, ush. peak).

Example 28.

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

As a source of reagent is used, the product XXI. Get 25 g (73%) of product XXVIII. So pl. 282-284°C.

H-NMR spectrum (δ, DMSO-d6): 3.75 (3H, s), 7.2 (1H, d, J=3.5 Hz), 8.4 (1H, s), 10.4 (1H, s), 12.0 (1H, ush. peak).

Example 29.

Synthesis of 7-chloro-6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXIX).

As a source of reagent is used, the product XV. Get 21 g (55%) of product XXIX. So pl. 310-312°C.

H-NMR spectrum (δ, DMSO-d6): 2.4 (3H, s), 7.4 (1H, s), 7.7 (1H, s), 8.4 (1H, s), 10.2 (1H, s), 12.0(1H, USEC).

Example 30.

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

As a source of reagent is used, the product XXIV. Obtain 26.5 g (74%) of product XXX. TPL 236-238°C.

H-NMR 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, ush. peak).

Example 31.

Synthesis of 7-methylsulfanyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (XXXI).

As a source of reagent is used, the product XX. Obtain 28 g (76%) of product XXXI. So pl. 273-275°C.

H-NMR spectrum (δ, DMSO-d6): 2.5 (3H, s), 7.4 (1H, d, J=8.5 Hz/J=3.5 Hz), 7.5 (1H, d, J=3.5 Hz), 7.7 (1H, d, J=8.5 Hz), 8.4 (1H, s), 10.15 (1H, s), 12.0 (1H, ush. peak).

Example 32.

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

As the source reagent is used Avenue is the product XIII. Obtain 26.5 g (67%) of product XXXII. So pl. 260-262°C.

H-NMR spectrum (δ, DMSO-d6): 1.3 (N, s), 7.25 (1H, d, J=8.5 Hz/J=3.5 Hz), 7.40 (1H, d, J=8.5 Hz), 7.60 (1H, d, J=3.5 Hz), 8.75 (1H, s), 10.2 (1H, s), 12.1 (1H, s).

Example 33.

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

As a source of reagent is used, the product XVI. Obtain 24.5 g (78%) of product XXXIII. So pl. 253-254°C.

H-NMR 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, ush. peak).

Example 34.

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

As a source of reagent is used, the product XXV. Obtain 28 g (80%) of product XXXIV. So pl. °>300°C.

H-NMR 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, ush. peak).

Examples 35-90 illustrate the third and fourth stages of the synthesis, i.e. the synthesis of Schiff bases and their subsequent recovery, resulting in the formation of the target product, using different reagents, obtained in the previous stages.

Example 35.

Synthesis of 3-(benzo[1,3]dioxole-5-aminomethyl)-6-methyl-1H-quinoline-2-it (XXXV).

Conducted according to the methodology described in example 3 (the third stage), using the product XXXIV as a starting reagent. Obtain 1.85 g (60%) of product XXXV, which is used further without additional purification.

Prima is 36.

Synthesis of 3-(benzo[1,3]dioxole-5-aminomethyl)-6-methyl-1H-quinoline-2-it (XXXVI).

Conducted according to the methodology described in example 4 (the fourth stage), using the product XXXV as a starting reagent. Obtain 1.12 g (67%) of the target product XXXVI. So pl. 278-280°C.

H-NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.7 (1H, t, J=7.5 Hz), 5.8 (2H, s), 6.0 (1H, d, J=8.5 Hz), 6.3 (1H, d, J=3.5 Hz), 6.6 (1H, d, J=8.5 Hz), 7.3 (2H, superposition of two d, J=8.5 Hz), 7.35 (1H, d, J-3.5 Hz), 7.65 (1H, s), 11.5 (1H, ush. peak).

Example 37.

Synthesis of 3-[(1H-indazole-5-imino)-methyl]-6-methyl-1H-quinoline-2-it (XXXVII).

Conducted according to the technique shown in example 3, using the product XXXIV as a starting reagent. Obtain 2.03 g (45%) of product XXXVII, which is used further without additional purification.

Example 38.

Synthesis of 3-[(1H-indazole-5-amino)-methyl]-6-methyl-1H-quinoline-2-it (XXXVIII).

Conducted according to the technique described in example 4 using the product XXXVII as a starting reagent. Obtain 1.33 g (70%) of the target product XXXVIII. So pl. 293-295°C.

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.9 (1H, t, J=7.5 Hz), 6.5 (1H, d, J=3.5 Hz), 6.9 (1H, d, J=8.5 Hz), 7.25 (4H, m), 7.7 (1H, s), 11.5 (1H, ush. peak), 12.5 (1H,ush. peak).

Example 39.

Synthesis of 6-methyl-3-(chinolin-5-aminomethyl)-1H-quinoline-2-it (XXXIX).

Conducted according to the technique shown in example 3, using the product XXXIV as a source of real the NTA. Obtain 1.68 g (58%) of product XXXIX, which is used for further syntheses without further purification.

Example 40.

Synthesis of 6-methyl-3-(chinolin-5-aminomethyl)-1H-quinoline-2-she (XL).

Conducted according to the technique described in example 4 using the product XXXIX as a starting reagent. Obtain 0.94 g (63%) of the target product XL. So pl. 272-274°C.

H-NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 4.4 (2H, d, J=7.5 Hz), 6.4 (1H, d, J=8.5 Hz), 7.0 (1H, t, J=7.5 Hz), 7.2 (3H, m), 7.4 (1H, d, J=3.5 Hz), 7.5 (2H, m), 7.6 (1H, s), 8.7 (1H, d, J=8.5 Hz), 8.8 (1H, d, J=5 Hz), 11.6 (1H, ush. peak).

Example 41.

Synthesis of 3-[(5-isopropyl-4-methoxy-2-methylphenylimino)-methyl]-6-methyl-1H-quinoline-2-it(XLI).

Conducted according to the technique shown in example 3, using the product XXXIV as a starting reagent. Obtain 1.69 g (73%) of product XLI, which is used for further syntheses without further purification.

Example 42.

Synthesis of 3-[(5-isopropyl-4-methoxy-2-methylphenylimino)-methyl]-6-methyl-1H-quinoline-2-it (XLII).

Conducted according to the technique described in example 4 using the product XLI as a starting reagent. Obtain 1.52 g (58%) of the target product XLII. So pl. 204-205°C.

H-NMR spectrum (δ, DMSO-d6): 1.0 (6N, d, J=7.5 Hz), 2.0 (3H, s), 2.4 (3H, s), 3.7 (3H, s), 4.2 (2H, degenerated d), 4.9 (1H, m), 6.3 (1H, s), 6.6 (1H, s), 7.2 (2H, superposition of two d), 7.4 (1H, d, J=3.5 Hz), 7.7 (1H, s), 11.5 (1H, s).

Example 43.

Synthesis of 3-[(3-methoxy-4-tetrasulfane the but)-methyl]-6-methyl-1H-quinoline-2-it (XLIII).

Conducted according to the technique shown in example 3, using the product XXXIV as a starting reagent. Obtain 1.93 g (74%) of product XLIII, which is used for further syntheses without further purification.

Example 44.

Synthesis of 3-[(3-methoxy-4-tetraallyltin)-methyl]-6-methyl-1H-quinoline-2-it (XLIV).

Conducted according to the technique described in example 4 using the product XLIII as the source reagent. Obtain 1.38 g (58%) of the target product XLIV. So pl. 264-266°C.

H-NMR spectrum (δ, DMSO=d6): 2.2 (3H, s), 3.6 (3H, s), 4.2 (2H, d, J=7.5 Hz), 6.3 (1H, d, J=8.5 Hz), 6.5 (1H, d, J=3.5 Hz), 6.8 (1H, t, J=7.5 Hz), 7.2 (2H, superposition of two d, J=8.5 Hz), 7.4 (1H, d, J=3.5 Hz), 7.6 (1H, s), 9.6 (1H, s), 11.6 (1H, s).

Example 45.

Synthesis of 3-[(2-chlorpheniramine)-methyl]-7-methoxy-1H-quinoline-2-it (XLV).

Conducted according to the technique shown in example 3, using the product XXXVII as a starting reagent. Obtain 1.47 g (49%) of product XLV, which is used for further syntheses without further purification.

Example 46.

Synthesis of 3-[(2-chlorpheniramine)-methyl]-7-methoxy-1H-quinoline-2-it (XLVI).

Conducted according to the technique described in example 4 using the product XLV as a starting reagent. Obtain 0.87 g (55%) of the target product XLVI. So pl. 235-236°C.

H-NMR spectrum (δ, DMSO-d6): 3.6 (3H, s), 4.2 (2H, d, J=7.5 Hz), 5.9 (1H, t, J=7.5 Hz), 6.6 (3H, superposition of two "d" and "t", J=8.5 Hz), 6.7 (1H, d, J=8.5Hz), 6.8 (1H, d, J=3.5 Hz), 7.1 (1H, t, J=8.5 Hz), 7.3 (1H, d, J=8.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.65 (1H, c), 11.5 (1H, ush. peak).

Example 47.

Synthesis of 7-methoxy-3-[(2-methyl-4-nitrophenylamino)-methyl]-1H-quinoline-2-it (XLVII)

Conducted according to the technique shown in example 3, using the product XXVII as a starting reagent. Obtain 1.28 g (45%) of product XLVII, which is used for further syntheses without further purification.

Example 48.

Synthesis of 7-methoxy-3-[(2-methyl-4-nitrophenylamino)-methyl]-1H-quinoline-2-it (XLVIII).

Conducted according to the technique described in example 4 using the product XLVII as the source reagent. Obtain 0.72 g (55%) of the target product XLVIII. So pl. 277-278°C.

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 3.8 (3H, s), 4.35 (2H, d, J=7.5 Hz), 6.5 (1H, d, J=8.5 Hz), 6.75 (2H, m), 6.85 (1H, d, J=3.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.6 (1H. d, J=3.5 Hz), 7.9 (1H, t, J=7.5 Hz), 8 (1H, s), 11.6 (1H, ush. peak).

Example 49.

Synthesis of 7-methoxy-3-{[2-(morpholin-4-carbonyl)-phenylamino]-methyl}-1H-chinolin-2-it (XLIX).

Conducted according to the technique shown in example 3, using the product XXVII as a starting reagent. Obtain 1.87 g (68%) of product XLIX, which is used for further syntheses without further purification.

Example 50.

Synthesis of 7-methoxy-3-{[2-(morpholin-4-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it (L).

Conducted according to the technique described in example 4 using the product XLIX as starting reagent. what are square 1.36 g (74%) of the target product L. TPL-218°C.

H-NMR spectrum (δ, DMSO-d6): 3.35 (4H, m), 3.6(4H, m), 3.8 (3H, s), 4.25 (2H, d, J=7.5 Hz), 5.8 (1H, t, J=7.5 Hz), 6.55 (2H, m), 6.7 (1H, d, J=8.5 Hz), 6.8 (1H, d, J=3.5 Hz), 7.0 (1H, d, J=8.5 Hz), 7.2 (1H, t, J=8.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.6 (1H, s), 11.6 (1H, ush. peak).

Example 51.

Synthesis of 7-methoxy-3-[(4-phenoxypyridine)-methyl]-1H-quinoline-2-she(LI).

Conducted according to the technique shown in example 3, using the product XXVII as a starting reagent. Obtain 1.93 g (65%) of the product of LI, which is used for further syntheses without further purification.

Example 52.

Synthesis of 7-methoxy-3-[(4-phenoxybenzamine)-methyl]-1H-quinoline-2-it (LII).

Conducted according to the technique described in example 4 using the product of LI as a starting reagent. Obtain 1.21 g (76%) of the target product LII. So pl. 206-208°C.

H-NMR spectrum (δ, DMSO-d6): 3.65 (3H, s), 4.2 (2H, viroid "d"), 6.0 (1H, ush. peak), 6.6 (2H, d, J=8.5 Hz), 6.8 (4H, m), 7.0 (1H, t, J=8.5 Hz), 7.2 (2H, t, J=8.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.8 (1H, c), 11.4 (1H, c).

Example 53.

Synthesis of 7-methoxy-3-{[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it (LIII).

Conducted according to the technique shown in example 3, using the product XXVII as a starting reagent. Obtain 1.84 g (70%) of product LIII, which is used for further syntheses without further purification.

Example 54.

Synthesis of 7-methoxy-3-{[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it (LIV).

Provo is drawn according to the method described in example 4 using the product LIII as starting reagent. Obtain 1.06 g (80%) of the target product LIV. So PL-217°C.

H-NMR spectrum (δ, DMSO-d6): 1.7 (4H, m), 3.5 (4H, m), 3.7 (3H, s), 4.2 (2H, d, J=7.5 Hz), 6.4 (1H, t, J=7.5 Hz), 6.7 (2H, d, J=8.5 Hz), 6.8 (1H, d, J=8.5 Hz), 3.5 (1H, d, J=3.5 Hz), 7.3 (2H, d, J=8.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.7 (1H, s), 11.5 (1H, ush. peak).

Example 55.

Synthesis of 3-[(2,4-dimethylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-she (LV).

Conducted according to the technique shown in example 3, using the product XXVIII as a starting reagent. Obtain 1.57 g (76%) of LV product, which is used for further syntheses without further purification.

Example 56.

Synthesis of 3-[(2,4-dimethylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-it (lvis).

Conducted according to the technique described in example 4 using the product of LV as a starting reagent. Obtain 0.94 g (80%) of the target product LVI. So pl. 221-223°C.

H-NMR spectrum (δ, DMSO-d6): 2.05 (3H, s), 2.15 (3H, s), 3.6 (3H, s), 4.2 (2H, d, J=7.5 Hz), 5.3 (1H, t, J=7.5 Hz), 6.25 (1H, d, J=8.5 Hz), 6.65 (1H, d, J=8.5 Hz), 6,8 (1H, d, J=3 Hz), 7.05 (1H, d, J=8.5 Hz), 7.15 (1H, d, J=3 Hz), 7.2 (1H, d, J=8.5 Hz), 7.6 (1H, s), 11.6 (1H, ush. peak).

Example 57.

Synthesis of 3-[(5-chloro-2-methoxybenzylidene)-methyl]-6-methoxy-1H-quinoline-2-it (LVII).

Conducted according to the technique shown in example 3, using the product XXVII as a starting reagent. Obtain 1.24 g (65%) of product LVII, which is used in dalnas the x syntheses without further purification.

Example 58.

Synthesis of 3-[(5-chloro-2-methoxybenzylamine)-methyl]-6-methoxy-1H-quinoline-2-it (LVIII).

Conducted according to the technique described in example 4 using the product LVII as starting reagent. Obtain 0.81 g (67%) of the target product LVIII. So pl. 207-208°C.

H-NMR spectrum (δ, DMSO-d6): 3.7 (3H, s), 3.8 (3H, s), 4.2 (2H, ush. peak), 5.9 (1H, ush. peak), 6.3 (1H, d, J=3.5 Hz), 6.6 (1H, d, J=8.5 Hz), 6.8 (1H, d, J=8.5 Hz), 7.0 (1H, d, J=8.5 Hz), 7.1 (1H, d, J=3.5 Hz), 7.2 (1H, d, J=8.5 Hz), 7.65 (1H, s), 11.7 (1H, ush. peak).

Example 59.

Synthesis of 3-[(4-methoxybenzylidene)-methyl]-6-triptoreline-1H-quinoline-2-it (LIX).

Conducted according to the technique shown in example 3. Obtain 1.37 g (74%) of product, which is used for further syntheses without further purification.

Example 60.

Synthesis of 3-[(4-methoxybenzylamine)-methyl]-6-triptoreline-1H-quinoline-2-she (LX).

Conducted according to the methodology described in example 4. Get 0.79 g (81%) of the desired product. So pl. 180-182°C.

H-NMR spectrum (δ, DMSO-d6): 3.7 (3H, s), 4.0 (2H, viroid "d"), 5.5 (1H, viroid. "t"), 6.5 (2H, d, J=8.5 Hz), 6.7 (2H, d, J=8.5 Hz), 7.4 (2H, m), 7.6 (1H, d, J=3.5 Hz), 7.9 (1H, s), 12.0 (1H, ush. peak).

Example 61.

Synthesis of 3-[(3-fluoro-4-methylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-it(LXI).

Conducted according to the technique shown in example 3, using the product XXVIII as a starting reagent. Obtain 1.62 g (79%) of product LXI, which is used for further syntheses without additional PTS is tough.

Example 62.

Synthesis of 3-[(3-fluoro-4-methylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-it (LXII).

Conducted according to the technique described in example 4 using the product LXI as a starting reagent. Obtain 0.82 g (69%) of the desired product. So pl. 212-214°C.

H-NMR spectrum (δ, DMSO-d6): 2.0 (3H, s), 3.7 (3H, s), 4.1 (2H, d, J=7.5 Hz), 6.1 (1H, t, J=7.5 Hz), 6.3 (2H, m), 6.9 (1H, t, J=8.5 Hz), 7.1 (2H, m), 7.25 (2H, d, J=8.5 Hz), 7.7 (1H, s), 11-12 (1H, ush. peak).

Example 63.

Synthesis of 3-[(4-ethoxybenzylidene)-methyl]-6-methoxy-1H-quinoline-2-it(LXII).

Conducted according to the technique shown in example 3, using the product XXVIII as a starting reagent. Obtain 1.71 g (75%) of the product LXIII, which is used for further syntheses without further purification.

Example 64. Synthesis of 3-[1-(4-ethoxybenzylidene)-ethyl]-6-methoxy-1H-quinoline-2-it (LXIV).

Conducted according to the technique shown in example 9, using product LXIII as starting reagent. Obtain 0.54 g (31%) of the target product LXIV. So pl. 221-223°C.

H-NMR spectrum (δ, DMSO-d6): 1.2 (3H, t, J=7.5 Hz), 1.3 (3H, d, J=7.5 Hz), 3.6 (3H, s), 3.8 (2H, q, J=7.5 Hz), 4.5 (1H, q, J=7.5 Hz), 5.6 (1H, d, J=7.5 Hz), 6.3 (2H, d, J=8.5 Hz), 6.6 (2H, d, J=8.5 Hz), 7.0 (2H, m), 7.2 (1H, d, J=8.5 Hz), 7.7 (1H, s), 11.4 (1H, s).

Example 65.

Synthesis of N-{4-[(6-methoxy-2-oxo-1,2-dihydroquinoline-3-methylene)-amino]-phenyl}-ndimethylacetamide (LXV).

Conducted according to the technique shown in example 3, using the product XXVIII as the outcome of the second reagent. Obtain 1.59 g (69%) of product LXV, which is used for further syntheses without further purification.

Example 66.

Synthesis of N-{4-[(6-methoxy-2-oxo-1,2-dihydroquinoline-3-methyl)-amino]-phenyl}-ndimethylacetamide (LXVI).

Conducted according to the technique described in example 4 using the product LXV as starting reagent. Obtain 0.91 g (67%) of the target product LXVI. So pl. 281-283°C.

H-NMR spectrum (δ, DMSO-d6): 2.0 (3H, s), 3.7 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.8 (1H, t, J=7.5 Hz), 6.5 (2H, d, J=8.5 Hz), 7.1 (2H, m), 7.3 (3H, m), 7.8 (1H, s), 9.4 (1H, s), 11.5 (1H, ush. peak).

Example 67.

Synthesis of 3-[(2,4-diftorhinolonom)-methyl]-6-methoxy-1 H-quinoline-2-it (LXVII).

Conducted according to the technique shown in example 3, using the product XXVIII as a starting reagent. Obtain 1.43 g (77%) of product LXVII, which is used for further syntheses without further purification.

Example 68.

Synthesis of 3-[(2,4-dipertanyakan)-methyl]-6-methoxy-1H-quinoline-2-it (LXVIII).

Conducted according to the technique described in example 4 using the product LXII as starting reagent. Obtain 1.04 g (73%) of the target product LXVIII. So pl. 203-204°C.

H-NMR spectrum (δ, DMSO-d6): 3.8 (3H, s), 4.2 (2H, d, J=7.5 Hz), 5.9 (1H, t, J=7.5 Hz), 6.6 (1H, m), 6.8 (1H, m), 7.2 (3H, m), 7.3 (1H, d, J=8.5 Hz), 7.8 (1H, s), 11.5 (1H, ush. peak).

Example 69.

Synthesis of 7-chloro-3-[(4-methoxybenzylidene)-methyl]-6-methyl-1H-quinoline-2-it (LXIX).

Conducted according to the technique prevedeno the example 3, using product XXIX as a starting reagent. Obtain 1.48 g (63%) of product LXIX, which is used for further syntheses without further purification.

Example 70.

Synthesis of 7-chloro-3-[(4-methoxybenzylamine)-methyl]-6-methyl-1H-quinoline-2-it(LXX).

Conducted according to the technique described in example 4 using the product LXIX as starting reagent. Obtain 0.87 g (70%) of the target product LXX. So pl. 225-227°C.

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 3.6 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.6 (1H, t, J=7.5 Hz), 6.5 (2H, d, J=8.5 Hz), 6.65 (2H, d, J=8.5 Hz), 7.3 (1H, s), 7.4 (1H, s), 7.6 (1H, s).

Example 71.

Synthesis of 7-chloro-6-methyl-3-(o-toeliminate)-1H-quinoline-2-it (LXXI).

Conducted according to the technique shown in example 3, using the product XXIX as a starting reagent. Obtain 1.58 g (58%) of product LXXI, which is used for further syntheses without further purification.

Example 72.

Synthesis of 7-chloro-6-methyl-3-(o-trilaminate)-1H-quinoline-2-it (LXXII).

Conducted according to the technique described in example 4 using the product LXXI as starting reagent. Obtain 0.82 g (67%) of the target product LXXII. So pl. 235-237°C.

H-NMR spectrum (δ, DMSO-d6): 2.1 (3H, s), 2.25 (3H, s), 4.2 (2H, d, J=7.5 Hz), 5.4 (1H, t, J=7.5 Hz), 6.3 (1H, d, J=8.5 Hz), 6.5 (1H, t, J=8.5 Hz), 6.85 (1H, t, J=8.5 Hz), 6.9 (1H, d, J=8.5 Hz), 7.3 (1H, s), 7.5 (1H, ), 7.6 (1H, s), 11.9 (1H, ush. peak).

Example 73.

Synthesis of 3-[(4-methoxybiphenyl-3-imino-methyl]-6,7-dimethyl-1H-quinoline-2-it (LXXIII).

Conducted according to the technique shown in example 3, using the product XXX as a starting reagent. Obtain 1.82 g (74%) of product LXXIII, which is used for further syntheses without further purification.

Example 74.

Synthesis of 3-[(4-methoxybiphenyl-3-amino)-methyl]-6,7-dimethyl-1H-quinoline-2-it (LXXIV).

Conducted according to the technique described in example 4 using the product LXIII as starting reagent. Obtain 1.53 g (80%) of the target product LXXIV. So pl. 246-248°C.

H-NMR spectrum (δ, DMSO-d6): 2.1 (3H, s), 2.2 (3H, s), 3.8 (3H, s), 4.25 (2H, ush. "d"), 5.5 (1H, ush. "t"), 6.7 (1H, s), 6.85 (2H, superposes "d"), 7.1 (1H, s), 7.25 (1H, t, J=8.5 Hz), 7.3 (3H, m), 7.5 (2H, d, J=8.5 Hz), 7.7 (1H, s), 11.7 (1H, ush. peak).

Example 75.

Synthesis of 3-[(2,3-dihydrobenzo[1,4]dioxines-6-imino)-methyl]-6,7-dimethyl-1H-quinoline-2-it (LXXV).

Conducted according to the technique shown in example 3, using the product XXX as a starting reagent. Obtain 2.03 g (81%) of product LXXV, which is used for further syntheses without further purification.

Example 76.

Synthesis of 3-[(2,3-dihydrobenzo[1,4]dioxines-6-amino)-methyl]-6,7-dimethyl-1H-quinoline-2-it (LXXVI).

Conducted according to the technique described in example 4 using the product LXXV as starting reagent. Obtain 1.57 g (73%) of the target product LXXVI. So pl. 263-264°C.

H-NMR spectrum (δ, DMSO-d6): 2.1 (3H, s), 2.2 (3H, s). 4.1 (6N, m), 5.5 (1H, t, J=7.5 Hz), 6.0 (1 is, d, J=3.5 Hz), 6.1 (1H, d, J=8.5 Hz), 6.5 (1H, d, J=8.5 Hz), 7.0 (1H, s), 7.3 (1H, s), 7.6 (1H, s), 11.5 (1H, ush. peak).

Example 77.

Synthesis of 3-[(3,4-dimethoxyphenylthio)-methyl]-7-methylsulfanyl-1H-quinoline-2-it (LXXVII).

Conducted according to the technique shown in example 3, using the product XXXI as a starting reagent. Obtain 1.77 g (76%) of product LXXVII, which is used for further syntheses without further purification.

Example 78.

Synthesis of 3-[(3,4-dimethoxyphenylthio)-methyl]-7-methylsulfanyl-1H-quinoline-2-it (LXXVIII).

Conducted according to the technique described in example 4 using the product LXXVII as starting reagent. Obtain 1.12 g (67%) of the target product LXXVIII. So PL-189°C.

H-NMR spectrum (δ, DMSO-d6): 3.5 (3H, s). 3.6 (3H, s), 4.1 (2H, d, J=7.5 Hz), 5.5 (1H, t, J=7.5 Hz), 6.0 (1H, d, J=8.5 Hz), 6.4 (1H, d, J=3.5 Hz), 6.7 (1H, d, J=8.5 Hz), 7.0 (1H, d, J=8.5 Hz), 7.15 (1H, d, J=3.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.7 (1H, s), 11.5 (1H, ush. peak).

Example 79.

Synthesis of 3-(benzo[1,3]dioxole-5-aminomethyl)-7-methylsulfanyl-1H-quinoline-2-it (LXXIX).

Conducted according to the technique shown in example 3, using the product XXXI as a starting reagent. Obtain 1.89 g (69%) of product LXXIX, which is used for further syntheses without further purification.

Example 80.

Synthesis of 3-(benzo[1,3]dioxole-5-aminomethyl)-7-methylsulfanyl-1H-quinoline-2-it (LXXX).

Conducted according to the technique described in example 4 using the product is LXXIX as starting reagent. Obtain 1.18 g (77%) of the target product LXXX. So pl. 257-259°C.

H-NMR spectrum (δ, DMSO-d6): 4.0 (2H, d, J=7.5 Hz), 5.5 (1H, t, J=7.5 Hz), 5.9 (2H, s), 6.0 (1H, d, J=8.5 Hz), 6.3 (1H, d, J=3.5 Hz), 6.6 (1H, d, J=8.5 Hz), 7.0 (1H, d, J=8.5 Hz), 7.2 (1H, d, J=3.5 Hz), 7.5 (1H, d, J=8.5 Hz), 7.7 (1H, s), 11.5 (1H, ush. peak).

Example 81.

Synthesis of 6-tert-butyl-3-{[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it (LXXXI).

Conducted according to the technique shown in example 3, using the product XXXII as starting reagent. Obtain 1.63 g (59%) of product LXXXI, which is used for further syntheses without further purification.

Example 82.

Synthesis of 6-tert-butyl-3-{[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it (LXXXII).

Conducted according to the technique described in example 4 using the product LXXXI as starting reagent. Obtain 1.01 g (82%) of the target product LXXXII. So pl. 198-200°C.

H-NMR spectrum (δ, DMSO-d6): 1.2 (S, s), 1.8 (4H, s), 3.5 (4H, m), 4.2 (2H, d, J=7.5 Hz), 6.4 (1H, t, J=7.5 Hz), 6.6 (2H, d, J=8.5 Hz), 7.2 (1H, d, J=8.5 Hz), 7.35 (2H, d, J=8.5 Hz), 7.5 (2H, m), 7.75 (1H, d, J=3.5 Hz), 10.5-11.5 (1H, ush. peak).

Example 83.

Synthesis of 3-[(2,4-dimethoxyaniline)-methyl]-1,6-dimethyl-1H-quinoline-2-it (LXXXIII).

Conducted according to the methodology described in example 7 using product XXIX as a starting reagent. Obtain 1.28 g (43%) of product LXXXIII, which is used for further syntheses without further purification.

Example 84.

Sin is ez 3-[(2,4-dimethoxyaniline)-methyl]-1,6-dimethyl-1H-quinoline-2-it (LXXXIV).

Conducted according to the technique described in example 4 using the product LXXXIII as starting reagent. Obtain 0.73 g (63%) of the target product LXXXIV. So pl. 120-122°C.

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 3.6 (3H, s), 3.7 (3H, s), 3.8 (3H, s), 3.95 (2H, d, J=7.5 Hz), 5.7 (1H, t, J=7.5 Hz), 6.1 (2H, d, J=8.5 Hz), 6.2 (1H, d, J=3.5 Hz), 6.25 (1H, d, J=8.53.5 Hz), 6.9 (1H, d, J=3.5 Hz), 7.0 (1H, d, J=3.5 Hz), 7.1 (1H, s), 7.3 (1H, d, J=8.53.5 Hz).

Example 85.

Synthesis of 3-[(1H-indazole-5-imino)-methyl]-5,7-dimethyl-1H-quinoline-2-it(LXXXV).

Conducted according to the technique shown in example 3, using the product XXXIII as a starting reagent. Obtain 1.23 g (52%) of product LXXXV, which is used for further syntheses without further purification.

Example 86.

Synthesis of 3-[(1H-indazole-5-amino)-methyl]-5,7-dimethyl-1H-quinoline-2-it(LXXXVI).

Get on the methodology described in example 4 using the product LXXXV as starting reagent. Get 0.79 g (75%) of the target product LXXXVI. So pl. 291-293°C.

H-NMR spectrum (δ, DMSO-d6): 2.3 (3H, s), 2.4 (3H, s), 4.0 (2H, finally. "d"), 6.0 (1H, ush. peak), 6.6 (1H, s), 6.7 (1H, s), 6.8 (2H, m), 7.3 (2H, d J=8.5 Hz), 7.7 (1H. s), 7.9 (1H, s), 11.5 (1H, ush. peak), 12.5 (1H, ush. peak).

Example 87.

Synthesis of 7-[(4-methylsulfonylamino)-methyl]-5H-[1,3]dioxolo[4,5-g]quinoline-6-she (LXXXVII).

Get on the methodology described in example 3, using the product XXXIV as a starting reagent. Obtain 1.62 g (68%) product is and LXXXVII, which is used for further syntheses without further purification.

Example 88.

Synthesis of 7-[(4-methylsulfonylamino)-methyl]-5H-[1,3]dioxolo[4,5-g]quinoline-6-she (LXXXVIII).

Conducted according to the technique described in example 4 using the product LXXXVII as starting reagent. Obtain 1.12 g (75%) of the target product LXXXVIII. So pl. 255-257°C.

H-NMR spectrum (δ, DMSO-d6): 2.2 (3H, s), 4.0 (2H, d, J=7.5 Hz), 6.0 (2H, s), 6.1 (1H, t, J=7.5 Hz), 6.5 (2H, d, J=8.5 Hz), 6.8 (1H, s), 7.0 (3H, superposes "d" and "C"), 7.6 (1H, s), 11.6 (1H, ush. peak).

Example 89.

Synthesis of 7-(chinoline-5-aminomethyl)-5H-[1,3]dioxolo[4,5-g]quinoline-6-she (LXXXIX).

Conducted according to the technique shown in example 3, using the product XXXIV as a starting reagent. Obtain 1.75 g (64%) of product LXXXIX, which is used for further syntheses without further purification.

Example 90.

Synthesis of 7-(chinoline-5-aminomethyl)-5H-[1,3]dioxolo[4,5-g]quinoline-6-it (LDL).

Conducted according to the technique described in example 4 using the product LXXXIX as starting reagent. Obtain 0.97 g (72%) of the target product XC. So pl. 146-147°C.

H-NMR spectrum (δ, DMSO-d6): 4.3 (2H, d, J=7.5 Hz), 6.0 (2H, s), 6.4 (1H, d, J=8.5 Hz), 6.8 (1H, s), 6.9 (1H, t, J=7.5 Hz), 7.1 (1H, s), 7.2 (2H, d, J=7.5 Hz), 7.5 (2H, m), 7.6 (1H, s), 8.7 (1H, d, J=8.5 Hz), 8.8 (1H, d, J=5 Hz), 11.7 (1H, ush. peak).

Example 91. The method of conducting biological tests.

For inhibition of NO-sintetizadores described above 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 at the same temperature, 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 1 nm to 100 μM

For inhibition of excessive conversion of arginine to NO by different pathological conditions with the settlement of edusim achievement of therapeutic effect use dosage, 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 was 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±2°C, 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 g is the 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 inhibitors the value of this parameter ranges from 1.5 to 400 μmol/kg the Results of biological tests are given in the Table:

Table:
The results of biological tests.
Substance NActivity*, IC50, nmActivity**, ES
IV6.6
VIII181.5 μmol/kg
IX170
XXXVI45.5400 μmol/kg
XXXVIII500
XL7700Ȋ
XLII37
XLIV8800
XLVI54000
XLVIII12000
L9400
LII9500
LIV56000
LVI81000
LVIII41000
LX130
LXII16000
LXIV4000
LXX120
LXXII29000
LXXIV11000
LXXVI25
LXXVIII57
LXXX400
LXXXII6200
LXXXIV78
LXXXVI5300
LXXXVIII280
XC7100
XCV44
L-NG-monomethyl-arginine (control)37000
* - Active substance as an inhibitor of inducible NO synthetase.

** - The ability of a substance to inhibit LPS caused a decrease in pressure, for other products has not been studied.

Example 92.

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

Conducted according to the technique described in example 1. Get 44 g (78%) of the desired product. So pl. 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 93.

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

Conducted according to the methodology described in example 2. Obtain 24.5 g (78%) of the desired product. 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 94.

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

Conducted according to the technique shown in example 3, using the product XCIII and 4-benzyloxyaniline as initial reagents. Obtain 1.93 g (64%) of product XCIV, which is used for further syntheses without further purification.

Example 95.

Synthesis of 3-[(4-benzyloxy-phenylamino)-methyl]-5,6,7-trimetoksi-1H-shall inolin-2-it (XCV).

Conducted according to the technique shown in example 4, using compound XCIV as starting reagent. Obtain 1.71 g (79%) of product. TPL 206-208°C.

H1NMR spectrum (δ, DMSO-d6): 3.6 (3H, s); 3.65 (3H, s); 3.70 (3H, s); 4.0 (2H, d, J=5.5 Hz); 4.9 (2H, s); 5.6 (1H, t, J=5.5 Hz); 6.50 (2H, d, J=8.5 Hz); 6.65 (1H, s); 6.75 (2H, d, J=8.5 Hz); 7.3 (5H, m); 7.8 (1H, s); 11.0 (1H, broadened peak).

Thus, the new derivatives of 3-aminomethylphenol-proyavlayut activity against NO-synthetase level is known, and in some cases superior to known inhibitors, and they are less toxic, with no identified side effects, so you can use them as an active ingredient in medicines and pharmaceutical compositions.

Sources of information

1. US Patent 5874472

2. JP Patent 10-120654

3. US Patent 6509352

4. RU Patent 2167874

5. JP Patent 58-225065

6. US Patent 5536709

7. US Patent 5646132

8. RU Patent 95109098

9. Meth-Cohn, Otto; Narine, Bramha; Tarnowski, Brian; JCPRB4; J. Chem. Soc. Perkin Trans. 1; EN; 1981; 1520-1530 years.

10. Tilakraj, T.; Ambekar, Sarvottam Y.; JICSAH; J. Indian Chem. Soc.; EN; 62; 3; 1985; 251-253.

11. Raj, Tilak T.; Ambekar, Sarvottam Y.; JPCEAO; J.Prakt.Chem.; EN; 330; 2; 1988; 293-298.

12. Meth-Cohn et al.; TELEAY; Tetrahedron Lett.; 1979; 3111, 3112, 3113.

1. Derivatives of 3-aminomethylphenol-2 formulas (1)

in which R1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-core 2O-; 4-OCF3; 2-Ph; -OPh; -NHCOR; 2-och3, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 5-iPr; di-OAlk, di-Alk, di-Hal

or R2represents the selected simultaneously and independently from each other halogen atom and alkyl group or halogen atom and alkoxygroup;

or R2represents a group-CONR4R5where R4and R5each is independently of each other a group Alk; or together form a group -(CH2)n-when n=2-6;

R = CH3;

R3= N or CH3;

X is selected from H; 6-(C1-C3)Alk; 6-iPr; 6-iBu; 7-(C1-C2)Alk; 8-(C1-C2)Alk; 6-(C1-C2)OAlk; 6-OCF3; 6-OPh; 7-(C1-C2)OAlk; 7-SCH3; 6,7-OCH2O-; 6,7-OCH2CH2O-; 5,6,7-och3; 6-F.

2. Derivatives of 3-aminomethylphenol-2 according to claim 1, selected from

3-[(2,4-dimethoxyaniline)-methyl]-6-methyl-1H-quinoline-2-it;

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

3-[1-(2,4-dimethoxyaniline)-ethyl]-6-methyl-1H-quinoline-2-it;

3-(benzo-[1,3]-dioxole-5-aminomethyl)-6-methyl-1H-quinoline-2-it;

3-[(1H-indazole-5-amino)-methyl]-6-methyl-1H-quinoline-2-it;

6-methyl-3-(chinolin-5-aminomethyl)-1H-quinoline-2-it;

3-[(2-chlorpheniramine)-methyl]-methoxy-1H-quinoline-2-it;

3-[(3-methoxy-4-tetraallyltin)-methyl]-6-methyl-1H-chinolin-it;

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

7-methoxy-3-{[2-morpholin-4-carbonyl)phenylamino]-methyl}-1H-quinoline-2-it;

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

7-methoxy-3{[4-pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it;

3-[(2,4-dimethylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-it;

3-[(5-chloro-2-methoxybenzylamine)-methyl]-6-methoxy-1H-quinoline-2-it;

3-[(4-methoxybenzylamine)-methyl]-6-triptoreline-1H-quinoline-2-it;

3-[(3-fluoro-4-methylphenylimino)-methyl]-6-methoxy-1H-quinoline-2-it;

3-[1-(4-ethoxybenzylidene)-ethyl]-6-methoxy-1H-quinoline-2-it;

3-[(3,4-dimethoxyphenylthio)-methyl]-7-methylsulfanyl-1H-quinoline-2-it;

3-(benzo[1,3]-dioxole-5-aminomethyl)-7-methylsulfanyl-1H-quinoline-2-it;

6-tertbutyl-3-{[4-(pyrrolidin-1-carbonyl)-phenylamino]-methyl}-1H-quinoline-2-it;

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

7-[(4-methylsulfonylamino)-methyl-5H-[1,3]dioxolo[4,5g]quinoline-6-it;

7-(chinoline-5-aminomethyl)-5H-[1,3]dioxolo[4,5g]quinoline-6-it.

3. Derivatives of 3-aminomethylphenol-2 formula (2):

in which R1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-och2O-; 4-OCF33, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 4-och3; 5-iPr; di-OAlk, di-Alk, di-Hal;

or R2represents the selected simultaneously and independently from each other halogen atom and alkyl group or halogen atom and alkoxygroup;

or R2represents a group-CONR4R5where R4and R5each is independently of each other a group Alk; or together form a group -(CH2)n-when n=2-6;

R = CH3;

R3= N or CH3;

X and Y are the same or different and selected from 7,8-CH3; 6,8-CH3; 5,8-CH3; 5,7-CH3; 6,7-CH3; 6,7-och3; 6-CHC, 7-Cl.

4. Derivatives of 3-aminomethylphenol-2 according to claim 3, selected from

7-chloro-3-(4-methoxybenzylamine)-methyl]-6-methyl-1H-quinoline-2-it;

7-chloro-6-methyl-3-(o-trilaminate)-1H-quinoline-2-it;

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

3-[(2,3-dihydrobenzo[1,4]dioxines-6-amino)-methyl]-6,7-dimethyl-1H-quinoline-2-it;

3-[(1H-indazole-5-amino)-methyl]-5,7-dimethyl-1H-quinoline-2-it.

5. Derivatives of 3-aminomethylphenol-2 formula (3)

in which R1=H or Alk;

R2selected from Alk; -OAlk; -SCH3; -Hal; -CF3; 3,4-och2CH2O-; 3,4-och2O-; 4-OCFsub> 3; 2-Ph; -OPh; -NHCOR; 2-och3, 5-Ph; 4-OBzl; 3-NO2; 2-CH3; 4-och3; 5-iPr; di-OAlk, di-Alk, di-Hal;

or R2represents the selected simultaneously and independently from each other halogen atom and alkyl group or halogen atom and alkoxygroup;

or R2represents a group-CONR4R5; where R4and R5each is independently of each other a group Alk; or together form a group -(CH2)n-when n=2-6;

R = CH3;

R3= N or CH3.

6. The method of obtaining derivatives of 3-aminomethylphenol-2 according to claims 1, 3 or 5, contains the following stages:

a) synthesis of 2-chlorhydrin-3-carbaldehyde, including obtaining formuliruya mixture of Vilsmeier by the interaction of dimethylformamide and POCl3when cooled, add to the mixture of Vilsmeier substituted acetanilide, the shutter speed of 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 crushed ice;

b) hydrolysis to 2-chinolin-3-carbaldehyde by boiling the compound obtained in stage a), in 80-90% acetic acid for 4-12 hours, cooling the reaction mixture, separating and washing the precipitate;

C) synthesis of Schiff bases by reacting p is oduct, obtained in stage b), when heated to 100-120°in the presence of a primary amine, taken in excess, in an environment of dimethylformamide;

g) recovery of Schiff bases obtained at the previous step.

7. The method according to claim 6, characterized in that as the source of the substituted acetanilide use compounds containing electron-donating substituents in the benzene ring.

8. The method according to claim 6, characterized in that as the source of the substituted acetanilide use compounds containing a weak electron-withdrawing substituents in the benzene ring.

9. The method according to any of PP-8, characterized in that the addition of the substituted acetanilide to a mixture of Vilsmeier carried out in small portions under vigorous stirring and cooling.

10. The method according to any of PP-8, characterized in that the addition of the substituted acetanilide to a mixture of Vilsmeier carry out small portions at a temperature of about 50°C.

11. The method according to any of PP-10, characterized in that the product obtained in stage a), before submitting to the step b) was subjected to purification by recrystallization from acetone, chloroform or ethyl acetate.

12. The method according to any of PP-11, characterized in that the product obtained in stage b), before submitting to the stage) was subjected to purification by recrystallization from acetic acid sludge is of dimethylformamide.

13. The method according to any of PP-12, characterized in that for obtaining 1,6-dimethyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde the product obtained in stage b)is dissolved by heating in methanol, add to it a solution of alkali and methyl iodide, boil, the precipitate is filtered and washed.

14. The method according to item 13, wherein the precipitate is purified by recrystallization in acetonitrile and directed for stage).

15. The method according to any of PP-14, characterized in that as a reducing reagent in stage g) using a complex hydride.

16. The method according to item 15, wherein as a complex hydride using sodium borohydride, cyanoborohydride, traceability sodium or DIBORANE.

17. The method according to any of p-16, characterized in that the target product after stage g) is purified by recrystallization from alcohol.

18. Biologically active compound, inhibition of NO-synthase, characterized in that it comprises as an active ingredient the compound according to any one of claims 1 to 5.

19. The pharmaceutical composition inhibiting NO-synthetase, wherein as the active ingredient it contains a compound according to any one of claims 1 to 5.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula (1):

wherein R1 means (C1-C6)-alkyl that can be substituted once or multiply with phenyl; R2 and R3 means independently of one another hydrogen atom, (C6-C10)-aryl, (C3-C8)-cycloalkyl, (C6-C10)-aryloxymethyl, O-benzyl can be substituted once or multiply with halogen atom, -CF3,, O-(C6-C10)-aryl or O-(C3-C8)-cycloalkyl, O-(C1-C6)-alkyl, that can be substituted once or multiply with fluorine atom or amino-group wherein amino-group, in turn, can be substituted once or multiply with (C1-C4)-alkyl; SO2-NH-(C1-C6)-alkyl substituted possibly with group N-[(C1-C6)-alkyl]2; SO2-NH-(2,2,6,6-tetramethylpiperidin-4-yl); SO2-NH-(C3-C8)-cycloalkyl substituted possible once or multiply with (C1-C4)-alkyl; SO2-N-[(C1-C6)-alkyl]2 or COX wherein X means N-[(C1-C6)-alkyl]2; and N-[(C1-C6)-alkyl-alkyl]2 can mean also pyrrolidine, piperidine, morpholine or piperizine group that if necessary can be substituted with (C1-C4)-alkyl; under condition that R2 and R3 don't mean hydrogen atom simultaneously, and to their physiologically acceptable salts and optical isomers. Compounds show inhibitory effect on activity of hormone-sensitivity lipase (HSL). Also, invention describes a method for preparing these compounds.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

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

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

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

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I):

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

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