Method for preparing 3,4-diaryl(hetaryl)maleimides

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

 

The invention relates to a method for producing new derivatives maleimido with aromatic and heteroaromatic substituents in positions 3 and 4, which are of considerable interest in several areas. Among 3,4-di-indolylmaleimide found antibiotics, such as staurosporin and rebeccamycin, and means having a high anti-cancer and anti-diabetic activity. So, for example, N-dimethylaminopropyl-3,4-di-indolylmaleimide (1), bis-indolylmaleimide (2) and (3) are strong antagonists to the protein kinase C(SW) (Toullec d, Pianetti P., et al., J. Biol. Chem. 1991, 266, 15771, Bit R.A., Davis P.D., et al., J.Med.Chem., 1993, 36, 21, Jirousek M.R., Gillig J.R et al., J.Med.Chem., 1996, 39, 2664).

On the other hand, some of 3,4-digitalization of maleimido have excellent photochromic properties and may find applications in computer engineering. (Krayushkin M.M., Shirinyan the old Testament, Belenky LI, Simkin A.A., Marcincin, A., Dinners BM, J. organ. chemistry 2002, 38, 1390).

There are several known methods for the synthesis of 3,4-diaryl(hetaryl)maleimide. The reaction arylmethylidene with alcoholate and iodine gain derived 1,2-dicyanomethylene (4), (scheme 1),

which is next to saponification in aqueous-alkaline solution and acidification dicarboxylic Ki is the lot forms anhydride (5), scheme 2 (Chalanay L., E. Knoevenagel, Ber. 1892, 25, 285),

which when processed by ammonia or amines enters maleimid (6).

The disadvantage of this method is the poor reproducibility of the results, because the resulting dinitrile in alkaline conditions are readily undergoes polymerization, and the inaccessibility of the original NITRILES, particularly in the heterocyclic series, and the multistage this way, making it difficult to obtain a whole series of 3,4-diaryl(hetaryl)maleimide.

There is also known a method based on the use of derivatives alloxanic acids, which consists in condensing their anhydrides with allglobaldelayed (Yamaguchi, T., Uchida, K., Irie, M., J Amer.Chem.Soc., 1997. 119, 6066, Uchida K., Kido Y., Yamaguchi T., Irie M., Bull. Chem. Soc. Japan, 1998. 71, 1101). (scheme 3)

The disadvantage of this method is the multistage and the need for complex synthesis reagents, which also makes it difficult to obtain a whole series of 3,4-diaryl(hetaryl)maleimide.

Another method of synthesis, applied to the preparation of natural alkaloids - Poliziano a and b

is the oxidation of the corresponding 3,4-diarylpyrazole-2,5-dicarboxylic acid (scheme 4), which in turn are obtained by oxidative dimerization arylpropionic acids to follow what they closure of pyrrole cycle with ammonia (Terpin A., Polborn, K., Steglich W., Tetrahedron, 1995, 51 (36), 9941).

The disadvantage of this method of synthesis is difficult availability of source arylpropionic acids. In addition, this method can only be obtained symmetric products.

Derivatives of 3,4-di(3-indolyl)-maleimides obtained by reaction of 3,4-dichloro - or 3,4-dibromomalonamide with N-MgBr-indoles (Faul M.M., K.A. Sullivan, Winneroski L.L., Synthesis, 1995, 1511) in a mixture of toluene and ether, and THF (5:1:1). However, this method is suitable only for N-MgBr-indole derivatives characterized by the flow of replacement transfer reaction center 3 position of indole cycle. For other aromatic and heteroaromatic derivatives such reaction is not feasible.

There is also known a method for the synthesis of 3,4-di(2,5-dimethyl-3-thienyl)-1-butylmalonate interaction of 2,5-dimethylthiophene dichloride with square acid under the reaction conditions of Friedel-and oxidation of the resulting cyclobutene-1,2-dione hydrogen peroxide on the Bayer-Villiger (Shirinian the old Testament, Krayushkin M.M., Belenky LI, Vorontsov L.G., Starikova Z.A., Marcincin, A., Ivanov V.L., Dinners BM, CHC, 2001, s, Krayushkin M.M., Shirinyan the old Testament, Belenky LI, Adronov, A., Vorontsov L.G., Starikova Z.A., Izv. EN ser. chem., 2002 (8), s).

The subsequent interaction of the obtained maleic anhydride with amines results in the final product the KTA (Krayushkin M.M., Shirinyan the old Testament, Belenky LI, Simkin A.A., Marcincin, A., Dinners BM, J. organ. chemistry 2002, 38, 1390) (scheme 5)

The disadvantages of this method include the need to use inaccessible dichloride square acids, as well as lack of stability of the intermediate cyclobutene-1,2-diones, making it difficult to obtain other 3,4-diaryl(hetaryl)-maleimide.

The purpose of this invention to provide new derivatives of 3,4-diaryl(hetaryl)-maleimide, which may find application as photochromes, convenient and affordable way with a high output.

The claimed method of obtaining 3,4-diaryl(hetaryl)-maleimido lies in the interaction aryl(hetaryl)-Bronevoy acid from readily available N-substituted 3,4-dibromomalonamide or 3-bromo-4-aryl(hetaryl)maleimide using as the catalyst complex of palladium in the presence of a base in a solvent environment. In the literature unknown similar way to obtain the di-aryl(hetaryl)maleimido of dibromo - or dichloromaleimide. In General, this method is depicted in scheme 6

Scheme 6

where R=C1-C4-alkyl or benzyl or phenyl.

R1=Br or aryl, such as phenyl or naphthyl, substituted alkyl, alkoxy, or halogen; hetaryl, unsubstituted or substituted, is the aka as thienyl, benzothiazyl-, furyl-, benzofuran - pyrrolyl-, or indolyl-, where the substituents are alkyl, alkoxy, alkylthio-, halogen atom or trifluoromethyl.

Ar= aryl, such as phenyl or naphthyl, substituted by alkyl, alkoxy or halogen; hetaryl, unsubstituted or substituted, such as thienyl-, benzothiazyl-, furyl, benzofuran - pyrrolyl or indolyl-, where the substituents are alkyl, alkoxy, alkylthio-, halogen atom or trifluoromethyl, with the exception of 3,4-di(2,5-dimethyl-3-thienyl)-1-butylmalonate,

3,4-Dibromomalonamide are readily available substances and are bromirovanii of maleimide or N-substituted maleimides with high yields (Choi D.S., Huang, S., Huang, M., Barnard T.S., Adams R.D., J.M. Seminario, Tour J.M, J.Org. Chem., 1998, 63, 2646).

Aryl(hetaryl)boranova acid is also easily obtained from the corresponding Grignard reagents or organolithium compounds by the action of trialkylborane. Many of Baranovich acids are prepared reagents.

The optimal ratio dibromide and Bronevoy acid is a slight excess Bronevoy acid from 2.1 to 2.2 mol Bronevoy acid per mole dibromide.

As a catalyst in this reaction using a complex palladium compounds such as tetrakis(triphenylphosphine) palladium. Also suitable for other palladium complexes, including those that are not sensitive to sour what kind of air, for example, palladacycles obtained from Li2PdCl4and N,N-dicyclohexylcarbodiimide, buildings (7) (Xiong Z., J.Org.Chem., 2004, 69 (19), 3337).

The amount of catalyst is taken up to 4 mol%, counting on mol dibromide. A smaller amount of the catalyst leads to a reduction of output, a higher number does not affect the output, and therefore impractical.

As the base in this reaction can be used carbonates, bicarbonates and phosphates of alkali metals such as sodium, potassium, cesium, however, best results are obtained by cesium fluoride.

The table shows the dependence of the yield of the final product from the base on the example of the reaction of N-butyl-3,4-dibromomalonamide 2-methylbenzothiazol-3-Bronevoy acid

Cross-coupling of 3,4-dibromo-1-butylmalonate 2-methylbenzothiazol-3-Bronevoy acid in the presence of various bases
BaseReaction time, hoursOutput %Note
CsF476
To3PO43030*
Na2CO33022*
To2CO330 13*
NaHCO3306*
Cs2CO3305*
* Main product of the reaction is 2-methylbenzamide.

Very significant is the number of bases. It is established that the quantity should not be less than 2.5-mol of 3-bromo-4-aryl(hetaryl)-maleimide and less than 5 moles per mole for 3,4-dibromomalonamide, otherwise the output is sharply reduced.

The solvent suitable solvent, such as simple dialkyl ethers, dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, acetonitrile, dimethyl sulfoxide. The most suitable solvent, allowing the reaction with the optimal outputs were dioxane, which removes oxygen by repeated cooling under vacuum and thawing under inert gas.

These conditions of the reaction are optimal for obtaining mixed 3,4-diaryl(hetaryl)maleimido on the basis of 3-bromo-4-aryl(hetaryl)maleimide.

So, for example, 3-bromo-4-(N-trebutien-2-methyl-3-indolyl)-N-butylmalonic(8) in collaboration with arylboronic acids gives mixed digitaalallkiri (10-12). Likewise, monobromide (9) is formed is small the imide (13) (scheme 7)

a.) LiN(SiMe3)2, THF, then 2 or 3,4-dibromo-1-benzylmaleimide. b.) Boc2O, DMAP, THF. c.) to 1.15 mol ArB(OH)2, 4 mol% Pd (Ph3R)4, 4 mol CsF.

DMAP - 4-dimethylaminopyridine

Boc - trebutien

THF - tetrahydrofuran

In the reaction used a slight excess (1.1 to 1.2 - mole for mole) of arylboronic acid ArBr(OH)2in relation to monobromide 8 and 9. The amount of catalyst, which is usually taken tetrakis-triphenylphosphine, not more than 4 mol%. The reaction is also carried out in a solvent such as dioxane, in the presence of a base. The optimal basis in this case is cesium fluoride CsF, the number of which has a significant impact on output. It should take at least 2.5 moles per mole of bromide.

The invention is illustrated by the following examples, which are not limited to the merits of the application.

Example 1

2-methylbenzofuran-3-baronova acid (1).

To a solution of 2-methyl-3-bromination (8.6 g, 37 mmol) in 100 ml THF at -78°With, in argon atmosphere, add 27 ml of a 1.6 M solution of n-BuLi in hexane. Stirred at this temperature for 15 minutes and then add 15.3 ml (13.07 g, 56 mmol) tributyrate. Stirred for further 1 hour at -78°With, remove the cooling bath and left overnight. Add 5 ml of the Meon, then evaporated reaction the second mixture on a rotary evaporator, ensuring that the bath temperature did not rise above +50°C. Add 100 ml of Et2O and, under ice cooling, a mixture of 5 ml of concentrated hydrochloric acid and 35 ml of water. Stirred for 1 hour. Separate the ether layer, and the aqueous phase extracted with Et2O (3×20 ml). The combined ether phases are washed with water and then with 5% NaOH (4×20 ml). The alkaline solution was washed with Et2O (2×20 ml), cooled with ice to -5°and acidified with stirring, 10 ml of concentrated HCl. Released Bronevoy acid is filtered off, washed with a small amount of water and dried in a desiccator. The output of 5.81 g (80%). The substance has no clear melting point and, according to PMR and mass spectra, is a cyclic trimeric anhydride (2-methylbenzofuran-3-biaxin).

1H NMR (300 MHz) (hereinafter in CDCl3) δ 3.05 (s, 3H), 7.23-7.43 (m, 3H), 8.55 (d, J=7.8 Hz, 1H).

MS m/z: 523 (M+1); 522 (M+); 173; 148; 147.

Found: C, 62.42; H, 4.43; S, 18.50%. With27H21In3About3S3. Calculated: C, 62.12; H, 4.05; S, 18.42%.

Example 2

2,5-Dimethyl-3-thienylboronic acid (1a).

Derived from 2,5-dimethyl-3-idioten as described above to yield 76%. TPL 180-183°C. According to the PMR and mass spectra exists in the form of cyclic trimeric anhydride.

1H NMR (250 MHz) δ 2.45 (s, 3H), 2.82 (s, 3H), 7.09 (s, 1H).

MS m/z: 416 (M+3), 415 (M+2), 414 (M+1), 413 (M+), 137, 111.

Found: C, 52.32; H, 5.3; S, 23.50%. With18H21In3About3S3. Calculated: C, 52.22; H, 5.11; S23.23%.

Example 3

Cross-coupling Baranovich acid with 3,4-dibromo-1-butylmalonate; General methods.

In a three-neck round-bottom flask equipped with a reflux condenser and the input of argon, placed 3,4-dibromo-1-butylmalonic (2), baronova acid (2.2 mol per 1 mol dibromide), 4 mol.% Pd(Ph3R)4, CsF (5 mol per 1 mol dibromide), 1,4-dioxane (100 ml/1 g Bronevoy acid). The reaction mixture is boiled in an argon atmosphere under vigorous stirring on a magnetic stirrer, within the specified time, then poured into water, extracted with CHCl3washed the organic phase with water, dried Na2SO4distilled off the chloroform on a rotary evaporator. The residue is purified using flash chromatography on SiO2

Example 4

3,4-di (2-methyl-3-benzothiazyl)-1-butylmalonic (3).

Is obtained from 2-methyl-benzothiophen-3-Bronevoy acid (1) (2.0 g, 11 mmol), 3,4-dibromo-1-butylmalonate (2) (1.62 g, 5.2 mmol), CsF (3.95 g, 26 mmol), Pd(Ph3R)4(0.24 g) in 200 ml of dioxane. The reaction mixture is boiled for 4 hours. The product is isolated in the form of orange crystals, after rubbing with Et2O the residue obtained by evaporation of the chloroform extract. Washed with cold Et2O and dried in a desiccator. Yield 1.77 g (76%). TPL 172-173°C.

1H NMR (300 MHz) δ 1.02 (t, J=8.5 Hz, 3H), 1.40-1.56 (m, 2H), 1.70-1.83 (m, 2H), 2.08 (s, 3H), 2.28 (s, 3H), 3.74 (t, J=8.2Hz, 2H), 7.06 (t, J=9.1 Hz, 1H), 7.15-7.35 (m, 4H), 7.45 (d, J=7.4Hz, 1H), 7.64-7.72 (m, 2H).

MS m/z: 447 (M+2); 446(M+1); 445(M+); 384; 318; 56; 43.

Found: C, 70.30; H, 5.27; N, 3.35%. With26H23NO2S2. Calculated: C, 70.08; H, 5.20; N, 3.14%.

Example 5

3,4-di(3-chlorophenyl)-1-butylmalonic (5).

Get 3-Chlorfenvinphos acid (0.55 g, 3.5 mmol), 3,4-dibromo-1-butylmalonate (2) (0.5 g, 1.6 mmol), CsF (1.22 g, 8.0 mmol), Pd(Ph3P)4(0.075 g) in 40 ml of dioxane. The reaction mixture is boiled for 30 minutes the Product is isolated in the form of lemon-yellow crystals, after rubbing with Et2O the residue obtained by evaporation of the chloroform extract. Washed with cold Et2O and dried in a desiccator. Yield 0.58 g (96%). MP 92-95°C.

1H NMR (300 MHz) δ 0.96 (t, J=8.5 Hz, 3H), 1.34-1.48 (m, 2H), 1.62-1.73 (m, 2H), 3.66 (t, J=8.3 Hz, 2H), 7.29-7.35 (m, 2H), 7.35-7.42 (m, 1H), 7.52 (s, 1H).

MS m/z: 375 (M+2); 374 (M+1); 373 (M+); 331; 246; 176; 56.

Found: C, 64.28; H, 4.27; N, 3.65%. With20H17Cl2NO2. Calculated: C, 64.18; H, 4.58; N, 3.74%.

Example 6

3,4-di (4-methoxyphenyl)-1-butylmalonic (6).

Obtained from 4-methoxyphenylacetic acid (0.53 g, 3.4 mmol), 3,4-dibromo-1-butylmalonate (2) (0.5 g, 1.6 mmol), CsF (1.22 g, 8.0 mmol), Pd(Ph3R)4(0.075 g) in 40 ml of dioxane. The reaction mixture is boiled for 1.5 hours. After chromatography on SiO2(hexane - EtOAc 6/1) to obtain 0.57 g (98%) of product as light yellow crystals. MP 110-114°C.

1H NMR (300 MHz) δ 0.97 (t, J=8.5Hz, 3H), 1.34-1.46 (m, 2H), 1.62-1.73 (m, 2H), 3.64 (t, J=8.3Hz, 2H), 3.84 (s, 6H), 6.87 (d, J=10.0Hz, 4H), 7.49 (d, J=10.1Hz, 4H).

MS m/z: 366 (M+1); 365 (M+); 238; 223; 152; 133; 43.

Found: C, 72.28; H, 6.27; N, 3.65%. With22H23NO4. Calculated: C, 72.31; H, 6.33 N 3.83%.

Example 7

3-(2-methyl-3-indolyl)-4-bromo-1-butylmalonic (7).

To a solution of 2-methylindole (1.01 g, 7.7 mmol) in 24 ml of THF, is added dropwise 16 ml of 20% solution of LiN(SiMe3)2in THF. The solution is stirred for 15 min at this temperature, then at -20°C in Ar atmosphere, is added dropwise a solution of 3,4-dibromo-1 butylmalonate (2.4 g, 7.7 mmol) in 24 ml of THF. The reaction mixture is allowed to reach room temperature, poured into 90 ml of 0.2 n HCl, extracted with EtOAc (3×30 ml). The organic phase is washed with 5% NaHCO3(30 ml), water (3×20 ml), saturated NaCl solution, dried with MgSO4. After distillation of the solvent to obtain 2.55 g (92%) of 3-(2-methyl-3-indolyl)-4-bromo-1-butylmalonate in the form of chromatographically pure (TLC, hexane-ethyl acetate 4/1) dark red oil.

1H NMR (300 MHz) δ 0.96 (t, J=6.6 Hz, 3H), 1.32-1.48 (m, 2H), 1.62-1.77 (m, 2H), 2.49 (s, 3H), 3.67 (t, J=7.5Hz, 2H), 7.15-7.25 (m, 2H), 7.31 (t, J=10Hz, 1H), 7.49 (d, J=7.7Hz, 1H), 8.44 (USS, 1H).

MS m/z: 363 (M+2); 362 (M+1); 361 (M+); 262; 182; 154; 108; 57.

Found: C, 56.42; H, 4.53; N, 7.59%. C17H17BrN2O2. Calculated: C, 56.52; H, 4.74; N, 7.75%.

Example 8

3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butylmalonic (8).

To a solution of 3-(2-what etyl-3-indolyl)-4-bromo-1-butylmalonate (2.5 g, 7 mmol) in 100 ml of THF are added 50 MG4-dimethylaminopyridine and, dropwise, over 10 min a solution of BOC2O (2.0 g, 9.1 mmol) in 20 ml of THF. The reaction mixture was stirred at room temperature until the disappearance of the original product (TLC, hexane-ethyl acetate 4/1) - 1 hour. THF is distilled off on a rotary evaporator and to the residue add 10 ml of the Meon and rubbed with a glass rod until the onset of crystallization. Then add 10 ml of the Meon and intensively stirred on a magnetic stirrer 5 o'clock Yellow precipitate product is filtered off and washed with little cold Meon. After drying in a desiccator obtain 3.03 g (95%) of 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butylmalonate in the form of a bright yellow powder with MP 90-94°C.

1H NMR (250 MHz) δ 0.96 (t, J=8.6 Hz, 3H), 1.30-1.47 (m, 2H), 1.59-1.69 (m, 2H), 1.70 (s, N), 2.58 (s, 3H), 3.67 (t, J=7.7 Hz, 2H), 7.20-7.35 (m, 3H), 8.12 (d, J=7.9 Hz, 1H).

MS m/z: 461 (M+); 406; 361; 281; 182; 154:57.

Found: C, 57.40; H, 5.57; N, 6.29%. C22H25BrN2O4: Calculated:C, 57.28; H, 5.46; N, 6.07%.

Example 9

3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-benzylmaleimide (9).

To a solution of 2-methylindole (2.62 g, 20 mmol) in 70 ml THF at -20°With, in argon atmosphere, is added dropwise 42 ml of 20% solution of LiN(SiMe3)2in THF. The solution is stirred for 30 min at this temperature, then added dropwise a solution of 3,4-dibromo-1-benzylmaleimide (7.0 g, 20 mmol) in 70 ml THF. The reaction the mixture is allowed to reach room temperature, poured into 200 ml of 0.2 N. HCl, extracted with ethyl acetate (3×50 ml). The organic phase is washed with 5% NaHCO3(50 ml), water (3×30 ml), saturated NaCl solution, dried with MgSO4. Evaporated the solvent on a rotary evaporator, the residue is dissolved in 100 ml of THF, add 0.1 g of 4-dimethylaminopyridine and dropwise over 10 min a solution of BOC2O (5.0 g, 23 mmol) in 30 ml THF. The reaction mass is stirred for 1 hour, evaporated on a rotary evaporator. After flash chromatography on SiO2(hexane - EtOAc, 10/1) to obtain 7.0 g (70%) of 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-benzylmaleimide in the form of light yellow crystals with MP 150-154°C.

1H NMR (250 MHz) δ 1.71 (s, 9H), 2.58 (s, 3H), 4.82 (s, 2H), 7.20-7.50 (m, 8H), 8.12 (d, J=7.9Hz, 1H).

MS m/z: 497 (M+2); 496(M+1); 495 (M+); 395; 91; 57.

Found: C, 60.62; H, 4.55; N, 5.47%. With25H23BrN2O4. Calculated: C, 60.62; H, 4.68; N, 5.65%.

Example 10

Cross-coupling Baranovich acid with 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butyl(1-benzyl)maleimide, a General method.

In a three-neck round-bottom flask equipped with a reflux condenser and the input of argon, placed 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butylmalonic (8), (or 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-benzylmaleimide (9)), baronova acid (1.15 mol per 1 mol of bromide), 4 mol.% Pd(Ph3P)4, CsF (4 mol per 1 mol of bromide), 1,4-dioxane (100 is l/ 1 g Bronevoy acid). The reaction mixture is boiled in an argon atmosphere with vigorous stirring on a magnetic stirrer within the specified time, then poured into water, extracted with CHCl3washed the organic phase with water, dried Na2SO4distilled off the chloroform on a rotary evaporator. The residue is purified using flash chromatography on SiO2.

Example 11

3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-(3-chlorophenyl)-1-butylmalonic (10).

Get 3-Chlorfenvinphos acid (0.16 g, 1.0 mmol), maleimide (8) (0.42 g, 0.9 mmol), CsF (0.57 g, 3.6 mmol), Pd(Ph3R)4(0.04 g) in 20 ml of dioxane. The reaction mixture is boiled for 1 hour. After chromatography on SiO2(hexane - EtOAc 14/1) obtain 0.32 g (71%) of product as an orange oil.

1H NMR (250 MHz) δ 0.96 (t, J=8.0Hz, 3H), 1.39-1.50 (m, 2H), 1.60-1.79 (m, 2H), 1.70 (s, N), 2.42 (s, 3H), 3.70 (t, J=8.0Hz, 2H), 6.92-7.40 (m, 6N), 7.70 (s, 1H), 8.12 (d, J=8.9 Hz, 1H).

MS m/z: 492 (M+); 395; 394; 393; 392; 265; 131; 57; 43.

Found: C, 68.41; H, 5.70; N, 5.54%. C28H29CIN2O4. Calculated: C, 68.22; H, 5.93; N, 5.68%.

Example 12

3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-(3-methoxyphenyl)-1-butylmalonic (11).

Get 3-methoxyphenylacetic acid (0.16 g, 1 mmol), 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butylmalonate (8) (0.42 g, 0.9 mmol), CsF (0.57 g, 3.6 mmol), Pd(Ph3P)4(0.04 g) in 20 ml of dioxane. The reaction mixture is boiled for 2 hours. After chrome is adopted on SiO 2(hexane - EtOAc 10/1) to obtain 0.4 g (90%) of product as an orange oil.

1H NMR (250 MHz) δ 0.96 (t, J=8.0Hz, 3H), 1.37-1.49 (m, 2H), 1.61-1.75 (m, 2H), 1.69 (s, 9H), 2.41 (s, 3H), 3.51 (s, 3H), 3.69 (t, J=8.0Hz, 2H), 6.85 (m, 1H), 6.97-7.29 (m, 7H), 8.12 (d, J=9.0 Hz, 1H).

MS m/z: 489 (M+1); 488 (M+); 389; 388; 365; 372; 261; 218; 133; 57; 43.

Found: C, 71.35; H, 6.76; N, 5.65%. With29H32N2O5. Calculated: C, 71.29; H, 6.60; N, 5.73%.

Example 13

3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-(2-methyl-3-benzothiazyl)-1-butylmalonic (12).

Is obtained from 2-methyl-benzothiophen-3-Bronevoy acid (1) (1.09 g, 6.2 mmol), 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-butylmalonate (8) (2.507 g, 5.4 mmol), CsF (3.80 g, 25 mmol), Pd(Ph3R)4(0.25 g) in 200 ml of dioxane.

The reaction mixture is boiled for 5 hours. After chromatography on SiO2(hexane - EtOAc 14/1) obtain 2.40 g (83%) of product as an orange oil.

1H NMR (250 MHz) δ 1.02 (t, J=8.5 Hz, 3H), 1.39-1.51 (m, 2H), 1.65 (s, 9H), 1.69-1.83 (m, 2H), 2.12-2.40 (three OSS, 6N), 3.74 (t, J=8.0Hz, 2H), 7.10-7.45 (m, 6H), 7.15-7.35 (m, 4H), 7.69 (d, J=8.9Hz, 1H), 8.02 (s, J=9.0 Hz, 2H).

MS m/z: 528 (M+); 472; 429; 315; 286; 101.

Found: C, 70.30; H, 6.27; N, 5.35%. With31H32N2O4S. Calculated: C, 70.43; H, 6.10; N, 5.30%.

Example 14

3(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-(2,5-dimethyl-3-thienyl)-1-benzylmaleimide (13).

Derived from 2,5-dimethyl-3-thienylboronic acid (0.95 g, 6.1 mmol), 3-(1-tert.-butoxycarbonyl-2-methyl-3-indolyl)-4-bromo-1-benzylmaleimide (9) (2.57 g, 5.2 mmol), CsF (3. g, 21 mmol), Pd(Ph3R)4(0.24 g) in 150 ml of dioxane. The reaction mixture is boiled for 2 hours. After flash chromatography on SiO2(hexane - Et2O, 10/1) to obtain 2.32 g (85%) of the product 13 in the form of light yellow crystals with TPL 130-135°C.

1H NMR (250 MHz) δ 1.69 (s, 9H), 1.79 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 4.82 (s, 2H), 6.80 (s, 1H), 7.0-7.40 (m, 6H), 7.48 (d, J=6.5 Hz, 2H), 8.09 (d, J=7.2Hz, 1H).

MS m/z: 527 (M+1); 526 (M+); 427; 91.

Found: C, 70.56; H, 5.76; N, 5.55%. With31H30N2O4S. Calculated:C, 70.70; H, 5.74; N, 5.32%.

The inventive method for production of diaryl(hetaryl)maleimido allows to obtain compounds with photochromic properties. So, for example, 3,4-di(2-methyl-3-benzothiazyl)-1-butylmalonic (3) and 3-(2-tert.-butoxycarbonyl-3-indolyl)-4-(2-methyl-3-benzothiazyl)-1-butylmalonic (12) undergo thermally irreversible, but photochemically reversible cyclization under irradiation of UV light with a wavelength of 330 nm. The reverse transition occurs when the action of light with a wavelength of 550 nm (see drawing). This transition can be carried out repeatedly that allows you to use this process for recording information.

1. The way to obtain 3,4-diaryl(hetaryl)maleimido formula (I)

where R is C1-C4-alkyl or benzyl, or phenyl;

R1 is Br or aryl, such as phenyl or naphthyl, substituted by alkyl, alkoxy or halogen; hetaryl, unsubstituted or replacement of the military, such as thienyl, benzothiazyl-, furyl-, benzofuran-, pyrrolyl or indolyl-, where the substituents are alkyl, alkoxy, alkylthio-, halogen atom or trifluoromethyl;

Ar is aryl, such as phenyl or naphthyl, substituted by alkyl, alkoxy or halogen; hetaryl, unsubstituted or substituted, such as thienyl-, benzothiazyl-, furyl, benzofuran-pyrrolyl or indolyl-, where the substituents are alkyl, alkoxy, alkylthio-, halogen atom or trifluoromethyl, with the exception of 3,4-di(2,5-dimethyl-3-thienyl)-1-butylmalonate,

characterized in that the aryl(hetaryl)baronova acid formula

where Ar has the above meaning,

subjected to interaction with the N-substituted 3,4-dibromomalonamide formula (III)

or N-substituted 3-bromo-4-aryl(hetaryl)maleimido formula (IV)

where R and Ar have the above values,

using a palladium catalyst in the presence of a base in an environment of organic solvent.

2. The method according to claim 1, characterized in that as the palladium catalyst used is a complex type tetrakis(triphenylphosphine)palladium in an amount up to 4 mol.%.

3. The method according to claim 1, characterized in that as the Foundation of the CsF is used.

4. With whom persons according to claim 1, characterized in that the solvent is dioxane.

5. The method according to claim 3, characterized in that the CsF used as the base, add in the amount of not less than 2.5 mol on mol bromide (IV) and at least 5 mol per mol dibromide (III).

6. The method according to claim 1, characterized in that the aryl(hetaryl)baronova acid is introduced into the reaction in the amount of 1.1 to 1.2 mol per mole of bromide (IV) and 2.1 to 2.2 mol per mol dibromide (III).

7. The compounds of formula I, including di(2-methyl-3-benzothiazyl)-1-butylmalonic, 3(1-tert-butoxycarbonyl-2-methyl-3-indolyl)-4(2-methyl-3-battier)-1-butylmalonic and 3(1-tert-butoxycarbonyl-2-methyl-3-indolyl)-4(2,5-dimethyl-3-thienyl)-1-benzylmaleimide.



 

Same patents:

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide. Method involves reaction of bromosalicylic aldehyde with compound of the formula (I): L-CH2-COOR1 (I) wherein L represents Cl, Br or J atoms, or reactive esterified group -OH; R1 means (C1-C6)-alkyl or benzyl followed by reaction with formamide to yield 5-L-benzofuran-2-carboxamide (II) and the following its amination with R2-piperazine wherein R2 represents hydrogen atom (H) or amino-protecting group in the presence of a catalyst based on transient metals; in case if R2 is not H then R2 is removed, and/or prepared 5-(1-piperazinyl)-benzofuran-2-carboxamide is converted to one of its salts by treatment with acid. Except for, the invention proposes two additional methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds of the formula (V): wherein R2 represents H or amino-protected group; R3 means H or -CH2R6; R4 and R5 in common represent carbonyl; R6 means -CN, -COOH, -COOR7 or -CONH2; R7 means (C1-C6)-alkyl, and also their salts and solvates. Invention provides a new method for preparing the valuable intermediate compound used in preparing pharmaceutical preparations and increase of the yield of the end compound.

EFFECT: improved preparing methods.

6 cl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

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

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

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