Method of obtaining 4-amino-3-quinolinecarbonitryls

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining 4-amino-3-quinolinecarbonitryl, which includes: a) combining aminocompound with cyanoacetic acid and acid catalyst obtaining cyanoacetomide; b) condensing cyanoacetomide from stage a with aniline, alcohol solvent and trialkylorthoformiate obtaining 3-amino-2-cyanoakrylamide; and c) combining 3-amino-2-cyanoakrylamide with phosphorus oxychloride in acetonitryl, butyronitrile, toluol or xylol, optionally in presence of catalyst, obtaining 4-amino-3-quinolinecarbonitryl. Also described is method (version) of obtaining 4-amino-3-quinolinecarbonitryl, method of obtaining 7-aminothieno[3,2-b]pyridine-6-carbonitrile and method of obtaining cyanoacetamide.

EFFECT: creation of efficient method of obtaining 4-amino-3-quinolinecarbonitryl.

24 cl, 50 ex

 

Background of invention

The invention relates to a method of producing 4-amino-3-chinainternational, which can serve as intermediate compounds for the synthesis of additional analogs of 4-amino-3-hinolincarbonova. Such substituted quinoline, and their pharmaceutically acceptable salts inhibit the activity of certain protein kinases (PK), thereby suppressing the abnormal growth of cells of some types.

The compounds obtained according to this invention are suitable, for example, for the treatment of polycystic kidney disease, polyps of the colon, cancer and stroke in mammals.

In this patent application quinoline cyclic system will be numbered as shown in the formula below:

This invention relates to the production of 7-aminothieno[3,2-b]pyridine-6-carbonitrile, suitable as intermediates for the synthesis of 7-aminothieno[3,2-b]pyridine-6-carbonitrile analogues. In this patent application thieno[3,2-b]pyridine cyclic system will be numbered as shown in the formula below:

Historically there are several ways to obtain 4-aminotoluene quinoline, and the two most commonly used method include intramolecular reactions FR the sharing of qualification (Friedel-Crafts) or ring closure by electrocyclization N(2-carboxyvinyl)aniline derivatives at elevated temperatures. Cyclodehydration corresponding amide substrates through an intermediate connection type Vilsmeier (Vilsmeier) seems attractive, but the literature data are scarce, and in the example below, the desired aminoquinolinic group unstable under the reaction conditions and chlorhydrin preferred [Meth-Cohn, O., Taylor, D.L. (1995) Tetrahedron, 51, 12869].

The approach described here is appropriate because of the ease of obtaining cyanoacetamide part of tsianuksusnogo acid, the desired aniline and correspondingly substituted aniline, which results in a carbocyclic ring. In the literature there is one example where 3-Chloroaniline spend reactions through a series of cyanoacetamide education recyclization, which is subjected to cyclization to 4-aminoquinolines in some cases. The conditions used to obtain ruminantia, are much more stringent than the conditions described in General terms here, and the conditions of the cyclization in some instances does not result in cyclodehydration [Price, C.C., Boekelheide, V. (1946) J. Am. Chem. Soc., 68, 1246]. In addition, the compounds described in this invention have significantly different types of substitution.

Brief description of the invention

This invention relates to a method for producing 4-amino-3-hinolincarbonova comprising a combination of amino compounds with linoxyn the th acid and an acid catalyst to obtain cyanoacetamide; condensation cyanoacetamide C, optional up to Tetra-substituted, aniline in ethanol solvent and trialkylaluminium with 3-amino-2-cyanoacetamide, and then the combination of 3-amino-2-cyanoacetamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst, to obtain 4-amino-3-hinolincarbonova.

This invention relates also to a method for producing 7-aminothieno[3,2-b]pyridine-6-carbonitrile, including the combination, not necessarily to dogsleding, 3-aminothiophene with cyanoacetamide and trialkylaluminium in an alcohol solvent to obtain 3-amino-2-cyanoacetamide, and the combination of 3-amino-2-cyanoacetamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst, to obtain 7-aminothieno[3,2-b]pyridine-6-carbonitrile.

In addition, this invention relates to a method for producing 4-amino-3-hinolincarbonova by the reaction of a combination of amino compounds with tsianuksusnogo acid and peptide binding reagent to obtain a solution, filtering the solution to obtain cyanoacetamide; condensation cyanoacetamide C, optional up to Tetra-substituted, aniline, alcohol solvent and trialkylaluminium with getting alkoxyamine; and the combination of alcox is ruminantia with phosphorus oxychloride to obtain 4-amino-3-hinolincarbonova.

The invention includes a method of producing cyanoacetamide with a combination of dimethylformamide (DMF), Amin and tsianuksusnogo acid to obtain a mixture; cooling the mixture; adding a solution of N,N'-dicyclohexylcarbodiimide in DMF so as to maintain the temperature below 15°obtaining the suspension; filtering the suspension and washing the obtained solid by-products to obtain a filtrate; adding water to the filtrate to obtain a mixture, and filtering the mixture to obtain cyanoacetamide.

The following details of the experiment are presented in order to help understanding of the invention and are not intended to limit in any way the present invention presented in the claims that follows.

Detailed description of the invention

This invention presents a simple method for the production of 4-amino-3-chinainternational optionally with substituents in the 5, 6, 7 and 8 positions with high yield and high purity, including:

(a) obtaining cyanoacetamide;

(b) obtaining 3-amino-2-cyanoacetamide optionally substituted anilines using cyanoacetamide and trialkylaluminium and

(C) cyclodehydration 3-amino-2-cyanoacetamide obtained, as presented above, with phosphorus oxychloride in a suitable dissolve the Le with the addition of the tertiary-amine bases or alcohols.

The methodology described here provides functionalized aniline containing substituents, which make possible intramolecular cyclization in the conditions of dehydrogenation.

In the sequence below describes an invention that is claimed here.

where

R1and R2, each independently, represent hydrogen, alkyl of 1-6 carbon atoms, substituted and unsubstituted aryl; and

R3, R4, R5and R6, each independently, represent hydrogen, hydroxy, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, quinil of 2-6 carbon atoms, alkoxy of 1-6 carbon atoms, -alkoxyalkane, halogenoalkane-,

-alkylglycerols, optionally substituted aryl, N-alkylpiperazine, and the alkyl part has from 1 to 6 carbon atoms, pyrrolidino, morpholino, piperazine derivatives, -alkoxy[(N)-alkylpiperazine], where the alkyl and alkoxygroup consist of 1-6 carbon atoms, or optionally substituted heteroaryl.

Cyanoacetamide 1 can be obtained from the corresponding amine and tsianuksusnogo acid in toluene with an acid catalyst or in tetrahydrofuran (THF) with peptide binder by heating under reflux. The examples included here, are the preferred conditions include the use of 1.03 is quivalent tsianuksusnogo acid relative to the amine, and 1,3-diisopropylcarbodiimide in THF at 77-80°C. the Optimal method allows you to filter the suspension, followed by dilution with water, to allow the product to precipitate, and collecting the last filtration. This procedure provides an almost quantitative yield 1 with sufficient purity for use in the subsequent stage without further purification.

The use of a binding reagent of the water-soluble peptide in THF enables the direct selection of cyanoacetamide when processing water.

The reaction of condensation of cyanoacetamide with, optionally, up to Tetra-substituted, aniline can be made with cleaners containing hydrochloride salt or the free base of aniline with trialkylaluminium using alcohol solvents at 20-140°C. the Optimal conditions for this transformation are carrying out the reaction in isopropanol at 80°With cleaners containing hydrochloride salt or the free base of aniline and a 2.0 to 7.0 equivalents of triethylorthoformate. These conditions give the possibility of buildup 2, which emit after filtering with a good yield and high purity, and can be used at a later stage without purification.

Cyclodehydration is carried out using phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally with alcohols Il is aminovymi bases as catalysts at 80-110° C. the Transformation can be performed by heating the substrate in acetonitrile or butyronitrile with methanol and phosphorus oxychloride. Salt of the product precipitated from the reaction mixture and can be directly neutralized or isolated and neutralized in a separate vessel with 3 in good yield and high quality. Add this base to the reaction mixture as pyridine, triethylamine or Diisopropylamine, can significantly accelerate the reaction.

In accordance with this invention a high yield and simple way to obtain 7-aminothieno[3,2-b]pyridine-6-carbonitrile with a high degree of purity of the get method, which comprises the sequence presented below:

where

R1and R2, each independently, represent hydrogen, alkyl of 1-6 carbon atoms, substituted and unsubstituted aryl; and

R3and R4, each independently, represent hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, quinil of 2-6 carbon atoms, -alkylether, aryl or heteroaryl.

The reaction of condensation of cyanoacetamide 1 with 3-aminothiophenol can be performed with cleaners containing hydrochloride salt or the free base 3-aminothiophene with trialkylaluminium when using alcoholic solvents at 20-140°C. optimalnyj conditions for this transformation are carrying out the reaction in isopropanol at 80° With 3-aminothiophenol and 2,0-7,0 equivalents of triethylorthoformate. These conditions allow for precipitation of the product 4 to be allocated after filtering with a good yield and high purity, and can be used at a later stage without purification.

Cyclodehydration perform with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally with alcohols or aminovymi bases as catalyst, at 80-110°C. the Optimal procedure for this transformation is the heating of the substrate in acetonitrile with phosphorus oxychloride. Product, salt, precipitates from the reaction mixture and can be directly neutralized or isolated and neutralized in a separate vessel with getting 7-aminothieno[3,2-b]pyridine-6-carbonitrile formula 5 in good yield and high quality. The described route 1 shown with the use of examples 4, 6, 42, 43, 44 and 45.

The described route 2 shown with examples 4, 46, 47, 48, 49 and 50.

In some embodiments of the present invention zanoxolo acid is used in amount of about 1-1 .5 equivalents relative to the amine with the preferred concentration equal to 1.03 equivalent.

In some embodiments of the present invention, it is not necessarily to Tetris is displaced, aniline is cleaners containing hydrochloride salt. In another embodiment, optional up to Tetra-substituted, aniline is a freelance basis.

Definition

For convenience, here are some terms used in this description, examples and appended claims.

The term "alkyl" refers to the radical of saturated aliphatic groups, including alkyl groups are straight chain alkyl groups, branched-chain, cycloalkyl (alicyclic) groups, substituted alkyl cycloalkyl groups and substituted cycloalkyl alkyl groups. In the preferred embodiment the alkyl straight or branched chain has 6 or fewer carbon atoms in its side chain. The term "alkyl" may be used separately or as part of a chemical name, such as "trialkylaluminium".

The terms "alkenyl" and quinil" refer to unsaturated aliphatic groups analogous in length and possible substitution to alcelam described above, but which contain at least one double or triple carbon-carbon bond, respectively.

The term "alkoxy", as used here, refers to an alkyl group defined above, having connected with it the oxygen radical. Presents CNS groups include methoxy, ethoxy, cut the XI, tert-butoxy and the like. The term alkoxy can be used separately or as part of a chemical name, such as "alkoxyamino".

A similar substitution can be made at alkenyl and etkinlik groups by obtaining, for example, alkanolamines, alkynylamino, alkanolamides, alkanolamines, alkanolamides, alkanolamines, tolchenov, tyulkanov, carbonization of alkenyl or alkinyl, Alenikov, alkyloxy, metallocenyl and metallocenyl.

The term "aryl", in accordance with the description includes 4-, 5-, 6-, 7 - and 10-membered carbocyclic monocyclic or condensed polycyclic aromatic group which may be substituted or unsubstituted.

The term "heteroaryl" refers to a 4-10-membered aromatic cyclic structure, which includes the structure of the cycle from one to four heteroatoms. Heteroaryl include, but are not limited to, pyrrolidine, oxolan, tolan, piperidine, piperazine, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazin, pyridazine and pyrimidine and morpholine.

The term "heteroatom", in accordance with the description, means an atom of any element, in addition to carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.

The term "halogen" about what is worn to the fluorine atom, chlorine, bromine and iodine.

In accordance with the description, the term "substituted"is supposed to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents of organic compounds include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more Deputy, the same or different for the respective organic compounds. For the purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which are bonded to the valencies of the heteroatoms. This invention is not limited to certain permissible substituents of organic compounds.

In accordance with the description of acid and alkaline catalysts of this invention include a substance that speeds up a reaction without modifying the overall standard Gibbs energy of the reaction. In the preferred embodiment of acid and alkaline catalysts include, for example, pyridine and 3-nitrophenylarsonic acid.

In accordance with the description, the connecting peptide reagent includes, for example, 1,3-diisopropylcarbodiimide, 1,3-[(di is ethylamino)propyl]-3-ethylcarbodiimide hydrochloride and dicyclohexylcarbodiimide (DCC; DCC).

In accordance with the description, the alcohol solvent is a liquid or homogenous liquid mixture, which is extracted(s) substance(s) and possible(s) modifier(s) may(may) be dissolved with the formation of the dissolved phase. When one of the embodiments of the alcohol solvent is, for example, ethylene glycol, methanol, isopropanol or butanol. In the preferred embodiment the alcohol solvent is isopropanol.

In accordance with the description, stage condensation of this invention is carried out at a temperature of 10-200°C. In a more preferred embodiment, the temperature is 140°C. In another preferred embodiment the temperature is 80°C.

When one of the some embodiments of the present invention the alcohol is the catalyst. In another embodiment the amine base is a catalyst.

In one of the embodiments of the present invention the peptide binding reagent is water-soluble.

Example 1

(3-chloro-4-fluoro)-2-cyanoacetamide

A 5-liter round bottom flask in an atmosphere of N2equipped with mounted above the mixer, refrigerator, thermocouple and a 500 ml addition funnel, was loaded zanoxolo acid (150 g, 1.77 mol), 3-chloro-4-ftoranila (250 g, 1,72 mol) and tetrahydrofuran (THF) (750 ml). The mixture was heated to 75°C. dropwise over 25 mine the solution was added 1,3-diisopropylcarbodiimide (221,6 g, 275 ml, 1.77 mol) in THF (50 ml) at 75-79°C. At the end of the addition of the solution to precipitate Diisopropylamine. The suspension was stirred for one hour, then was cooled to 13°C. the Suspension was filtered and the filter cake washed with THF (2×250 ml). The filtrate was transferred into a 2-l addition funnel and the solids were removed.

A 12-liter round bottom flask equipped with a mounted top stirrer and a thermocouple, were loaded water (4250 ml) at 15°C. the Filtrate above was slowly added into the water for 25 minutes with the formation of a white suspension. The suspension was stirred at room temperature overnight.

The suspension was filtered and the filter cake washed with water (2×250 ml) and dried under vacuum (50 mm Hg) at 45°obtaining (3-chloro-4-fluoro)-2-cyanoacetamide in a solid white color (294,5 g, 81% yield, >99% purity by HPLC, TPL 155,7-157°).1H NMR (300 MHz, DMSO-d6): of 10.4 (s, 1H), 7,80 (d, J=8 Hz, 1H), 7.5 to to 7.3 (m, 2H), 3,92 (s, 2H).

Example 2

(3-Chloro-4-fluoro)-2-cyanoacetamide

In a 500-ml round bottom flask in an atmosphere of N2equipped with mounted above the mixer, refrigerator, thermocouple and a 100 ml dropping funnel, was loaded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21,17 g of 0.11 ml) and THF (140 ml). In an addition funnel was added a solution tsianuksusnogo acid (there is a 10.03 g, 0.18 mol) and 3-chloro-4-ftoranila (15,44 g, 0,106 mol) in THF (60 ml) and was added into the reaction flask at 25-45°C. At the end of the addition the reaction mixture became a transparent solution. The solution was stirred at room temperature for 1.5 hours, then was slowly poured into water (500 ml) with formation of a white suspension. The suspension was stirred at room temperature overnight, then filtered, and the filter cake was washed with water and dried under vacuum (50 mm Hg) at 45°obtaining (3-chloro-4-fluoro)-2-cyanoacetamide in a solid white color (21,27 g, 94% yield, 97,5% by HPLC).1H NMR (300 MHz, DMSO-d6): of 10.4 (s, 1H), 7,80 (d, J=8 Hz, 1H), 7.5 to to 7.3 (m, 2H), 3,92 (s, 2H).

Example 3

(3-Chloro-4-fluoro)-2-cyanoacetamide

In a 500-ml round bottom flask in an atmosphere of N2equipped with mounted above the mixer nozzle Dean-stark, refrigerator, thermocouple, downloaded zanoxolo acid (28,04 g, 0.33 mol), 3-chloro-4-ftoranila (40,0 g, 0.28 mol), 3-nitrophenylarsonic acid (2.28 g, 0.014 mol) and toluene (200 ml). The mixture was heated to boiling c reflux and water was collected in the trap Dean-stark. After 5.5 hours thin layer chromatography (TLC) showed complete depletion of aniline. The reaction mixture was cooled to room temperature (CT) with the formation of a pink suspension. A solid substance was separated by filtration, washed with MTBE (2×200 ml) and is sewed to obtain (3-chloro-4-fluoro)-2-cyanoacetamide in the form of a solid pale pink color (46,40 g, 79% yield, 96,7% by GC-MS).1H NMR (300 MHz, DMSO-d6): of 10.4 (s, 1H), 7,80 (d, J=8 Hz, 1H), 7.5 to to 7.3 (m, 2H), 3,92 (s, 2H).

Example 4

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide

2,4-Dichloro-5-methoxyaniline (5,00 g, 26 mmol) and zanoxolo acid (2.28 g, 26.8 mmol) were mixed in 50 ml of tetrahydrofuran until then, until it formed a solution. This solution was heated to boiling under reflux and was added dropwise 1,3-diisopropylcarbodiimide (4,2 ml, 26.8 mmol). After 30 minutes the mixture was cooled to ˜15°in an ice bath. The solid is collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and was stirred for 30 minutes. White solid was collected by filtration, washed with water and then dissolved in 500 ml of ethyl acetate. The solution was dried over sodium sulfate and concentrated in vacuum to obtain 5.9 g (88%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide in a solid white color, TPL 180-181°;1H NMR (400 MHz, DMSO-d6) δ: of 3.84 (s, 3H), was 4.02 (s, 2H), 7,58 (s, 1H), 7,66 (s, 1H), 10,00 (s, 1H).

MS(ES) m/z 257,0, 259,0(M-N)-

Analysis for C10H8Cl2N2About2

Calculated: C, 46,36; N, 3,11; N, 10,81

Found: C, 46,25; N, 3,10; N, 10,85.

An alternative example 4

In the reaction flask was loaded dimethylformamide (DMF) (500 ml), 2,4-dichloro-5-methoxyaniline (100 g, 0.52 mol) and qi is noxudol acid (46.6 g, 0.55 mol). The mixture was cooled to 10°in an ice bath. The cooled mixture was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (119,1 g of 0.58 mol) in DMF (240 ml) so that the temperature remained below 15°C. After the addition was completed, cooling was stopped and the reaction mixture was stirred for 2 hours. A byproduct urea was then removed by filtration and the precipitate was washed twice DMF. To the filtrate was added 700 ml of water. From the solution precipitated solid product. The suspension was cooled to 5°and was sustained for at least 30 minutes. The product was collected by filtration and washed with water, and then dried in vacuum at 60°obtaining 127,08 g solid of light yellow-brown color.

Example 5

2-Cyano-N-(3,4,5-trimethoxyphenyl)ndimethylacetamide

3,4,5-Trimethoxyaniline (10,00 g of 54.6 mmol) and zanoxolo acid (4,78 g, 56,19 mmol) were mixed in 100 ml of tetrahydrofuran and heated under reflux. To the resulting solution was added dropwise 1,3-diisopropylcarbodiimide (8,8 ml, 56,29 mmol). The mixture was cooled in an ice bath and the solid was collected by filtration, washing with tetrahydrofuran. The filtrate was slowly poured into water and was stirred for 30 minutes. White solid was collected by filtration, washed with water and dried to obtain 2.58 g of 2-cyano-N-(3,4,5-trimethoxyphenyl)AC is tumida in a solid white color, TPL 146-147°;1H NMR (400 MHz, DMSO-d6) δ: 3,61 (s, 3H), 3,74 (C, 6N), 3,86 (s, 2H), 6.90 to (s, 2H), 10,23 (s, 1H);

MS(ES) m/z 251,1 (M+N)+

Analysis for C12H14N2About4

Calculated: C, 57,59; N, 5,64; N, 11,19

Found: C, 57,24; N, 5,67; N, 11,08.

Example 6

2-(3-Chloropropoxy)-1-methoxy-4-nitrobenzene

A mixture of 2-methoxy-5-NITROPHENOL (16,90 g, 100 mmol), 3-chlorpropyl-p-toluensulfonate (29,2 g, 120 mmol) and potassium carbonate (27,0 g, 195 mmol) in 160 ml of N,N-dimethylformamide was heated and kept at 80°C for 2 hours. The reaction mixture was cooled to room temperature and distributed between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. The solution was concentrated in vacuo and recrystallized from hexane and ethyl acetate to obtain 4.68 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene in the form of a first portion of off-white crystals. The second portion of the 11,10 g was obtained from the mother liquor. The remaining solution was concentrated in vacuo, and purified flash column-chromatography, elwira a mixture of hexane:ethyl acetate 4:1 to obtain 1.31 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene in the form of off-white crystals, TPL 85-87°;1H-NMR (400 MHz, DMSO-d6) δ: of 2.23 (m, 2H), 3,79 (t, J=6 Hz, 2H), 3,92 (s, 3H), is 4.21 (t, J=6 Hz, 2H), 7,19 (d, J=9 Hz, 1H), to 7.77 (d, J=2 Hz, H), a 7.92 (DD, J=9,2 Hz, 1H);

MS(ES) m/z 246,1; 248,1(M+N)+

Analysis for C10H12ClNO4

Calculated: C, 48,89; N, To 4.92; N, 5,70

Found: C, 49,09; N, To 4.68; N, 5,62.

An alternative example 6

2-methoxy-5-NITROPHENOL (50 g, 0.30 mol) was combined with 250 ml of isopropyl alcohol. To the mixture was added a 1N solution of sodium hydroxide, 310 ml (0.31 mol) at such a speed that the temperature remained below 40°C. After the addition was completed, the mixture was stirred for at least 30 minutes. In the reaction mixture is then loaded 1-bromo-3-chloropropane (br93.1 g, 0.59 mol) in one portion. The mixture was heated to 75°and periodically controlled by high performance liquid chromatography (HPLC). After 8 hours heating was discontinued and the reaction mixture was allowed to cool to room temperature overnight. The product gradually precipitated from the mixture in the form of a solid light-yellow/yellow-brown color. Added water, 200 ml, one portion and the resulting suspension was stirred for at least 30 minutes. The suspension was filtered and washed with water. From the moist crude product was preparing a suspension in 650 ml of methanol and heated under reflux until then, until the solids were dissolved or mostly dissolved. The solution was let to cool gradually with stirring at room themes is the temperature value within 3-5 hours or more. The mixture then was cooled to 10-15°and was sustained for at least 30 minutes. The solids were filtered and washed with cold methanol. The product was then dried in vacuum to obtain 60,3 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene.

Example 7

3-(3-Chloropropoxy)-4-methoxyaniline

A mixture of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (2.15 g, 8,77 mmol) and chloride dihydrate tin (II) (6,1 g, 27,11 mmol) in 50 ml of ethyl acetate was heated under reflux for 6.5 hours. The reaction mixture was cooled to room temperature and poured into 250 ml of saturated aqueous sodium bicarbonate solution. After stirring for 40 additional minutes were added ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution and water, then dried over magnesium sulfate and filtered. The solution was concentrated in vacuo, and purified flash column-chromatography, elwira a mixture of hexane:ethyl acetate 1:1 to receive 753 mg of 3-(3-chloropropoxy)-4-methoxyaniline in the form of oil dark brown;1H-NMR (400 MHz, DMSO-d6) δ: 2,13 (m, 2H), 3,62 (s, 3H), of 3.78 (t, J=6 Hz, 2H), 3.96 points (t, J=6 Hz, 2H), 4,77 (Shir. s, 2H), 6,10 (DD, J=8,2 Hz, 1H), 6,29 (d, J=2 Hz, 1H), 6,66 (d, J=8 Hz, 1H);

MS(ES) m/z 216,1, 218,1 (M+N)+.

Example 8

1 Ethoxy-2-iodine-4-nitrobenzene

A suspension of 2-iodine-4-NITROPHENOL (21 g, 79.2 mmol) [source: Kometani, T.; Watt, .S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], ethyliodide (9 ml, 0.48 mol) and potassium carbonate (40,7 g, 0.3 mol) in 100 ml of N,N-dimethylformamide was heated and kept at 70°C for 3 hours. The reaction mixture was cooled to room temperature and was added ethyl acetate. Inorganic salts were filtered off and washed with ethyl acetate. Organic matter washed three times with water and saturated salt solution, dried over magnesium sulfate and filtered. When the concentration of the filtrate precipitated solid. This solid was filtered and washed with hexane with the receipt of 5.2 g of 1-ethoxy-2-iodine-4-nitrobenzene in the form of white crystals. Concentration of the filtrate gives a further 11.3 g of the desired product, TPL 81-83°;1H-NMR (400 MHz, DMSO-d6) δ: of 1.42 (t, 3H), 4.26 deaths (square, 2H), 7,18 (d, 1H), compared to 8.26 (DD, 1H), 8,55 (d, 1H)

Analysis for C8H8INO3

Calculated: C, 32,79; N, Of 2.75; N, 4,78

Found: C, 32,71; N, 2,58; N, 4.53-In.

Example 9

(4 Ethoxy-3-itfinal)Amin

A suspension of iron (3,81 g, 0.70 mmol) and ammonium chloride (vs. 5.47 g, 102 mmol) in 80 ml of ethanol and 25 ml of water was heated under reflux. Portions were added 1-ethoxy-2-iodine-4-nitrobenzene (5.0 g, 20 mmol)and the reaction mixture was heated under reflux for 1 hour. The hot mixture was filtered through celite, washing with hot ethanol. The filtrate was concentrated in vacuum and about amityvale with ethyl acetate and water. The organic layer was extracted, washed with saturated salt solution, dried over magnesium sulfate and filtered. Removal of solvent in vacuo gave a 5.1 g (4 ethoxy-3-itfinal)amine in the form of butter, light brown;1H NMR (400 MHz, DMSO-d6) δ: of 1.30 (s, 3H), 3,89 (square, 2H), 4,82 (Shir. s, 2H), 6,53 (DD, 1H), 6,72 (d, 1H), 7,11 (d, 1H);

MS(ES) m/z 263,9(M+N)+

Analysis for C8H10INO

Calculated: C, 36,52; N, A 3.83; N, 5,32

Found: C, 36,84; N, 3,71; N, 4,96.

Example 10

2-Iodine-1-(2-methoxyethoxy)-4-nitrobenzene

A suspension of 2-iodine-4-NITROPHENOL (15.5 g, of 58.7 mmol) [source: Kometani, T.; Watt, D.S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], 2-chloroethylnitrosourea ether (10,69 ml, 117 mmol), potassium carbonate (16,8 g, 117 mmol) and sodium iodide (100 mg) in 160 ml of N,N-dimethylformamide was heated at 70-80°C for 4 hours. Additionally added to 5.35 ml of 2-chloroethylnitrosourea ether and the reaction mixture was heated up until thin layer chromatography (TLC) showed the absence of phenol. The mixture was filtered, and the filtrate was concentrated in vacuum. A solid substance was distributed between ethyl acetate and 1 N sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography, elwira gradient from hexane to 50% ethyl acetate in hexane. The resulting oil was recrystallized from ether with the teachings of 7.5 g of 2-iodine-1-(2-methoxyethoxy)-4-nitrobenzene in the form of a solid white color, TPL 35-36°;1H NMR (400 MHz, DMSO-d6) δ: 3,37 (s, 3H), 3,74 (t, 2H), 4,33 (t, 2H), 7,20 (m, 1H), compared to 8.26 (d, 1H), 8,56 (s, 1H)

Analysis for C9H10INO4

Calculated: C, 33,46; N, 3,12; N, 4,34

Found: C, 34,39; N, 3,11; N, To 4.41.

Example 11

[3-Iodine-4-(2-methoxyethoxy)phenyl]amine

A suspension of iron (to 3.89 g, to 69.7 mmol), ammonium chloride (5.0 g, 93,5 mmol) in 100 ml of ethanol and 28 ml of water was heated under reflux. Was added 2-iodine-1-(2-methoxyethoxy)-4-nitrobenzene (7.5 g, 23.2 mmol) and the reaction mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature and filtered through celite (Celite), washed with ethanol. The filtrate was concentrated in vacuum until then, until a precipitate appeared. The precipitate was removed by filtration through Magnesol (Magnesol) and the filtrate was concentrated in vacuum to obtain 4.0 g of [3-iodine-4-(2-methoxyethoxy)phenyl]amine in the form of butter;1H NMR (300 MHz, DMSO-d6) δ: of 3.33 (s, 3H), 3,62 (t, 2H), 3,95 (t, 2H), free 5.01 (d, 2H), 6,55 (d, 1H), 6.73 x (d, 1H), 7,03 (s, 1H);

MS(ES) m/z 294,0(M+N)+

Analysis for C9H12INO2

Calculated: C, 36,88; N, 4,13; N, 4,78

Found: C, 37,28; N, The 4.29; N, 4,80.

Example 12

3,4-Dimethoxyaniline-N-(dimethyl)-2-cyano-2-propenamide

3,4-Dimethoxyaniline (1.50 g, 0,010 mol), dimethylaminoazobenzene (1.50 g, of 0.013 mol) and triethylorthoformate (2 ml, 0.012 mol) was mixed with ethylene glycol (10 ml) and Rast is the PR was heated under reflux. The solution was stirred for 5 hours, then it was allowed to cool to room temperature until the formed precipitate. Was added water (120 ml) and the suspension was filtered. Wet solids suspended in dichloromethane (100 ml)was stirred with magnesium sulfate, filtered and concentrated to obtain 3,4-dimethoxyaniline-N-(dimethyl)-2-cyano-2-propenamide in a solid gray color (1.54 g, 57% yield, 88% purity by GC).1H NMR (300 MHz, DMSO-d6): 10,9 (d, J=21 Hz, 1H), 8,23 (d, J=21 Hz, 1H), was 7.08 (s, 1H), 6,9-6,9 (m, 2H), of 3.78 (s, 3H), and 3.72 (s, 3H), 3,03 (Shir. C, 6N)

Example 13

3,4-Dimethoxyaniline-N-(3-chloro-4-forfinal)-2-cyano-2-propenamide

3,4-Dimethoxyaniline (0,30 g, 0.002 mol) and (3-chloro-4-fluoro)-2-cyanoacetamide (0.50 g, 0,0024 mol) and triethylorthoformate (2 ml, 0.012 mol) was mixed with ethylene glycol (4 ml) and heated under reflux. The solution was stirred for 1.5 hours, then it was allowed to cool to ˜50°and added water (15 ml). The suspension was allowed to cool to room temperature and the solids were separated by filtration, washed with MTBE (2×15 ml) to give 3,4-dimethoxyaniline-N-(3-chloro-4-forfinal)-2-cyano-2-propenamide in a solid beige color (0.55 g, 93% purity by IHMS):1H-NMR (DMSO-d6): 11,3 (d, J=15 Hz, 1H), 9,76 (s, 1H), to 8.70 (d, J=15 Hz, 1H), of 7.97 (d, J=8 Hz, 1H), 7,6-EUR 7.57 (m, 1H), 7,51 (d, J=9 Hz, 1H), 7,38 (t, J=9 Hz, 1H), 7,29 (s, 1H), 6,97 (d, J=8 Hz,1H), and 3.72 (s, 3H), 3,03 (Shir. C, 6N).

Example 14

4-Bromo-3-ethoxyaniline-(N-3-chloro-4-forfinal)-2-cyano-2-propenamide

A 2-l round bottom flask in an atmosphere of N2equipped with mounted above the mixer, refrigerator, thermocouple and a 100 ml dropping funnel, was loaded (3-chloro-4-fluoro)-2-cyanoacetamide (100 g, 0.47 mol), 4-bromo-3-ethoxyaniline hydrochloride (100,4 g, 0.40 mol) and isopropanol (500 ml). Added triethylorthoformate (64 ml, 57 g, 0.38 mol) and the suspension was heated to 72°C. After 1.5 hours was added following aliquot part of triethylorthoformate (64 ml, 57 g, 0.38 mol) and continued reflux. After another 2 hours at the boil under reflux was added to the third aliquot part of triethylorthoformate (64 ml, 57 g, 0.38 mol) and heating was continued for 10 hours. The reaction mixture was cooled to 20-25°and the precipitate was collected by filtration. The filter cake was washed with isopropanol (2×100 ml) and dried under vacuum (45°, 50 mm Hg) to give 4-bromo-3-ethoxyaniline-(N-3-chloro-4-forfinal)-2-cyano-2-propenamide in the form of solid substances not quite white (136,5 g, 70% yield, >97.5% purity by HPLC, TPL 226-228°).1H-NMR (DMSO-d6): 11,3 (d, J=15 Hz, 1H), 9,76 (s, 1H), to 8.70 (d, J=15 Hz, 1H), of 7.97 (d, J=8 Hz, 1H), 7,6-EUR 7.57 (m, 1H), 7,51 (d, J=Hz, 1H), 7,38 (t, J=9 Hz, 1H), 7,29 (s, 1H), 6,97 (d, J=8 Hz, 1H), 4,14 (square, J=9 Hz, 2H), of 1.37 (t, J=9 Hz, 3H).

Example 15

3-Fluoro-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (1,00 g, 3,86 mmol) in 200 ml of isopropanol was added 3-fluoro-p-anisidine (0,60 g of 4.25 mmol). This mixture was heated under reflux with obtaining a transparent yellow solution. To this solution was added dropwise triethylorthoformate (1,72 ml, 10,34 mmol)and the reaction mixture was heated under reflux overnight. Added an additional 2 ml of triethylorthoformate, and the mixture was heated under reflux overnight. Additionally added 2 ml of triethylorthoformate and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and the white solid was collected by filtration, washed with isopropanol and dried overnight at ˜40°With under reduced pressure. Cleaning suspension in hot ethyl acetate followed by the addition of cold hexane gave 1.08 g (68%) of 3-fluoro-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in a solid white color, TPL 275-276°C; MS 408,1; 410,1 (M-N)-.

Analysis for C18H14Cl2FN3About3

Calculated: C, 52,70; N, 3,44; N, 10,24

Found: C, 52,44; N, 3,26; N, 10,14.

Example 16

3-(3-Chloropropoxy)-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (73 mg, 2,84 mmol) in 100 ml isopropanol was added 3-(3-chloropropoxy)-4-methoxyaniline (611 mg, 2,84 mmol). The mixture was heated under reflux and was added dropwise triethylorthoformate (3.0 ml, 18.0 mmol). The reaction mixture was heated under reflux overnight. The warm mixture was filtered and the collected solid is white washed with isopropanol to obtain 610 mg of 3-(3-chloropropoxy)-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, TPL 185-192°C; MS(ES) m/z 482,1, 484,2, of 486.0 (M-N)-.

Analysis for C21H20Cl3N3About4

Calculated: C, 52,03; N, 4,16; N, 8,67

Found: C, 51.89ˆ; N, 4,11; N 8,53.

Example 17

3-Bromo-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (900 mg, 3.46 mmol) in 100 ml isopropanol was added 3-bromo-4-methoxyaniline (700 mg, 3.46 mmol). This mixture was heated under reflux and was added dropwise triethylorthoformate (3,3 ml of 19.8 mmol). The reaction mixture was heated under reflux for 6 hours. The warm mixture was filtered and the collected solid is white washed with isopropanol to obtain 376 mg of 3-bromo-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, TPL >250°C; MS(ES) m/z 467,7; 469,9; 471,7 (M-N)-.

Analysis for C18H14BrCl2N3the 3

Calculated: C, 45,89; N, 3,00; N, 8,92

Found: C, 45,75; N, 2,77; N, 8,78.

Example 18

3-Bromo-4-ethoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (715 mg, is 2.74 mmol) in 50 ml of isopropanol was added 3-bromo-4-ethoxyaniline (586 mg, a 2.71 mmol). This mixture was heated under reflux and was added dropwise triethylorthoformate (2.7 ml, 16.2 mmol). The reaction mixture was heated under reflux overnight. The warm mixture was filtered and the collected solid is white washed with isopropanol to obtain 666 mg of 3-bromo-4-ethoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, TPL >250°C; MS(ES) m/z 482,0; 484,0; of 486.0 (M-N)-.

Analysis for C19H16BrCl2N3About3

Calculated: C, 47,04; N, Of 3.32; N, 8,66

Found: C, 46,64; N, 3,40; N, 8,59.

Example 19

4-Bromo-3-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (6,1 g, 23.5 mmol) in 500 ml of isopropanol was added 5-amino-2-bromoanisole (5.0 g, of 24.8 mmol). This mixture was heated under reflux with obtaining a transparent yellow solution. To this solution was added dropwise triethylorthoformate a (10.6 ml, 63.5 mmol) and the reaction mixture was heated under reflux for 5 hours. Additionally added is to 10.6 ml of triethylorthoformate and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature. The solid is collected by filtration, washed with isopropanol and ethyl acetate, and then dried overnight at ˜40°With under reduced pressure to obtain 8.1 g (73%) of 4-bromo-3-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in a solid yellow color, TPL >250°C; MS(ES) m/z 470,0; 472.0 M. (M+N)+.

Analysis for C18H14BrCl2N3About3

Calculated: C, 45,89; N, 3,00; N, 8,92.

Example 20

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodine-4-methoxyphenyl)amino]prop-2-ename

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (5,00 g, 19,30 mol) in 400 ml isopropanol in an atmosphere of N2added 3-iodine-p-anisidine (5,80 g, 23,16 mmol). This mixture was heated under reflux with obtaining a transparent yellow solution. To this solution was added dropwise triethylorthoformate (at 8.60 ml, br52.11 mmol) and the reaction mixture was heated under reflux overnight. Additionally added 10 ml of triethylorthoformate and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and a solid white substance was collected by filtration, washed with isopropanol and dried overnight at ˜40°With under reduced pressure. Cleaning suspendirovanie in hot ethyl acetate with p the following add cold hexane gave of 8.50 g (85%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodine-4-methoxyphenyl)amino]prop-2-enamide in a solid yellow color, TPL 289-290°C; MS(ES) m/z byr516.7 (M-N)-.

Analysis for C18H14Cl2IN3About3

Calculated: C, 41,73; N, 2,72; N, 8,11

Found: C, 40,66; N, To 2.94; N, Of 7.90.

Example 21

4 Ethoxy-3-foronline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (5.9 g, 22.7 mmol) in 400 ml of isopropanol was added 4-ethoxy-3-ftoranila (3.7 g, to 23.8 mmol). This mixture was heated under reflux to obtain a clear solution. To this solution was added dropwise triethylorthoformate (to 11.6 ml, to 69.6 mmol) and the reaction mixture was heated under reflux for 18 hours. Additionally dropwise added triethylorthoformate (to 11.6 ml, to 69.6 mmol) and the reaction mixture was heated under reflux for 42 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with ethyl acetate and dried in vacuum at 40°to obtain 6.4 g (67%) 4 ethoxy-3-foronline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in a solid gray color, TPL 245-247°C; MS 424,1; 426,1 (M+N)+.

Analysis for C19H16Cl2FN3About3

Calculated: C, 53,79; N, Of 3.80; N, 9,90

Found: C, 53,39; N, Of 3.97; N, RS 9.69.

Example 22

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(Tien-3-ylamino)prop-2-ename

To a suspension of 2-cyano-N-(2,4-di the ENT-5-methoxyphenyl)ndimethylacetamide (1,57 g, 0.06 mmol) in 200 ml of isopropanol was added 3-aminothiophene (600 mg, the 6.06 mmol). The mixture was heated under reflux and was added dropwise triethylorthoformate (6.5 ml, 39,1 mmol). The mixture was heated under reflux overnight. Additionally added 3-aminothiophene (214 mg, of 2.16 mmol) and the reaction mixture was heated under reflux for 5 hours. Additionally added 3-aminothiophene (100 mg, 1.01 mmol) and the reaction mixture was heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with isopropanol to obtain 572 mg (26%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(Tien-3-ylamino)prop-2-enamide in the form of a solid yellow-brown, TPL >250°C; MS 366,0; 368,2 (M-N)-.

Analysis for C15H11Cl2N3About2S - 1,0 N2About

Calculated: C, 46,64; N, 3,39; N, 10,88

Found: C, 46,37; N, To 2.94; N, Or 10.60.

Example 23

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-itfinal)amino]acrylamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (5,44 g, 21,0 mmol) in 350 ml of isopropanol in an atmosphere of N2was added (4-ethoxy-3-itfinal)amine (5.0 g, 19,30 mmol). The mixture was heated under reflux and was added dropwise triethylorthoformate (8.53 ml, 51,30 mmol)and the reaction mixture was heated with reverse hall is dildocam during the night. The mixture was allowed to cool to room temperature and the yellow solid was collected by filtration, washed with isopropanol and dried overnight at ˜40°With under reduced pressure to get 5,46 g (54%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-itfinal)amino]prop-2-enamide in a solid yellow color, TPL >245°C; MS (ES and RI) m/z 531,01(M)+.

Analysis for C19H16Cl2IN3About3

Calculated: C, 42,88; N, 3,03; N, of 7.90

Found: C, 42,99; N, Of 2.97; N, 7,74.

Example 24

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodine-4-(2-methoxyethoxy)phenyl]amino}acrylamide

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (3.2 g, 12.4 mmol) and [3-iodine-4-(2-methoxyethoxy)phenyl]amine (4.0 g, 13.7 mmol) in 350 ml of isopropanol was heated under reflux and was added dropwise triethylorthoformate (5.6 ml, or 33.7 mmol). The reaction mixture was heated under reflux for 3 hours. Additionally dropwise added triethylorthoformate (2.0 ml, of 12.0 mmol) and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with isopropanol, diethyl ether and ethyl acetate, and then dried in vacuum to obtain 5.5 g of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodine-4-(2-methoxyethoxy)phenyl]amino}acrylamide as the firmness of the Dogo substances yellow TPL 209-210°C; MS(ES) 560, 0M; 562,1 (M-N)-.

Analysis for C20H18Cl2IN3About4

Calculated: C, 42,73; N, 3,23; N, 7,47

Found: C, 43,04; N, Of 3.07; N, 7,28.

Example 25

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromo)phenyl)amino]acrylamide

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (3.0 g, 11.5 mmol) and 3-bromoaniline (1.3 ml, with 11.9 mmol) in 250 ml of isopropanol was heated under reflux and was added dropwise triethylorthoformate (12 ml, 72.2 mmol). The reaction mixture was heated under reflux overnight. The mixture was let cool slightly, and a solid substance was collected by filtration still warm solution, washed with isopropanol and diethyl ether to obtain 2,05 g 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromo)phenyl)amino]acrylamide in a solid yellow color, TPL >250°C; MS(ES) 437,8; 439,7; 441,8 (M-N)-.

Analysis for C17H12BrCl2N3About2

Calculated: C, 46,29; N, To 2.74; N, at 9.53

Found: C, 46,33; N, 2,73; N, 9,40.

Example 26

6-Bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova

In a 22-l round bottom flask in an atmosphere of N2equipped with a mounted top stirrer, a thermocouple, a refrigerator and a 1000-ml addition funnel, was loaded with 4-bromo-3-ethoxyaniline-(N-3-chloro-4-forfinal)-2-cyano-2-propenamide (1000 g, to 2.29 mol), methanol (40 ml) and acetonitril the (7,50 l). The suspension was heated to 80-82°C. In the addition funnel was loaded phosphorus oxychloride (740 g of 4.83 mol) was added within 30 minutes. The suspension was heated under reflux for 24 hours up until the present <3% of the original substances by HPLC. The mixture was cooled to 0-10°and filtered. The filter cake was washed with acetonitrile (3×0,63 kg) and dried on the filter funnel for 2 hours. In a 50 l round bottom flask, equipped with a mounted top stirrer, a thermocouple, a refrigerator and a 1000-ml addition funnel, was loaded sludge from the filter specified above. Added THF (of 4.44 kg) and the suspension was heated to 35-40°C. In the flask was mixed 28% ammonium hydroxide (0,63 kg) and water (2 kg) and transferred into an addition funnel. To a suspension in THF solution was added ammonium hydroxide for 30 minutes, keeping the temperature below 55°C. was Added water (10 kg) for 25 minutes, then the obtained suspension was cooled to 15-20°C. the Precipitate was collected by filtration, then washed with hot water (3×1 kg), acetonitrile (2×1 kg) and dried in vacuo (55 mm Hg, 65° (C) to obtain 6-bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova in a solid orange-yellow (806 g, 84% yield, >96% purity by HPLC, TPL 213-215°C.1H-NMR (300 MHz, CDCl3): 8,7 (s, 1H), to 7.99 (s, 1H), 7,40-6,91 (m, 5H), 4,18 (sq, J=7.5 Hz, 2H), and 1.56 (t, J=7.5 Hz, 3H)

Example 27

6-bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova

In a 250 ml round bottom flask in an atmosphere of N2equipped with a mounted top stirrer, a thermocouple, a refrigerator and a 10-ml addition funnel, was loaded with 4-bromo-3-ethoxyaniline-(N-3-chloro-4-forfinal)-2-cyano-2-propenamide (10.0 g, is 0.023 mol), pyridine (3.80 g, 0,048 mol) and toluene (100 ml). The suspension was heated to 110°C. In the addition funnel was loaded phosphorus oxychloride (4,4 ml 0,047 mol) was added in a period of 3.75 hours. Was heated for 0.25 hour before until attended <3% of the original substances by HPLC, and then the suspension was allowed to cool to room temperature. To the reaction mixture was slowly added water (50 ml), then the mixture was podslushivaet by adding 50% aqueous sodium hydroxide solution. The suspension was cooled to 10-15°and the precipitate was collected by filtration, then washed with water (2×10 ml), toluene (2×10 ml) and dried in vacuo (55 mm Hg, 65° (C) to obtain 6-bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova in a solid orange-yellow (6,90 g, 72% yield, >92,2% purity by HPLC).1H-NMR (300 MHz, CDCl3): 8,7 (s, 1H), to 7.99 (s, 1H), 7,40-6,91 (m, 5H), 4,18 (sq, J=7.5 Hz, 2H), and 1.56 (t, J=7.5 Hz, 3H).

Example 28

6-bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova

A 5-l round bottom flask in an atmosphere of N2the equipment is nnow mounted on top of the agitator, thermocouple, a refrigerator and a 500-ml addition funnel, was loaded with 4-bromo-3-ethoxyaniline-(N-3-chloro-4-forfinal)-2-cyano-2-propenamide (500 g, to 1.14 mol), 1-butanol (15 g, 0.20 mol) and toluene (3.5 l). The suspension was heated to 105-108°C. In the addition funnel was loaded phosphorus oxychloride (370 g, 2,41 mol) was added to the suspension for 10 hours. Was heated for another 16 hours before until attended <3% of the original substances by HPLC. The mixture was cooled to 0-10°and filtered. The filter cake was washed with toluene (2×0.3 kg) and the filter cake was dried on the filter funnel over 2 hours.

A 12-l round bottom flask, equipped with a mounted top stirrer, a thermocouple, a refrigerator and a 1000-ml addition funnel, was loaded sludge from the filter specified above. Added THF (2,22 kg) and the suspension was heated to 35-40°C. In the flask was mixed 28% ammonium hydroxide (0,63 kg) and water (1 kg) and transferred into an addition funnel. To a suspension in THF solution was added ammonium hydroxide for 30 minutes, keeping the temperature below 55°C. was Added water (5 kg) for 25 minutes, then the obtained suspension was cooled to 15-20°C. the Precipitate was collected by filtration, then washed with hot water (3×1 kg), acetonitrile (2×0.4 kg) and dried in vacuo (55 mm Hg, 65° (C) to obtain 6-bromo-[7-ethoxy-4-(3-chloro-4-forfinal)amino]-3-hinolincarbonova in the form of solid substances is orange-yellow (389,1 g, 81% yield, >97.5% purity by HPLC).1H-NMR (300 MHz, CDCl3): 8,7 (s, 1H), to 7.99 (s, 1H), 7,40-6,91 (m, 5H), 4,18 (sq, J=7.5 Hz, 2H), and 1.56 (t, J=7.5 Hz, 3H)

Analysis for C18H12BrClFN3About

Calculated: C, 51,39; N, Is 2.88; N, 9,99

Found: C, 51,50; N, Of 2.75; N, Of 10.09.

Example 29

6,7-Dimethoxy-4-(N,N-dimethylamino)-3-hinolincarbonova

A suspension of 3,4-dimethoxyaniline-N-(dimethyl)-2-cyano-2-propenamide (0,500 g, 1.82 mmol) in acetonitrile (10 ml) was treated with phosphorus oxychloride (0.17 ml, 0.28 g, 1.82 mmol) and was heated under reflux. The mixture was stirred for 1 hour and was then combined with an additional aliquot part of the phosphorus oxychloride (0.17 ml, 0.28 g, 1.82 mmol). The mixture was heated under reflux for 8 hours, then stirred at room temperature for 24 hours. The resulting solution was concentrated in vacuo and stirred with an aqueous solution of sodium carbonate. The mixture was extracted with methylene chloride (3×30 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 6,7-dimethoxy-4-(N,N-dimethylamino)-3-hinolincarbonova in the form of a solid yellow-brown (0,37 g, 79%, 89% purity by GC).

Example 30

6,7-Dimethoxy-4-[(3-chloro-4-forfinal)amino]-3-hinolincarbonova

A suspension of 3,4-dimethoxy-N-(3-chloro-4-forfinal)-2-cyano-2-propenamide (0.84 g, of 2.23 mmol) in acetonitrile is (10 ml) was treated with phosphorus oxychloride (0,42 ml, of 0.68 g, 4,50 mmol) and was heated under reflux for 8 hours. The suspension was cooled to room temperature and was stirred with a saturated solution of sodium carbonate (70 ml). The mixture was extracted with methylene chloride (3×70 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 6,7-dimethoxy-4-[(3-chloro-4-forfinal)amino]-3-hinolincarbonova in a solid brown color (0.74 g, 93%, 95% by LC-MS, 1.3% of isomer by LC-MS).1H NMR (300 MHz, DMSO-d6).

Example 31

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-hinolincarbonova

A suspension of 4-ethoxy-3-foronline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (6,28 g of 14.8 mmol) in 54 ml of acetonitrile and 2.0 ml of methanol was heated under reflux and was added dropwise phosphorus oxychloride (8,3 ml, and 88.8 mmol). The mixture was heated under reflux for 17 hours. The resulting solution was concentrated in vacuo and to the residue was added acetonitrile. The solid is collected by filtration, washed with acetonitrile. The solid is suspended in tetrahydrofuran and neutralized with concentrated ammonium hydroxide. After stirring for 30 minutes was added water and the mixture was stirred for 1 hour. The solid is collected by filtration, washed with water and the placenta is brilliant washing with diethyl ether and hexane 1:1. Solid light yellow color was dried in vacuum to obtain 2.2 g (37%) 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-hinolincarbonova, TPL 185-187°;1H-NMR (400 MHz, DMSO-d6) δ: 1,95 (t, J=7 Hz, 3H), a 3.87 (s, 3H), 4,29 (sq, J=7 Hz, 2H), 7,39 (s, 1H), 7,66-7,81 (m, 2H), of 8.09 (d, J=9 Hz, 1H), 8,49 (s, 1H), 9,80 (s, 1H);

MS(ES) m/z 406,1; 408,2(M+N)+

Analysis for C19H14Cl2FN3About2- 0,4 H2About

Calculated: C, 55,20; N, 3,61; N, 10,16

Found: C, 55,25; N, Of 3.53; N, 10,15.

Example 32

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-hinolincarbonova

To a suspension of 3-fluoro-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (360 mg, 0.88 mmol) in 40 ml of acetonitrile was added 0.1 ml of methanol. The reaction mixture was heated under reflux and was added dropwise phosphorus oxychloride (0,65 ml, 7.0 mmol) with a syringe. After 2 hours the mixture became a clear orange solution. This solution was heated under reflux overnight. After 24 hours the reaction mixture was cooled in an ice bath and the solid was collected by filtration, washed with cold acetonitrile (20 ml) and then suspended in tetrahydrofuran (50 ml). And to the filtrate of acetonitrile, and to tetrahydropyranol suspension was added concentrated ammonium hydroxide solution (2×25 ml) and the mixture was stirred for 1 hour is. Was added water (2×400 ml) and stirring was continued for 2 hours. The obtained solids were combined, washed with hot water and dried under reduced pressure at ˜40°during the night to obtain 189 mg (55%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-hinolincarbonova in the form of orange crystals, TPL 219-221°;1H-NMR (400 MHz, DMSO-d6) δ: a 3.87 (s, 3H), was 4.02 (s, 3H), of 7.36 (s, 1H), 7,65-7,80 (m, 2H), 8,08 (d, J=9 Hz, 1H), 8,48 (s, 1H), 9,85 (s, 1H);

MS(ES) m/z 392,0; 394,0(M+N)+

Analysis for C18H12Cl2FN3About2- 0.5 N2About

Calculated: C, 53,88; N, Of 3.27; N, 10,48.

Found: C, 54,09; N, 3,20; N, 10,24.

Example 33

7-(3-Chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-hinolincarbonova

A suspension of 3-(3-chloropropoxy)-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (462 mg, 0.95 mmol) in 40 ml of acetonitrile was heated under reflux and dropwise via a syringe was added phosphorus oxychloride (0,60 ml). The reaction mixture was heated under reflux overnight, then cooled to room temperature and concentrated in vacuum. The residue was cooled to 0°and added a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for 10 minutes and the solid is collected by filtration, washing with water. The solid is suspended is in hot ethyl acetate and methanol and then filtered to obtain 200 mg of 7-(3-chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-hinolincarbonova in the form of a solid pale yellow color. 1H-NMR (400 MHz, DMSO-d6) δ: 2,30 (m, 2H), 3,84 (t, J=6 Hz, 1H), 3,88 (s, 3H), 4,01 (s, 3H), 4,32 (t, J=6 Hz, 2H), 7,46 (s, 1H), 7,51 (s, 1H), 7,81 (s, 1H), 8,14 (s, 1H), 8,81 (s, 1H), 10,83 (Shir. s, 1H);

MS(ES) m/z 466,1; 468,1(M+N)+.

Example 34

7-Bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-hinolincarbonova

A suspension of 3-bromo-4-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (4,00 g, 8.50 mmol) in 200 ml of acetonitrile was heated under reflux and dropwise via a syringe was added phosphorus oxychloride (5.0 ml). The reaction mixture was heated under reflux overnight, then cooled to room temperature and concentrated in vacuum. The residue was cooled to 0°and added a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for 1 hour and then was extracted with a large volume of ethyl acetate. The organic layer was washed saturated aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. Reduced the volume of the filtrate until then, until you appear solid. The solids were collected by filtration, washing with diethyl ether and hexane to obtain 1.73 g of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-hinolincarbonova in the form of a solid light yellowish-brown color, TPL >250°C.1H-NMR (400 MHz, DMSO-d6) δ: a 3.87 (s, 3H), Android 4.04 (s, 3H), 7,41 (s, 1 is), for 7.78 (s, 1H), to 7.99 (s, 1H), they were 8.22 (s, 1H), 8,48 (s, 1H), to 9.93 (s, 1H);

MS(ES) m/z 449,9; 451,9; 453,9(M-N)-

Analysis for C18H12BrCl2N3About2

Calculated: C, 47,71; N, To 2.67; N, 9,27

Found: C, 47,94; N, To 2.74; N, 9,03.

Example 35

7-Bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-3-hinolincarbonova

A suspension of 3-bromo-4-ethoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (630 mg, 1,29 mmol) in 35 ml of acetonitrile was heated under reflux and dropwise via a syringe was added phosphorus oxychloride (0,80 ml). The reaction mixture was heated under reflux overnight, then cooled to room temperature. The solids were collected by filtration, washing with saturated aqueous sodium bicarbonate solution. The solids were stirred with saturated aqueous sodium bicarbonate for 1 hour and then collected by filtration, washing with saturated aqueous sodium bicarbonate solution and water. A solid substance was recrystallized from methanol and dried in vacuum to obtain 225 mg of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-3-hinolincarbonova in a solid yellow color, TPL >250°C.1H-NMR (400 MHz, DMSO-d6) δ: 1,47 (t, J=7 Hz, 3H), a 3.87 (s, 3H), 4,32 (sq, J=7 Hz, 2H), 7,45 (s, 1H), 7,82 (s, 1H), 8,16 (s, 1H), of 8.27 (s, 1H), 8,76 (s, 1H), of 10.73 (s, 1H);

MS(ES) m/z 466,1; 468,0; 470,1(M+N)+.

Analysis of DL is 19H14BrCl2N3About2- 2,0 H2About

Calculated: C, 45,35; N, 3,61; N, 8,35

Found: C, 44,97; N, 3,17; N, 8,07.

Example 36

6-Bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-methoxy-3-hinolincarbonova

To a suspension of (5,13 g, 11 mmol) 4-bromo-3-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in 400 ml of acetonitrile was added 1.5 ml of methanol. The mixture was heated under reflux and was added dropwise phosphorus oxychloride (4,10 ml, to 44.0 mmol). The resulting mixture was heated under reflux for 26 hours. Addition was added phosphorus oxychloride (2.1 ml) and methanol (0.75 ml) and the mixture was heated under reflux for 21 hours. After cooling to 0-5°in an ice bath, the solid was collected by filtration, washed with cold acetonitrile (100 ml) and then suspended in tetrahydrofuran (100 ml). To tetrahydropyranol suspension was added concentrated ammonium hydroxide solution and the mixture was stirred for 1 hour. Was added water (300 ml) and stirring was continued for 1 hour. The solid is collected by filtration, washed with hot water (46° (C)acetonitrile and dried in vacuum over night with the release of 2.1 g of 4-bromo-3-methoxyaniline-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide. The combined acetonitrile filtrate and wash liquid were combined and added to the end of utrirovanny ammonium hydroxide. Received the combined acetonitrile and the mixture was stirred for 1 hour. Added water and the stirring was continued for 1 hour. The solid is collected by filtration, washed with water, ethyl acetate and ether, then dried in vacuum to obtain 1.92 g (39%) of 6-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-methoxy-3-hinolincarbonova in a solid yellow color, TPL 256-257°;1H-NMR (400 MHz, DMSO-d6) δ: 3,85 (s, 3H), Android 4.04 (s, 3H), 7,37 (s, 1H), 7,46 (s, 1H), of 7.75 (s, 1H), 8,56 (s, 1H), 8,89 (s, 1H), to 9.93 (s, 1H);

MS(ES) m/z 451,9; 454,0 (M+N)+.

Analysis for C18H12BrCl2N3About2

Calculated: C, 47,71; N, To 2.67; N, 9,27

Found: C, 47,41; N, To 2.67; N, 9,56.

Example 37

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-iodine-6-methoxy-3-hinolincarbonova

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodine-4-methoxyphenyl)amino]prop-2-enamide (720 mg, of 1.39 mmol) in 40 ml of acetonitrile was added 0.2 ml of methanol. The mixture was heated under reflux and dropwise via a syringe was added phosphorus oxychloride (1,24 ml of 13.9 mmol). This solution was heated under reflux overnight. After 24 hours the mixture was cooled in an ice bath and the solid was collected by filtration, washing with cold acetonitrile (40 ml), and then suspended in tetrahydrofuran (100 ml). As to the combined acetonitrile filtrate and tetrahydropyranol suspension on balali concentrated ammonium hydroxide solution (2× 50 ml) and the mixture was stirred for 1 hour. Was added water (2×800 ml) and stirring was continued for 2 hours. The obtained solids were combined, washed with hot water and dried under reduced pressure at ˜40°during the night to obtain 200 mg (29%) 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodine-6-methoxy-3-hinolincarbonova in a solid yellow color, TPL 253-254°;1H-NMR (400 MHz, DMSO-d6) δ: 3,86 (s, 3H), of 4.00 (s, 3H), 7,33 (s, 1H), 7,74 (s, 1H), 7,86 (s, 1H), 8,39 (s, 1H), 8,43 (s, 1H), being 9.61 (s, 1H);

MS(ES) m/z 500,0; 502,1 (M+N)+

Analysis for C18H12Cl2IN3About2H2About

Calculated: C, 41,72; N, 2,72; N, 8,11

Found: C, 41,80; N, 2,52; N, 7,87.

Example 38

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-iodine-3-hinolincarbonova

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-ethoxy-3-itfinal)amino]prop-2-enamide (2.0 g, 3,76 mmol) in 100 ml of toluene was heated under reflux and dropwise via a syringe was added phosphorus oxychloride (3.5 ml, of 37.6 mmol). The suspension was heated under reflux for 6 hours and addition was added phosphorus oxychloride (3.5 ml, of 37.6 mmol), which gave a slow formation of a dark solution. After 72 hours the mixture was cooled to room temperature, the solid was filtered and washed with toluene and ether. Solid light brown what about the colors were dried under reduced pressure at ˜ 40°during the night to obtain 1.47 g (76%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-iodine-3-hinolincarbonova in a solid yellow color, TPL 213-215°;1H-NMR (400 MHz, DMSO-d6) δ: to 1.48 (t, 3H, J=6.9 Hz), 4,32 (square, 2H, J=6.9 Hz), 3,88 (s, 3H), 7,53 (s, 1H), 7,87 (s, 1H), of 8.06 (s, 1H), 8,49 (s, 1H), of 9.02 (s, 1H), 11,14 (Shir. s, 1H);

MS(ES) m/z 514,1 (M+N)+.

Analysis for C19H14Cl2IN3About2- 4,0 HCl

Calculated: C, 34,58; N, Of 2.75; N, 6,37

Found: C, 34,79; N, 2,60; N, 6,13.

Example 39

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-iodine-6-(2-methoxyethoxy)-3-hinolincarbonova

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodine-4-(2-methoxyethoxy)phenyl]amino}acrylamide (1.0 g, of 1.80 mmol) in 35 ml toluene was heated under reflux and was added dropwise phosphorus oxychloride (1.7 ml, 18.0 mmol). The mixture was heated under reflux for 2 hours and was added an additional 1.7 ml of phosphorus oxychloride. The mixture continued to heat under reflux for 2 hours and additionally was added 1.7 ml of phosphorus oxychloride and the reaction mixture was heated under reflux overnight. Then the reaction mixture was cooled to room temperature and added water, followed by adding 10 N sodium hydroxide. The mixture was stirred in an ice bath for 30 minutes and the precipitate was collected by filtration, washed with meth what langarica to obtain 870 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodine-6-(2-methoxyethoxy)-3-hinolincarbonova in the form of a solid yellow; 1H-NMR (400 MHz, DMSO-d6) δ: to 3.41 (s, 3H), 3,81 (t, 2H), a 3.87 (s, 3H), 4,34 (t, 2H), 7,40 (s, 1H), 7,78 (s, 1H), 7,88 (s, 1H), 8,43 (s, 1H), 8,45 (s, 1H), 9,85 (s, 1H);

MS(ES) m/z 542,1; 544,1 (M-N)-.

Analysis for C20H16Cl2IN3About2- 4,0 HCl

Calculated: C, 34,81; N, 2,92; N, 6,09

Found: C, 35,04; N, 2,53; N, 5,95.

Example 40

7-Bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-hinolincarbonova

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-bromo)phenyl]amino)acrylamide (1.5 g, 3,40 mmol) in 50 ml of acetonitrile was heated under reflux and was added dropwise phosphorus oxychloride (4.0 ml, 42,4 mmol). The mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and volatiles were removed in vacuum. To the residue was added ice followed by the addition of saturated aqueous sodium bicarbonate solution. The mixture was stirred, and then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was recrystallized from ethyl acetate to obtain 310 mg of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-hinolincarbonova. The mother liquid was concentrated in vacuo, and purified flash column-chromatography, elwira gradient from 3:1 hexane:ethyl acetate to 1:1 hexane:ethyl acetate to obtain 310 mg of 7-bromo-4-[(2,4-dichloro-5-IU is oxyphenyl)amino]-3-hinolincarbonova in the form of a solid light orange color; 1H-NMR (400 MHz, DMSO-d6) δ: a 3.87 (s, 3H), 7,42 (s, 1H), 7,79 (s, 1H), of 7.97 (s, 1H), 8,14 (s, 1H), 8,56 (s, 1H), cent to 8.85 (s, 1H);

MS(ES) m/z 422,0; 423,9; 426,0 (M+N)+.

Analysis for C17H10BrCl2N3About

Calculated: C, 48,26; N, Of 2.38; N, to 9.93

Found: C, 48,47; N, Is 2.37; N, 9,70.

Example 41

7-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(Tien-3-ylamino)prop-2-enamide (500 mg, 1.35 mmol) in 35 ml of acetonitrile was heated under reflux and was added dropwise phosphorus oxychloride (from 0.84 ml, 8.98 mmol). The mixture was heated under reflux overnight. The resulting solution was concentrated in vacuo and the residue was cooled to 0°C. was Added ice water, followed by slow addition of saturated aqueous sodium bicarbonate solution. The mixture was stirred for 10 minutes and was distributed between ethyl acetate and additional saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue is triturated with ethyl acetate and hexane to obtain 337 mg (71%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile, TPL 208-210°;1H NMR (400 MHz, DMSO-d6) δ: 3,85 (s, 3H), 7,39 (s, 1H), 7,46 (d, J=5 Hz, 1H), 7,76 (s, 1H), 8,11 (d, J=5 Hz, 1H), 8,61 (s, 1H), 9,74 (s, 1H);

MS(ES) m/z 348,1; 35,0 (M-N) -.

Analysis for C15H9Cl2N3About2S - 0.5 N2About

Calculated: C, 50,15; N, Of 2.81; N, 11,70

Found: C, 50,32; N, 2,62; N, 11,54.

Example 42

1-[3-(2-Methoxy-5-nitrophenoxy)propyl]-4-methylpiperazin

2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (100 g, 0,407 mol) and sodium iodide (9.2 grams, 0,614 mol) was added to 520 ml of anhydrous 1,2-dimethoxyethane. To the mixture was then added N-methylpiperazine (82 g, 0,814 mol). The reaction mixture was stirred and heated under reflux. The reaction mixture was monitored by HPLC. After 8 hours of warming casing was removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture is then immersed in 1 l of ethyl acetate and stirred for at least 1 hour. Precipitated solid bright yellow. The mixture was filtered and washed, and the salt was collected with ethyl acetate. The filtrate is once washed with 400 ml of 0.5 N NaOH. The layers were separated and the organic layer was washed with water (3×390 ml). The combined organic layers were concentrated under vacuum at 35-40°With receipt of 97.8 g (oil light orange) (77%);1H-NMR (300 MHz, CDCl3) δ: to $ 7.91 (DD, J=2,6, 9 Hz, 1H), to 7.77 (d, J=2.6 Hz, 1H), make 6.90 (d, J=9 Hz, 1H), 4,14 (t, J=7 Hz, 2H), 3.96 points (s, 3H), of 2.54 (t, J=7 Hz, 2H), 2,48 (m, 8H), is 2.30 (s, 3H), of 2.06 (m, 2H);

MS(ES) m/z 310,1 (M+H).

Example 43

4-Methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamine

It is aStore 1-[3-(2-methoxy-5-nitrophenoxy)propyl]-4-methylpiperazine (2.5 g, 8.1 mmol) in 25 ml of isopropanol was added 10% Pd-C (0.25 g, 10 wt.%). The mixture was shaken at 35-40 lbs/inch2hydrogen in a Parr shaker until then, until he stopped absorption of hydrogen. The reaction mixture was purged with nitrogen and filtered through celite. The resulting solution was concentrated in vacuo to obtain crude 4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamine in the form of a yellow oil, which was directly used at the stage of the combinations described below.1H-NMR (300 MHz, CDCl3) δ: of 6.71 (d, J=8 Hz, 1H), 6,33 (d, J=2.4 Hz, 1H), 6,23 (DD, J=2,4, 8 Hz, 1H), of 4.05 (t, J=8 Hz, 2H), 3,80 (s, 3H), 2,53 (m, 10H), is 2.30 (s, 3H), 2,02 (m, 2H).

Example 44

2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamino}acrylamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (1,75 g of 6.75 mmol) in 8.2 ml of isopropanol was added triethylorthoformate (1.5 g, 10.1 mmol). The mixture was heated under reflux. After 20 minutes, was added dropwise 4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamine in 20 ml of isopropanol so as to maintain the boil. After 26 hours, the reaction mixture was cooled to room temperature and suspended solids were filtered off. The solids were washed with isopropanol until then, until the wash liquid became colorless. Solid yellow svetasunshine in vacuum with the receipt of 3.45 g (93%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamino}acrylamide in the form of a mixture of isomers. 1H-NMR (300 MHz, CDCl3) δ: 11,35 (Shir. d, 1H), 8,17 (m, 2H), 7,76 (d, 1H), 7,41 (s, 1H), to 6.88 (m, 1H), 6,69 (m, 2H), 4,10 (t, J=7 Hz, 2H), 3.96 points (s, 3H), a 3.87 (s, 3H), by 2.55 (t, J=7 Hz, 2H), 2,48 (m, 8H), to 2.29 (s, 3H), of 2.06 (m, 2H);

MS(ES) m/z 548,1 (M+).

Analysis for C10H14ClNO2

Calculated: C, 55,69; N, Is 6.54; N, of 6.49

Found: NA, 55,49; N, 6,59; N, 6,32.

Example 45

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy-3-hinolincarbonova

A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]phenylamino}acrylamide (6 g, 10.9 mmol) in 9 ml of acetonitrile was heated under reflux and was added dropwise phosphorus oxychloride (21.8 g, 142 mmol). The reaction mixture was heated under reflux for 40 hours and then cooled to room temperature. The mixture was cooled to 0°and slowly and carefully added 10 N sodium hydroxide solution to neutralize the reaction mixture. Damping was very exothermic; sodium hydroxide was added so that the temperature of the mixture was maintained below 55°C. the Mixture was podslushivaet to pH 9-10. After cooling to <30°With added 500 ml of ethyl acetate and the resulting mixture was stirred for 15 minutes. The solids were filtered off and then washed with ethyl acetate. The layers of the filtrate were separated and the organic layer was concentrated in vacuum. Neojidannaya was dissolved in 45 ml of methanol and stirred at room temperature for 1 hour. A solid crystalline substance, which was formed, was filtered and washed with a minimal amount of cold methanol. The filtrate was concentrated and the procedure was repeated approximately half this amount of methanol. Two portions were combined to obtain 4.3 g (75%) of the crude 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy-3-quinoline-3-carbonitrile;1H-NMR (300 MHz) δ: 8,71 (s, 1H), 7,50 (s, 1H), 7,43 (s, 1H), 6.90 to (s, 1H), 6,46 (s, 1H), 4.26 deaths (t, J=7 Hz, 2H), of 3.78 (s, 3H), to 3.67 (s, 3H), 2.57 m (t, J=7 Hz, 2H), 2,48 (m, 8H), to 2.29 (s, 3H), 2,12 (m, 2H);

MS(ES) m/z 265,6; 530,1 (M+).

Example 46

4-(2-Methoxy-5-nitrophenyl)-2-furaldehyde

To a mixture of 2-iodine-4-nitroanisole (565 mg, 2.02 mmol) and pinacolone ether 2-formylfuran-4-Bronevoy acid (670 mg, 3.03 mmol) in 20 ml of dimethyl ether of ethylene glycol and 12 ml of saturated aqueous sodium bicarbonate solution was added 80 mg of tetrakis(triphenylphosphine)palladium(0). The reaction mixture was heated under reflux overnight and then allowed to cool to room temperature and added to a biphasic mixture of 10% methanol in ethyl acetate and water. The solid is collected by filtration, washed with ethyl acetate and water to obtain 259 mg (52%) of 4-(2-methoxy-5-nitrophenyl)-2-furaldehyde in the form of a solid light brown color.1H-NMR (DMSO-d6) δ: 4,07 (s, 3H), 7,37 (d, J=9 Hz, 1H), 8,20-8,29(m, 2H), 8,55 (d, J=3 Hz, 1H), 8,69 (s, 1H), 9,68 (s, 1H);

MS 247,1 (M-N)-.

Example 47

1-{[4-(2-Methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazin

A mixture of 4-(2-methoxy-5-nitrophenyl)-2-furaldehyde (230 mg, of 0.93 mmol) and N-methylpiperazine (0,90 ml, 8.1 mmol) in 20 ml of dichloromethane and 2 ml of 1-methylpyrrolidinone was cooled to 0°C. Portions were added triacetoxyborohydride sodium (1,21 g, 5.7 mmol) followed by addition of several drops of acetic acid. The resulting mixture was stirred at 0°C for 10 minutes, then at room temperature for 1.5 hours. The mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified column flash chromatography, elwira gradient from 20% methanol in ethyl acetate to 1% ammonium hydroxide in a solution of 20% methanol in ethyl acetate. Rubbing in diethyl ether and hexane gave 57 mg (18%) 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine in the form of a solid of light yellow color.1H-NMR (DMSO-d6) δ: 2,14 (s, 3H), 2,25-2,36 (Shir. s, 4H), 2,38-2,46 (Shir. s, 4H), 3,52 (s, 2H), Android 4.04 (s, 3H), of 6.96 (s, 1H), 7,31 (d, J=8 Hz, 1H), 8,14-to 8.20 (m, 2H), scored 8.38 (d, J=3 Hz, 1H);

MS 332,1 (M+N)+.

Analysis for C17H21N3About4:

Calculated: C, 61,62; N, To 6.39; N, 12,68

Found: C, 61,46; N, Of 6.68; N, 2,54.

Example 48

(4-Methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine

To a solution of 1-{[4-(2-methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpiperazine (396 mg, 1,19 mmol) in 20 ml of methanol was added 10% palladium on coal (40 mg). The resulting mixture was shaken with hydrogen in a Parr shaker until then, until he stopped absorption of hydrogen. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuum to obtain 358 mg (100%) of (4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine in the form of a brown oil.1H-NMR (DMSO-d6) δ: 2,14 (s, 3H), 2,29 (Shir. s, 4H), 2.40 a (Shir. s, 4H), 3,49 (s, 2H), and 3.72 (s, 3H), br4.61 (s, 2H), 6,47 (d, J=8 Hz, 1H), return of 6.58 (s, 1H), 6,78 (d, J=9 Hz, 1H), 6,80 (s, 1H), to $ 7.91 (s, 1H);

MS m/z 302,1 (M+N)+.

An alternative example 48

(4-Methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine

To a solution of 1-[(4-bromo-2-furyl)methyl]-4-methylpiperazine (1,43 g, 5,52 mmol) and tri-isopropylmalate (1,76 g, 9,38 mmol) in 20 ml of tetrahydrofuran at -78°C was added 1.6 M n-utility in hexane (5,38 ml, 8,61 mmol) in 10 minutes. After stirring at -78°within 10 minutes the temperature of the reaction mixture was allowed to rise to room temperature. Was added water (1.0 ml) and the solvents were removed in vacuum. The obtained intermediate compound, baronova acid, was dissolved in 20 ml of dimethyl ether of ethylene glycol was added 2-iodine--nitroanisole (1,06 mg, of 4.25 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with dichloromethane (1:1) (87 mg, 0.11 mol). Solution was added 2.25 g of sodium carbonate in 6.5 ml of water and the resulting mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature and distributed between ethyl acetate and water. The aqueous layer was additionally extracted with ethyl acetate and the organic layers were combined, washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified column flash chromatography, elwira gradient from 5% methanol in dichloromethane to 10% methanol in dichloromethane to obtain 900 mg (70%) of (4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine in the form of oil red.

Example 49

(2E/Z)-2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide

To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)ndimethylacetamide (261 mg, 1.01 mmol) in 5 ml of isopropanol was added triethylorthoformate (0,504 ml, 3.03 mmol). The mixture was heated under reflux and was added dropwise (4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine (320 mg, 1.06 mmol) in 9 ml of isopropanol. The mixture was heated under reflux for 25 hours. The mixture was allowed to cool to room temperature and the solid Sobir is whether filtering washed with isopropanol to obtain 465 mg (81%) (2E/Z)-2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide in the form of a solid gray color, TPL 198-199°C; MS 570,1 (M+N)+.

Analysis for C28H29Cl2N5About40.2 g of N2About

Calculated: C, 58,58; N, 5,16; N, 12,20

Found: C, 58,50; N, 5,07; N, 12,07.

Example 50

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-{7-[5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-hinolincarbonova

A suspension of (2E/Z)-2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amino]acrylamide (409 mg, to 0.72 mmol) in 20 ml of butyronitrile was heated to 105°and was added dropwise phosphorus oxychloride (0,856 ml, 9,36 mmol). After 14 hours of additional added phosphorus oxychloride (0,430 ml)and the reaction mixture was heated and kept at 105°for another 8 hours. Addition was added phosphorus oxychloride (0,430 ml) and the temperature of the reaction mixture was raised to 115°C. the Reaction mixture was heated and kept at 115°C for 18 hours. Addition was added phosphorus oxychloride (0,856 ml) and the reaction mixture was heated and kept at 115°for another 26 hours. The reaction mixture was concentrated in vacuo and the residue suspended in a mixture 1:1 of ethyl acetate and tetrahydrofuran and neutralise the Wali concentrated ammonium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The solvents were removed in vacuum and the residue was purified column flash chromatography, elwira gradient dichloromethane to 20% methanol in dichloromethane. Subsequent preparative thin layer chromatography, exhibited 10% methanol in dichloromethane, gave 61 mg (15%) 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-{7-[5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-hinolincarbonova in a solid yellow color, TPL 174-176°C.

Calculated: 552,15638

Found: 552,15723

HPLC: 96.8 per cent.

1. The way to obtain 4-amino-3-hinolincarbonova, including

a) combination of the amino compounds with tsianuksusnogo acid and an acid catalyst to obtain cyanoacetamide;

b) condensation of cyanoacetamide from stage a) with aniline, alcohol solvent and trialkylaluminium with 3-amino-2-cyanoacetamide; and

c) the combination of 3-amino-2-cyanoacetamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst, to obtain 4-amino-3-hinolincarbonova.

2. The method according to claim 1, and the ratio tsianuksusnogo acid to amine is from 1 to 1.5 equivalents.

3. The method according to claim 1, and the ratio tsianuksusnogo acid to amine is 1.03 equivalent.

4. The method according to claim 1, and Ani who is in cleaners containing hydrochloride salt.

5. The method according to claim 1, and aniline is a freelance basis.

6. The method according to claim 1, and an alcohol solvent is isopropanol.

7. The method according to claim 1, and stage condensation occurs when the temperature of 10-200°C.

8. The method according to claim 1, and stage condensation occurs when the temperature of 20-140°C.

9. The method according to claim 1, and stage condensation occurs at a temperature of 80°C.

10. The method according to claim 1, wherein the catalyst is alcohol.

11. The method according to claim 1, wherein the catalyst is an amine base.

12. The method according to claim 1, the combination in stage C) occurs at a temperature of 50-200°C.

13. The method according to claim 1, the combination in stage C) occurs at a temperature of 80-110°C.

14. The way to obtain 4-amino-3-hinolincarbonova, including

a) combination of the amino compounds with tsianuksusnogo acid, peptide binding reagent to obtain a suspension;

b) filtering the suspension from step a) obtaining cyanoacetamide;

c) condensation of cyanoacetamide from stage b) with aniline, alcohol solvent and trialkylaluminium with 3-amino-2-cyanoacetamide and

d) the combination of 3-amino-2-cyanoacetamide from the stage with phosphorus oxychloride to obtain 4-amino-3-hinolincarbonova.

15. The method according to 14, with respect tsianuksusnogo acid to amine is the t 1 to 1.5 equivalents.

16. The method according to 14, with respect tsianuksusnogo acid to amine is 1.03 equivalent.

17. The method according to 14, and peptide binding reagent is water-soluble.

18. The method according to 14, and peptide smaoui reagent is 1,3-diisopropylcarbodiimide.

19. The method according to 14, and the said method is carried out at a temperature of 50-100°C.

20. The method according to 14, and the said method is carried out at a temperature 77-80°C.

21. The method according to 14, and the amine is pyridine, triethylamine or Diisopropylamine.

22. The way to obtain 7-aminothieno[3,2-b]pyridine-6-carbonitrile, including

a) combining 3-aminothiophene with cyanoacetamide and trialkylaluminium in an alcohol solvent to obtain propenamide;

b) a combination of propenamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene, or xylene, optionally in the presence of a catalyst to obtain 7-aminothieno[3,2-b]pyridine-6-carbonitrile.

23. The method of producing cyanoacetamide, including (a) a combination of DMF, aniline and tsianuksusnogo acid to obtain a mixture; b) cooling the mixture; c) adding a solution of N,N'-dicyclohexylcarbodiimide in DMF maintaining the temperature below 15°and the receipt of the suspension; (d) filtering the suspension and washing the obtained solid by-product to obtain a filtrate; e)adding water to the filtrate from step d) to obtain a suspension, cooling to 5°and (f) filtering the suspension to obtain cyanoacetamide.

24. The method according to item 23, and the secondary product is urea.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: novel compounds are selected from group, consisting of: 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-hydroxymethyl-cyclopropylmethyl)-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopentylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl- 4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-(2-cyclopropyl-ethyl)-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihudro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-fluorine-4-(3-methyl-4,10-dihydro-3H-2,3,4;9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 3-ethyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclobutylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; 4-cyclopropylmethyl-piperazine-1-carboxylic acid 2-chlorine-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide and 4-cyclobutylmethyl-piperazine-1-carboxylic acid 3-methoxy-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-benzylamide. Invention also relates to pharmaceutical composition and to application of compounds of general formula 1.

EFFECT: obtaining novel biologically active compounds and based on them pharmaceutical composition, possessing antagonistic activity with respect to vasopressin receptors.

60 cl, 153 ex

FIELD: agriculture.

SUBSTANCE: new chemically biologically active compound 3-amino-4,5,6-trimethyl-2-(benzimidazolyl-2)tieno[2,3-b]pyridine of formula 1 revealing growth regulating properties is described.

EFFECT: increasing sugar beet crop yield and sugar content.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted indoles of general formula , where: X stands for -S(O)n-, -C(O)-; A stands for C1-C6alkyl, -(CH2)p-NRaRb; R1, R2, R3 and R4 each is independently selected from group including H, halogen, halogen(C1-C6)alkyl, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, NO2, -NRaRb, phenyl, benzyl and benzyloxy, said phenyl cycles are optionally substituted with substituent, selected from group including C1-C6alkyl, halogen, NO2, halogen(C1-C6)alkyl, C1-C6alkoxy; R5 stands for H, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy C1-C6alkyl, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, hydroxyl-(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, halogen, halogen(C1-C6)alkyl-NRaRb, -NRc-( C1-C6)alkylene-NRaRb, or R5 and A together form radical C2-C3alkylene; R6 stands for H, C1-C6alkyl; R' and R" each independently stand for H, C1-C6alkyl; Ra, Rb and Rc each is independently chosen from group including H, C1-C6alkyl, hydroxy(C1-C6)alkyl, C2-C6alkenyl, C3-C6cycloalkyl-(C1-C6)alkyl, or Ra and Rb together with nitrogen atom, to which they are attached, form 5-7 member non-aromatic heterocyclic cycle, optionally containing in cycle O as additional heteroatom; m is equal 1 or 2; n is equal 0, 1 or 2 under condition that, if n is equal 0, R5 does not stand for NRaRb, and p is equal 0, 1 or 2; or their pharmaceutically acceptable salts.

EFFECT: obtaining compounds possessing agonistic activity which allows using them in pharmaceutical composition.

24 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to substituted 3-cyanotiophenacetamides of general formula I , in which R1 and R2 are independently designate (lower) alkyl, or R1 and R2 together with carbon atoms, to which they are bound, including bond between said carbon atoms, form 5-6 member, unsubstituted carbocyclic or 6-member heterocyclic cycle, probably having substitutes, independently selected from group, including (lower) alkyl, alkylsulfonyl and alkoxycarbonyl, R3 is selected from group, which includes (lower) alkyl, unsubstituted aryl, unsubstituted aralkyl and unsubstituted cycloalkyl, R4 - hydrogen, n is zero, or their pharmaceutically acceptable salts. Compounds can be applied for treatment and/or prevention of diseases, associated with antagonistic action on glucagon receptor, such as diabetes. Pharmaceutical composition based on compounds I and their application are also described.

EFFECT: obtaining substituted 3-cyanotiophenacetamides, which can be applied for treatment and/or prevention of diseases, associated with antagonistic action on glucagon receptor, such as diabetes.

22 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula I their pharmaceutically acceptable salts and solvate I where X represents O or S; Y and Z mutually independently denote hydrogen or halogen; R1 is hydroxy-C1-C7-alkyl, carboxy, C1-C7-alkyloxycarbonyl, or substitute of formula II R2 is hydrogen, carboxy or alkyloxycarbonyl. Compounds can be used as inhibitors of cytokine or inflammation mediator producing. Intermediate compounds of compounds I and application of compounds 1 are also described.

EFFECT: production of compounds used as inhibitors of cytokine or inflammation mediator producing.

12 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: (I) , in which R1 and R2 independently represent C1-6alkyl, C3-5cycloalkyl C1-3alkyl or C3-6dikloalkyl; Q represents CR4R5, where R4 represents hydrogen; or C1-6alkyl, and R5 represents carbon; Ar represents 5-6-membered aromatic ring system, where heteroatoms can represent up to 2 ring atoms, independently selected from nitrogen and sulphur, notably that this ring system can be substituted by one or more then one substitute, independently selected from C1-4alkyl; Ar2 represents 5-6-membered aromatic ring system containing up to 2 ring atoms, independently selected from nitrogen and sulphur, notably the ring contains at least one heteroatom and can be substituted by one or more then one group, independently selected from C1-4alkyl. The compositions can be used in autoimmune disease modulation. The methods of compounds production, pharmaceutical composition and use of the compounds in the treatment of respiratory disease are described.

EFFECT: production of thienopyrimidindion compounds for autoimmune disease modulation and respiratory disease treatment.

14 cl, 3 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to derivatives of thienopyrimidine with general formula I , where R1 represents C1-4alkyl; R2 represents C1-6alkyl, possibly substituted (1') by a hydroxyl group, (2') C1-4alkoxy, (3') C1-4alkoxycarbonyl, (4') di-C1-4alkylcarbamoil, (5') 5-6-member nitrogen containing heterocyclic group, (6') C1-C4alkylcarbonyl and (7') halogen, 5-6-member nitrogen containing heterocyclic group, phenyl, which can contain a substitute, R3 - C1-4alkyl, R4 - C1-4alkoxy. The compounds have antagonist activity to gonadotropin releasing hormones (GnRH). Description is given of a medicinal preparation based on formula I compounds, used of the compounds in making pharmaceutical compositions and the antagonist effect of the compounds on gonadotropin releasing hormone.

EFFECT: obtaining derivatives of thienopyrimidine with antagonist effect on gonadotropin releasing hormones.

17 cl, 143 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to thienopyrimidine diones with general formula (I), , where R1 and R2 each independently represents C1-6alkyl, C3-5cycloalkylC1-3alkyl or C3-6cycloalkyl; R3 represents a CO-G group, where G is a 5- or 6-member ring, containing a nitrogen atom and a second oxygen heteroatom, adjacent to the nitrogen atom. This ring can be substituted by at least one group, chosen from C1-4alkyl and hydroxyl; Q represents CR4R5, where R4 represents hydrogen or C1-6alkyl, and R5 represents hydrogen; and Ar represents a 5-10-member aromatic ring system, where up to 3 ring atoms can represent heteroatoms, independently chosen from nitrogen and sulphur. This ring system can be substituted with one or more groups. The invention also relates to pharmaceutical salts and solvates of thienopyrimidine diones. Description is also given of the method of obtaining these compounds, pharmaceutical compositions containing them, and their use in therapy, particularly in immunosuppressive therapy.

EFFECT: obtaining thienopyrimidine diones for use in immunosuppressive therapy.

17 cl, 29 ex

New compounds // 2331646

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to thienopyridazinones with formula , where R1 represents C1-6alkyl, or C3-6cycloalkyl, R2 represents C1-6alkyl; R3 represents a CO-G group, where G is a 5-member ring, containing a nitrogen atom and a second heteroatom, chosen from oxygen, adjacent to the nitrogen atom, and can be substituted with groups in quantity of up to 2, chosen from hydroxyl and C1-4alkyl; Q represents CR5R6, where R5 and R6 - hydrogen, and R4 represents a 5-10-member mono- or bi-cyclic aromatic ring system, containing 2 heteroatoms, independently chosen from nitrogen. This ring system can be substituted. The invention also relates to pharmaceutical salts and solvates of thienopyridazinones. Description is also given of the method of obtaining these compounds, pharmaceutical compositions containing them, and their use in therapy, particularly in the modulation of autoimmune disease.

EFFECT: obtaining thienopyridazinones for use in modulation of autoimmune disease.

12 cl, 17 ex

The invention relates to derived hydroxyethylaminophenol formulas I, II, III, where R is phenyl-C1-C8alkoxycarbonyl, where phenyl may be substituted C1-C8alkoxy; chinainternational, mono - or di-C1-C8alkylamino-C1-C8alkanoyl; R' is H, C1-C8alkyl; R1- H, C1-C8alkyl, C2-C8alkenyl, -C(O)NH2CH2C(O)NH2, -CH2C(O)NHCH3C(CH3)2(SCH3), amino acid side chain, such as glycine; R1'and R1"both - H; R2- phenyl-C1-C8alkyl; R3- H, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C2-C8alkenyl; R4- C1-C8alkyl, phenyl, methoxyphenyl; R6Is H; Y Is O; x = 1, 2; t = 0 or 1

The invention relates to new heterocyclic derivatives of the formula I, where one of R1, R2, R5are carboxy, C2-C5-alkoxycarbonyl, C1-C8by alkyl, substituted hydroxy, carboxy, C2-C5-alkoxycarbonyl or a group of the formula - NR9R10where R9, R10each independently is C1-C6the alkyl, and the other two are each independently is a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R3or R4group - NHCOR7where R7-C1-C20alkyl, C1-6alkoxy, - C1-C6alkyl, C1-C6alkylthio - C1-C6alkyl, C3-C8- cycloalkyl, C3-C8cycloalkyl-C1-C3alkyl, phenyl, phenyl-C1-C4alkyl group-other8where R8-C1-C20alkyl, and the others are a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R6-C1-C20alkyl, C3-C12alkenyl, C1-C6alkoxy, C1-C6alkyl, C1-C6alkylthio C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-CLIGN="ABSMIDDLE">and is a bridging group to the nitrogen atom, provided that when one of R1, R2, R5is carboxy or C2-C5alkoxycarbonyl, Z is a group of

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen

The invention relates to new substituted-quinoline intermediate compounds used for the synthesis of the herbicide, namely, 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolidinyl)-5-ethoxymethyleneamino acid, and the method of production of intermediate compounds, such as 3-methoxymethyl-7 - or 8-hydroxyquinoline, which can be used to synthesize the specified herbicide

The invention relates to new derivatives of hydroxyacetone with valuable properties, in particular the derivative of quinoline-2-yl - methoxybenzylideneamino General formula (I)

(I) where a, b, D, E, G, L and M are identical or different and mean hydrogen, hydroxy, halogen, cyano, carboxy, nitro, trifluoromethyl, triptoreline, or a linear or branched alkyl or alkoxy, each containing up to 8 carbon atoms, or an unsubstituted or substituted with halogen, hydroxy or cyano aryl with 6-10 carbon atoms;

R1means cycloalkyl or alkenyl with 3-12 carbon atoms, a linear or branched alkyl containing up to 8 carbon atoms;

R2and R3the same or different and mean hydrogen, linear or branched alkyl containing up to 8 carbon atoms or phenyl or benzyl, or R2the hydrogen and R3a group of the formula SO2R5where R5linear or branched alkyl containing up to 8 carbon atoms which may be substituted with halogen, nitro, cyano, hydroxy, trifluoromethyl or aryl with 6-10 carbon atoms, or aryl with 6-10 carbon atoms, which is substituted up to TP or alkoxy, containing up to 8 carbon atoms, trifluoromethyl or triptoreline,

R4means hydrogen or a linear or branched acyl containing up to 8 carbon atoms, or benzoyl, and mixtures of their isomers, or individual isomers or their salts, which are, in particular, the pharmacological activity

The invention relates to the production of aminocinnamate, which is used as an intermediate product to obtain imidazoles, pyrazines, purines or pteridine

The invention relates to a new industrial connections required as intermediates for producing compounds of formula (I)

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining 4-amino-3-quinolinecarbonitryl, which includes: a) combining aminocompound with cyanoacetic acid and acid catalyst obtaining cyanoacetomide; b) condensing cyanoacetomide from stage a with aniline, alcohol solvent and trialkylorthoformiate obtaining 3-amino-2-cyanoakrylamide; and c) combining 3-amino-2-cyanoakrylamide with phosphorus oxychloride in acetonitryl, butyronitrile, toluol or xylol, optionally in presence of catalyst, obtaining 4-amino-3-quinolinecarbonitryl. Also described is method (version) of obtaining 4-amino-3-quinolinecarbonitryl, method of obtaining 7-aminothieno[3,2-b]pyridine-6-carbonitrile and method of obtaining cyanoacetamide.

EFFECT: creation of efficient method of obtaining 4-amino-3-quinolinecarbonitryl.

24 cl, 50 ex

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