C-2'-methylated derivatives of paclitaxel for using as antitumor agents

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel C-2'-methylated derivatives of paclitaxel of the formula (I): wherein R represents trifluoromethyl group, phenyl, 2-furyl, 2-thienyl; R1 represents tert.-butoxycarbonyl or benzoyl group; R2 represents hydroxy-group; R3 means hydrogen atom or in common with R2 forms residue of cyclic carbonate of the formula: under condition that when R3 means hydrogen atom then R is not phenyl. Also, invention relates to a pharmaceutical composition based on thereof and using for preparing medicinal agents possessing an antitumor activity. Invention provides preparing novel derivatives of paclitaxel that possess antitumor activity.

EFFECT: valuable medicinal property of derivatives and pharmaceutical composition.

4 cl, 1 tbl, 6 ex

 

The present invention relates to new derivatives taxane with antitumor activity, and methods for their preparation.

In particular, the present invention relates to compounds of formula (I):

where

R is trifluoromethyl, phenyl, 2-furyl, 2-thienyl;

R1represents tert-butoxycarbonyl or benzoyl;

R2represents hydroxy;

R3represents hydrogen or together with R2forms the residue of a cyclic carbonate of the formulaprovided that when R3is hydrogen, R is not phenyl.

The compounds of formula (I) are derivatives of paclitaxel or docetaxel, known drugs with antitumor activity.

The compounds of formula (I), where R3is hydrogen and R is phenyl, described by Greene et al., J. Chem. Soc. Perkin Trans. 1, 1995, p. 1811-1815. Derivatives of paclitaxel, carrying With-2'-methylated(2R,3S) side chain described by Kant et al., Tetrahedron, vol. 37, n. 36, p. 6495-6498, 1996. Kant demonstrated that this structural modification induces a significant enhancement of the response in comparison with the reference compound paclitaxel in certain tests (inhibition of depolymerization of microtubules) because of better affinity binding to microtubules and more cytotoxic the activity in relation to KBVI. In addition, some of these taxan synthesized from 14β-hydroxyacetic 1,14-carbonate, have improved solubility in water. Finally, one of the taxan contains triptorelin Deputy in position C-3 in order to block routes of metabolism associated with a class of enzymes cytochrome P-450. Improved pharmacological characterization data of new compounds can be due to modification of the spectrum of activity against various types of cancer.

Preferred compounds according to the invention are the following:

(2'R,3'R)-13-[N-benzoyl-3-(2-furyl)-2-methylisoborneol]baccatin III;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-furanyl)isuserinrole] baccatin III;

(2'R,3'S)-13-[N-BOC-2-methyl-3-phenylisoxazol]-14β-hydroxyacetic III 1,14-carbonate;(2'R,3'R)-13-[N-BOC-2-methyl-3-triftormetilfosfinov]-14β-hydroxyacetic III 1,14-carbonate;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-furanyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-thienyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate.

The compounds of formula (I) obtained by reaction of compounds of formula (II)

in which R2and R3defined above, and R4is a protective group, preferably, triethylsilyl, with the compound of formula (III)

where R and R 1defined above.

The compound of formula (III) can be obtained from the appropriate alilovic esters, in particular Izmailovo ether, known from Tetrahedron Asymm. 2001, 12, 1015-1027 and J. Chem. Soc. Perkin Trans.1 1995, 1811-1816, by hydrolysis in an alcohol solvent. The obtained acid, without isolation, can be directly condensed with a derivative baccatin III of the formula (II) in the presence of a suitable condensing agent, such as di-2-pyridylmethylamine and dimethylaminopyridine in a suitable solvent. Hydroxyamino group in position 7 is removed to obtain the desired compounds of formula (I).

Alternatively, can be carried out the reaction of compounds of formula (II) with compounds of the formula (IV)

where R is defined above.

The compound of formula (IV)in which R represents phenyl, described in J. Org. Chem. 1991, 56, 1681-1684; Tetrahedron, 1992, 48, 6585-7012, EP 400971, US 5175315.

The compound of formula (IV)in which R represents a trifluoromethyl, can be obtained in accordance with the following scheme:

The compound of formula (IV)in which R1represents 2-furyl, can be obtained from (3R,4R)-4-(furan-2-yl)-3-hydroxy-3-methylaziridine-2-it is known from J. Org. Chem. 1999, 64, 4643, 4651, in accordance with the following scheme:

Connect four is uly (II) are known from J. Med. Chem. 1997, 40, 267-278.

The reaction between the compound (II) and compound (IV) is carried out in an aprotic solvent in an inert environment.

Typically, the reaction is carried out at a temperature of about -40 to 5°in the presence of hexamethyldisilazane sodium. Hydroxyamino group in position 7 is removed to obtain the desired compounds of formula (I).

Compounds according to the present invention possess strong antitumor activity against breast cancer cells, lung, ovary, colon, prostate, kidney, pancreas, as well as in cells that are resistant to known anticancer drugs such as adriamycin, vinblastine and derivatives of platinum.

Therefore, the present invention relates to pharmaceutical compositions containing an effective amount of the compounds according to the invention, together with pharmacologically acceptable carriers and excipients. In particular, these compounds may be made in the form of tablets, powder, granules, capsule, solution for injection, suppository, emulsion, dispersion, etc. For intravenous preferably a mixture Chremophor L and ethanol, Polysorbate and ethanol or preparations of liposomes obtained by the use of natural or synthetic phosphatidylcholine or see what this natural phospholipids in the presence of cholesterol; for oral administration preferably are soft gelatin capsules in which this product is dissolved in Polysorbate, PEG or their mixtures, optionally in the presence of phospholipids. The compound (I) can be administered to the people in the concentration range from 50 to 500 mg/m2.

The following examples illustrate the invention in more detail.

Use the following abbreviations:

TES = triethylsilyl; DMF = dimethylformamide; DMAP = (N,N-dimethylamino)pyridine; NaHMDS = hexamethyldisilazide sodium; LiHMDS = hexamethyldisilazide lithium; THF = tetrahydrofuran; HMPA = hexamethylphosphoric triamide.

EXAMPLE 1

Methyl ester (4S,5R)-3-benzoyl-2-(2,4-acid)-4-(furan-2-yl)-5-methyloxazolidine-5-carboxylic acid (0,128 g, 0,285 mmol) in methanol was stirred with K2CO3(2 EQ.) at 25°C for 24 hours in an anhydrous environment. The reaction mixture was concentrated in vacuo, diluted with saturated solution of NH4Cl and extracted with ethyl acetate. The aqueous phase was acidified to pH 4 with 5% NaHSO4and were extracted with ethyl acetate. The organic phase was dried and the solvent evaporated. The remainder (1 EQ.) was added to a solution of 7-TES-baccatin III in toluene (0.04 g, 0,057 mmol) in the presence of di-2-pyridylmethylamine (1 EQ.) and dimethylaminopyridine (0.5 EQ.) at 20°C in argon atmosphere. The reaction mixture was heated to 60� With over 80 hours with stirring. After adding ethyl acetate, the reaction mixture was extracted with brine. The organic phase was washed with brine, then dried and evaporated. When chromatography (SiO2, ethyl acetate/n-hexane, 1:1) received (2'R,3'R)-13-[N-benzoyl-N,O-(2,4-dimethoxybenzamide)-3-(2-furanyl)-2-methylisoborneol]-7-TES-baccatin III (0,023 g, 2.28 mmol, 40%). The connection has the following characteristics:

1H-NMR (CDCl3): δ = 0,61 (m, 6N, SN2), of 0.95 (t, N, me), 1,22 (s, 3H, Me), 1.27mm (s, 3H, Me), by 1.68 (s, 3H, Me), 1,89 (m, 1H C6-H), 2,10-of 2.25 (m, 2H C14-H), of 2.21 (s, 3H, Me), 2,24 (s, 3H, Me), of 2.33 (s, 3H, Me), 2,50 (m, 1H C6-H), 2,65 (, 3H, Me, SLA-4), are 3.90 to 4.0 (m, 8H, 6N me, 1H C3-H and 1H, HE), of 4.12 (d, 1H C20-H, J=8.0 Hz), 4,32 (d, 1H C20-H), 4,58 (m, 1H C7-H, J1=5.8 Hz, J2=10,2 Hz), of 4.95 (DD, 1H, C5-H, J1=1.5 Hz, J2=9.6 Hz), 5,55 (Shir, 1H C3'-H), 5,70 (d, 1H C2-H, J=5.7 Hz), 6.30-in-6,40 (m, 2H), 6,40-6,50 (m, 3H), is 6.54 (s, 1H), PC 6.82 (s, 1H), 7,20-7,40 (m, 5H, aromatics), 7,40-to 7.50 (m, 3H, aromatics), 7,54-of 7.60 (m, 1H, aromatic compounds), 8,04-8,07 (m, 2H, aromatics).

The compound obtained (0,023 g, 2.28 mmol) was dissolved in CH2Cl2(3.0 ml) and treated with a solution (100 μl) acetylchloride in methanol (70 ál acylchlorides in 10 ml Meon) at 25°C. After 7 hours the reaction mixture was extracted with H2O. the Organic solvent was dried and evaporated. The remainder of chromatographia is whether (SiO 2, n-hexane/ethyl acetate, 1:1) to obtain 0,019 g (of 0.022 mmol, 98%) (2'R,3'R)-3'-dephenyl-3'-(2-furyl)-2'-methylpyridoxine.

The compound obtained has the following characteristics:

1H-NMR (CDCl3): δ=1,13 (s, 3H, Me)to 1.23 (s, 3H, Me), of 1.55 (s, 3H, Me), to 1.70 (s, 3H, Me), is 1.81 (s, 3H, Me), 1,89 (m, 1H, H-6β), 2,07 (m, 1H C14-H), 2,24 (s, 3H, Me), is 2.40 (m, 1H C14-H), 2.49 USD (d, 1H, HE, C7-H), to 2.55 (m, 1H C6-H), to 2.65 (s, 3H, Me in), 3.75 (s, 1H, HE), 3,82 (d, 1H C3-H, J=7,2 Hz), is 4.21 (d, 1H C20-H, J=8,4 Hz), or 4.31 (d, 1H C20-H), and 4.40 (m, 1H C7-H), of 4.95 (DD, 1H, C5-H, J1=1.5 Hz, J2=9.6 Hz), to 5.66 (d, 1H C2-H), 5,79 (d, 1H C3'-H, J=9.5 Hz), of 6.26 (s, 1H C10-H), 6.30-in (m, 1H C13-H), 6,41 (m, 2H, 2-furyl), 7,12 (d, 1H, NH), 7,33 (m, 2H, aromatics), 7,44 (m, 1H, 2-furyl), 7,46 (m, 1H, aromatic compounds), 7,52 (m, 2H, aromatics), 7,60 (m, 1H, aromatic compounds), to 7.67 (m, 2H, aromatics), 8,19 (m, 2H, aromatics).

EXAMPLE 2

The complex interaction of the methyl ester of (4S,5R)-N-Boc-N,O-(2,4-dimethoxybenzamide)-3-phenyl-2-methylinosine (J.Chem.Soc. Perkin Trans. 1995, 1811-1816) (0,154 g, 0,336 mmol) of 7-TES-baccatin III 1,14-carbonate1(0.05 g, 0,067 mmol) according to the procedure described in example 1, resulted in obtaining 0,021 g (is 0.023 mmol, 34%) of (2'R,3'S)-13-(N-Boc-2-methyl-3-phenylisoxazol)-14β-hydroxyacetone III 1,14-carbonate.

The compound obtained has the following characteristics:

1H-NMR (CDCl3): δ = 1,28 (s, N, mA tert-BOC), of 1.30 (s, 3H, Me-15), to 1.38 (s, 3H, Me-15), of 1.41 (s, 3H, M Is C2'), of 1.73 (s, 3H, Me-8), of 1.84 (s, 3H, Me-12), with 1.92 (m, 1H C6-H), and 2.26 (s, 3H, Me, SLA-10), 2,36 (Shir, 1H, HE), of 2.56 (m, 1H C6-H), 2,69 (s, 3H, Me, SLA-4), 3,52-3,55 (Shir, 1H, HE), to 3.73 (d, 1H C3-H, J=7,3 Hz), 4,25 (d, 1H C20-H, J=8.5 Hz), or 4.31 (d, 1H C20-H), to 4.38 (m, 1H, C7-H), is 4.85 (d, 1H C14-H, J=7,1 Hz), of 4.95 (DD, 1H, C5-H, J1=2.4 Hz, J2=9.6 Hz), 5,09 (d, 1H C3'-H), to 5.57 (d, 1H, NH, J=10.0 Hz), 6,13 (d, 1H C2-H), 6,27 (s, 1H C10-H), 6,36 (m, 1H, C13-H), 7,30-7,40 (m, 5H, aromatics), of 7.48 (m, 2H, aromatics), to 7.59 (m, 1H, aromatic compounds), of 8.04 (m, 2H, aromatic connection).

EXAMPLE 3

a) (3R,4S)-3-triethylsilyl-4-(furan-2-yl)-3-methylaziridine

Triethylsilane (0,316 g, 2.1 mmol) and imidazole (0,100 g, 1.5 mmol) was added to a stirred solution of (3R,4R)-4-(furan-2-yl)-3-hydroxy-3-methylaziridine-2-it (0.167 g, 1.0 mmol) in DMF (6.0 ml) at 25°C in argon atmosphere. The reaction solution after 4 hours extinguished saturated aqueous NH4Cl and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. By chromatography of the residue (SiO2, ethyl acetate/n-pentane 1:2) received 0,190 g (0.67 mmol, 67%) of (3R,4S)-4-(furan-2-yl)-3-triethylsilyl-3-methylaziridine-2-it:

[α]D20=+42,8 (c 1,04, CHCl3); IR (CDCl3cm-1): 3600-3000, 3413, 2957, 1768, 1458, 1377, 1012;1H-NMR (CDCl3): δ = 0,65 (m, 6N, SN2), of 0.95 (t, N, me), 1,19 (s, 3H, Me), of 4.54 (s, 1H), 6,27 (d, 1H, 2-furyl), 6,28 (m, 1H, 2-furyl), 6,72 (Shir, 1H, NH), 7,40 m, 1H, 2-furyl);13H-NMR (CDCl3): δ = 5,71 (CH2), 6.73 x (IU), And 19.3 (IU)61,0 (CH), 89,1 (C), 108,1 (CH), 110,5 (CH), 142,7 (CH), 150,9 (C), which is 171,5 (S).

b) (3R,4S)-1-tert-butoxycarbonyl-3-triethylsilyl-4-(furan-2-yl)-3-methylaziridine

To the solution derived from the previous stage (to 0.060 g, 0.21 mmol), DMAP (0,010 g) and triethylamine (88 μl, was 0.63 mmol) in CH2Cl2(3.0 ml) at 0°solution was added di-tert-BUTYLCARBAMATE (121 ml, 0.52 mmol) in CH2Cl2(1.0 ml). The reaction mixture was stirred at 25°°C for 1 hour, then reduce saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried and concentrated under reduced pressure. Chromatography (SiO2n-pentane/ethyl acetate, 8:2) received 0,077 g (at 0.020 mmol, 97%) of (3R,4S)-1-tert-butoxycarbonyl-3-triethylsilyl-4-(furan-2-yl)-3-methylaziridine:

[α]D20=+26,6 (c 0,98, CHCl3); IR (CDCl3cm-1): 2958, 1813, 1726, 1327, 1152;1H-NMR (CDCl3): δ = 0,54 (m, 6N, SN2), 0,80 (t, N, mi), of 1.41 (s, N, me), to 1.61 (s, 3H, Me), to 4.73 (s, 1H), 6,27 (m, 1H, 2-furyl), 6,34 (m, 1H, 2-furyl), 7,37 (m, 1H, 2-furyl);13H-NMR (CDCl3): δ = 5,6 (CH2), 6,5 (IU)23,0 (IU)27,8 (me), 62,7 (SN), and 83.3 (C)85,4 (C), 108,9 (CH), 110,3 (CH), 142,4 (CH), 147,9 (C), 148, 7mm (C), 167,7 (S).

(C) (2'R,3'R)-13-[N-Boc-2-methyl-3-(2-furanyl)isuserinrole]baccatin III

β-lactam from stage b) (0,082 g, 0,214 mmol) and 7-TES-bakat the n III (to 0.060 g, 0,086 mmol) was dissolved in THF in an argon atmosphere. The solution was cooled to -45°C. NaHMDS (solution 1.0 M in n-hexane, 2.5 EQ.) was added dropwise with stirring. The temperature was raised to -20°C for four hours. The reaction extinguished saturated NH4Cl; the mixture was extracted with ethyl acetate and dried. After evaporation of the solvent the crude product was purified by chromatography. The reaction product was dissolved at 0°in solvent MeCN/pyridine 1:1. A solution of HF/pyridine (70/30) was added dropwise (0.1 ml/10 ml reagent). The reaction mixture was stirred at 0°C for 1 h, then at 25°C for 6 hours, then was extracted with ethyl acetate. The extracts were washed three times with saturated CuSO4and water and dried over anhydrous MgSO4to obtain 0.035 g level (0.041 mmol, 48%) specified in the header of the product:

1H-NMR (CDCl3): δ = 1,15 (s, 3H, Me-15), of 1.23 (s, N, mA tert-BOC), of 1.30 (s, 3H, Me-15), to 1.42 (s, 3H, Me C2'), was 1.69 (s, 3H, Me-8), of 1.84 (s, 3H, Me-12), 1,89 (m, 1H, H-6β), of 2.15 (m, 1H, H-14 in), 2.25 (s, 3H, Me, SLA-10), is 2.37 (m, 1H, H-14), to 2.55 (m, 1H C6-H), 2,61 (s, 3H, Me, SLA-4), to 3.58-3,65 (Shir, 1H, HE), 3,82 (d, 1H C3-H, J=7.0 Hz), 4,18 (d, 1H C20-H, J=8,4 Hz), or 4.31 (d, 1H C20-N), was 4.42 (DD, 1H C7-H, J1=6,4 Hz, J2=to 10.8 Hz), of 4.95 (DD, 1H, C5-H, J1=2.4 Hz, J2=9.6 Hz), 5,23 (d, 1H, J=9.6 Hz, NH), of 5.39 (d, 1H C3'-H), to 5.66 (d, 1H C2-H), 6,28 (s, 1H C10-H), 6,34 (m, 1H, 2-furyl), 6,36 (m, 1H, H-13), 6,38 (m, 1H, 2-furyl), 7,42 (m, 1H, 2-furyl), 7,49 (m, 2H, aromatic with the unity), to 7.59 (m, 1H, aromatic compounds), 8,14 (m, 2H, aromatics).

EXAMPLE 4

(2'R,3'R)-13-[N-Boc-2-methyl-3-(2-furanyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate

7-TES-14β-hydroxyacetic III 1,14-carbonate (0,080 g, 0.125 mmol) interacted with (3R,4S)-1-tert-butoxycarbonyl-3-triethylsilyl-4-(furan-2-yl)-3-methylaziridine (0.12 g, 0,312 mmol) under the conditions described in example 3C, which led to the formation of a (2'R,3'S)-13-[N-Boc-2-methyl-3-(2-furanyl)isuserinrole]-3',7-di-TES-14β-hydroxyacetic III 1,14-carbonate (0,087 g, 0,0775 mmol, 62%):

1H-NMR (CDCl3): δ = 0.5 to 0.6 (m, N, SN2), 0,85-0,95 (m, N, me), 1,25 (s, 3H, Me), of 1.29 (s, N, me), is 1.31 (s, 3H, Me), and 1.56 (s, 3H, Me), a 1.75 (s, 3H, Me), with 1.92 (m, 1H C6-H, J6-6'=14,3 Hz), 2,02 (s, 3H, Me), measuring 2.20 (s, 3H, Me), of 2.51 (m, 1H C6-H), a 2.71 (s, 3H, Me), 3,76 (d, 1H C3-H, J=8.1 Hz), 4.26 deaths (kV, 2H C20, J=8.5 Hz), of 4.44 (m, 1H C7-H, J1=to 10.8 Hz, J2=to 10.8 Hz), is 4.85 (d, 1H C14-H, J=7.0 Hz), 4,89 (m, 1H, C5-H, J1=1.8 Hz, J2=9.8 Hz), 5,24 (d, 1H, 1H C3'-H, J=10.0 Hz), 5,28 (d, 1H, NH), 6,10 (d, 1H C2-H), of 6.26 (d, 1H, 2-furyl), 6,38 (m, 1H, 2-furyl), 6.42 per (s, 1H C10-H), 6,47 (d, 1H C13-H), 7,38 (m, 1H, 2-furyl), 7,42-to 7.50 (m, 2H, aromatics), 7,54-of 7.60 (m, 1H, aromatic compounds), 8,02-8,08 (m, 2H, aromatics).

The obtained derivative was treated with a solution of HF/pyridine to obtain specified in the connection header (0,063 g 0,070 mmol, 91%):

1H-NMR (CDCl3): δ = 1,25 (s, N, mi), of 1.28 (s, 3H, Me), was 1.43 (s, 3H, Me), 1.75 per, 3H, Me), to 1.86 (s, 3H, Me) of 1.92 (m, 1H C6'-H, J6-6'=14,3 Hz), 2,24 (s, 3H, Me), to 2.55 (m, 1H C6-H), 2.63 in (s, 3H, Me), to 3.73 (d, 1H C3-H, J=8.0 Hz), 4.26 deaths (kV, 2H C20, J=8.5 Hz), to 4.38 (m, 1H C7-H, J1=to 10.8 Hz, J2=7,0 Hz), a 4.86 (d, 1H C14-H, J=7.0 Hz), is 4.93 (m, 1H, C5-H, J1=1.8 Hz, J2=9.8 Hz), 5,26 (d, 1H, 1H C3'-H, J=9.5 Hz), 5,44 (d, 1H, NH), 6,12 (d, 1H C2-H), 6,28 (s, 1H C10-H), 6,36 (d, 1H, 2-furyl), 6,40 (m, 1H, 2-furyl), 6,47 (d, 1H C13-H), 7,42 (m, 1H 2-furyl), 7,44 is 7.50 (m, 2H, aromatic compounds), 7,58 to 7.62 (m, 1H, aromatic compounds), 8,02-8,08 (m, 2H, aromatics).

EXAMPLE 5

a) (3R,4R)-3-hydroxy-1-(4-methoxyphenyl)-3-methyl-4-triftormetilfosfinov-2-he

To a solution of (2S,5S)-2-tert-butyl-2,5-dimethyl[1,3]dioxolane-4-it (described in J. Org.Chem., 1999, 64, 4643-4651) (0,344 g, 2.03 mmol) in THF was added a 1 M solution of LIHMDS (2.4 ml, 2.4 mmol) in THF at -78°C. After 30 minutes consistently added HMPA solutions and N-(4-methoxyphenyl)triptorelin (0,81 g, 4.00 mmol) (THF:HMPA=85:15). After 4 hours the reaction mixture was subjected to 5 ml of 1 M aqueous solution of CH3CO2H at -78°With, was extracted with 1 N. HCl, then NH4Cl finally with brine. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure. By chromatography of the residue (SiO2, EtOAc/n-pentane 1:2) was obtained 0.25 g (of 0.91 mmol, 45%) specified in the header β-lactam (3R,4R):

[α]D20=+28,4 (c 1,01, CHCl3);1H-NMR (CDCl3): δ 1,70 (d, 3H, IU, J=1.2 Hz), 3,02-3,10 (Shir, 1H, HE), of 3.78 (s, 3H, OMe), to 4.33 (q, 1H, JN-F=5.7 Hz) 6,85-7,40 (m, 4H, aromatics);13H-NMR (CDCl3): δ = 22,2 (IU)of 55.5 (OMe), and 63.9 (CV, CH, J=31 Hz), 82,8 (C), TO 114.4 (2CH), 119,7 (2CH), 123,7 (CF3, J=279 Hz), Which Is 129.3 (C), 157,3 (C), 167,9 (S).

b) (3R,4R)-3-triethylsilyl-1-(4-methoxyphenyl)-3-methyl-4-triftormetilfosfinov-2-he

To a solution of compound of stage a) (0.25 g, of 0.91 mmol) in DMF (3.0 mmol) was added Et3SiCl (0.31 g, 2.0 mmol) and N-Mei (0.28 g, 4 mmol) at 25°C. After 2 hours stirring, the reaction mixture was poured into ice water, extracted with ethyl acetate and dried. The solvent is evaporated and the residue was chromatographically to obtain 0.32 g (0.82 mmol, 90%) specified in the header of the product:

IR (CDCl3cm-1): 2957, 2878, 1778, 1514, 1298, 1251;1H-NMR (CDCl3): δ = 0,75 (m, 6N, SN2), and 0.98 (t, N, mi), of 1.65 (s, 3H, Me), 3,79 (s, 3H, OMe), 4,22 (kV, 1H, JN-F=5,9 Hz) 6,85-7,40 (m, 4H, aromatics);13H-NMR (CDCl3): δ = 5,7 (CH2), 6,6 (IU)And 23.4 (IU)of 55.5 (OMe), 64,3 (CV, CH, J=32 Hz), 84,0 (C), TO 114.4 (2CH), 119,5 (2CH), 123,6 (CF3, J=283 Hz), 129,8 (C), 157,1 (C), 167,1 (S).

(C) (3R,4R)-3-triethylsilyl-3-methyl-4-triftormetilfosfinov-2-he

To a solution of the compound from stage b) (0,30 g, 0.77 mmol) in acetonitrile (13,0 ml) was added dropwise to the ammonium nitrate and cerium (IV) (1.5 g, to 2.74 mmol) in water (20,0 ml)and then water (30 ml) over 2 hours at -50°C. the Mixture divorce is whether water (30 ml) and was extracted with ethyl acetate. The organic phase was washed with saturated solution of NaHCO3, a saturated solution of NaHSO3and then a saturated solution of NaHCO3. The organic layer was dried and concentrated in vacuum. The residue was subjected to column chromatography (SiO2CH2Cl2/ethyl acetate, 3:1) to obtain specified in the header of the product has 0.168 g, 0.59 mmol, 77%):

1H-NMR (CDCl3): δ = 0.69 (m, 6N, SN2), were 0.94 (t, N, me), to 1.60 (s, 3H, Me), of 3.77 (q, 1H, JN-F=6.2 Hz), 6,20-6,45 (Shir, 1H, NH);13H-NMR (CDCl3): δ = 5,8 (CH2), 6,8 (IU)23,7 (IU) 61,0 (CV, CH, J=32 Hz), 86,3 (C)123,8 (CF3, J=280 Hz), 170,8 (S).

d) (3R,4R)-1-(tert-butoxycarbonyl)-3-triethylsilyl-3-methyl-4-triftormetilfosfinov-2-he

To a solution of compound of stage (C) (has 0.168 g, 0.59 mmol), DMAP (10 mg) and triethylamine (0.25 ml, 1.77 mmol) in dichloromethane (2.0 ml) at 0°solution was added di-tert-BUTYLCARBAMATE (0.32 g, of 1.47 mmol) in dichloromethane (1.0 ml). The reaction mixture was stirred at 25°C for 2 hours, then extinguished with saturated solution of NH4Cl. The mixture was extracted with ethyl acetate and the organic layer was washed with saline, dried and concentrated under reduced pressure. Chromatography (SiO2n-pentane/ethyl acetate, 4:1) received 0,210 g (0,56 mmol, 95%) specified in the header of the product:

1H-NMR (CDCl3): δ = 0.69 (m, 6N, SN2), of 0.95 (t, N, me), 1,52 (N, Me), and 1.63 (c, 3H, Me), 4,10 (kV, 1H, JN-F=6.2 Hz);13H-NMR (CDCl3): δ = 5,6 (CH2), 6,5 (IU), 23.5cm (IU), 27,8 (me), 63,2 (CV, CH, J=32 Hz), 84,7 (C), 122,8 (CF3, J=281 Hz), To 147.2 (S), 167,4 (S).

(e) (2'R,3'R)-13-[N-Boc-2-methyl-3-triftormetilfosfinov]-14β-hydroxyacetic III 1,14-carbonate

In the reaction of 7-TES-14β-hydroxyacetone III (0,080 g, 0.11 mmol) with compound of stage (d) (0,103 g, 0.27 mmol) according to the method of example 4 was obtained 7,3'-di-TES-derived specified in the connection header (0,071 g 0,063 mmol, 57%):

1H-NMR (CDCl3): δ = 0,62-0,72 (m, N, SN2), from 0.88 to 0.95 (m, N, me), 1,25 (s, N, me), is 1.31 (s, 3H, Me), of 1.52 (s, 6N, me), and 1.63 (s, 3H, Me), 1,90 (m, 1H C6'-H), from 2.00 (s, 3H, Me), are 2.19 (s, 3H, Me), 2,48 (m, 1H C6-H), 2,58 (s, 3H, Me), 3,74 (d, 1H C3-H, J=7.5 Hz), 4,24 (kV, 2H C20, J=8,8 Hz)to 4.41 (m, 1H C7-H, J1=to 10.6 Hz, J2=6,4 Hz), 4,74 (m, 1H, C3'-H), a 4.83 (d, 1H C14-H, J=6.9 Hz), a 4.86 (m, 1H, C5-H, J1=1.90 Hz, J2=9.8 Hz), 5,10 (d, 1H, NH), 6,10 (d, 1H C2-H), 6,40 (s, 1H C10-H), 6.42 per (m, 1H C13-H), 7,44 is 7.50 (m, 2H, aromatics), 7,58-of 7.60 (m, 1H, aromatic compounds), 8,06-8,10 (m, 2H, aromatics).

The obtained derivative was subjected to solution of HF/pyridine to obtain specified in the connection header (0,048 g, 0.54 mmol, 85%):

1H-NMR (CDCl3): δ = 1,28 (s, N, me), is 1.31 (s, 3H, Me), of 1.33 (s, 3H, Me), at 1.73 (s, 3H, Me), 1,90 (s, 3H, Me), 1,90 (m, 1H C6'-H in), 2.25 (s, 3H, Me), to 2.55 (m, 1H C6-H), to 2.57 (s, 3H, Me), 3,736 (d, 1H C3-H, J=7,6 Hz), 4.26 deaths (kV, 2H C20, J=8,8 Hz), to 4.38 (m,1H C7-H, J1=to 10.8 Hz, J2=6,4 Hz), 4,82 (m, 1H C3'-H), a 4.86 (d, 1H C14-H, J=6.8 Hz), the 4.90 (m, 1H, C5-H, J1=2.3 Hz, J2=9.9 Hz), 5,24 (d, 1H, NH), 6,10 (d, 1H C2-H), of 6.26 (s, 1H C10-H), 6,47 (d, 1H C13-H), of 7.48-rate of 7.54 (m, 2H, aromatics), 7,58-to 7.64 (m, 1H, aromatic compounds), 8,08-to 8.12 (m, 2H, aromatics).

EXAMPLE 6

(2'R,3'R)-13-[N-Boc-2-methyl-3-(2-thienyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate

7-TES-14β-hydroxyacetic III 1,14-carbonate (0.24 g, the 0.375 mmol) interacted with (3R,4S)-1-tert-butoxycarbonyl-3-triethylsilyl-4-(Tien-2-yl)-3-methylaziridine (0.36 g, 0,936 mmol) under the conditions described in example 3C.

After protection with a solution of HF/pyridine specified in the title compound was obtained as white solid (0,189 g, 2.1 mmol, 55%):

1H-NMR (CDCl3): δ = 1,25 (s, N, mi), of 1.28 (s, 3H, Me), was 1.43 (s, 3H, Me), a 1.75 (s, 3H, Me), to 1.86 (s, 3H, Me), with 1.92 (m, 1H C6'-H, J6-6'=14,3 Hz), 2,24 (s, 3H, Me), to 2.55 (m, 1H C6-H), 2.63 in (s, 3H, Me), to 3.73 (d, 1H C3-H, J=8.0 Hz) 4.26 deaths (kV, 2H C20, J=8.5 Hz), to 4.38 (m, 1H C7-H, J1=to 10.8 Hz, J2=7,0 Hz), a 4.86 (d, 1H C14-H, J=7.0 Hz), is 4.93 (m, 1H, C5-H, J1=1.8 Hz, J2=9.8 Hz), 5,26 (d, 1H, 1H, C3'-H, J=9.5 Hz), 5,44 (d, 1H, NH), 6,12 (d, 1H C2-H), 6,28 (s, 1H C10-H), 7,07 (DD, 5,0, 3.6 Hz, H-3 thienyl), 7,16 (DD, 3,6, 1.0 Hz, H-4 thienyl), 6,47 (d, 1H C13-H), 7,35 (DD, 5,0, 1,0 N-5 thienyl), 7,44 is 7.50 (m, 2H, aromatics), 7,58 to 7.62 (m, 1H, aromatic compounds), 8,02-8,08 (m, 2H, aromatics).

Pharmacological experiments

The wire is whether pharmacological experiments with the compounds according to this invention at 0.1% concentration in dimethyl sulfoxide. Used cell lines A2780wt, A2780cis, A2780adr and A2780tax. The cells were placed in 96-well flat tablets (Viewplates, Packard). After 24 hours, culture medium was replaced and after washing was added to the medium containing the test compounds. Created logarithmic curve dose-effect in four repetitions for each plate, from 0.01 to 100000000 nm. Each analysis was performed in two repetitions three times. After 72 hours of culturing in the presence of test compounds, cells were collected and evaluated the number of viable cells in a dose of ATP using ATP-deficient kit (Packard, Meridien, MO, USA) and an automatic Topcount luminometer (Packard). For each line the drug/cell built curve dose-effect and calculated IC50 curve concentration-effect obtained in the three tests with the model sigmoidal Emax using nonlinear regression, weighted by the inverse value of the square of the estimated effect. The obtained IC50 values after continuous exposure to the test compounds for 72 hours are presented in the following table.

Table
ConnectionA2780wtA2780cisA2780taxA2780adr
Paclitaxel5,3±1,34,6±0,7448± 1232688±454
Example 13,1±0,22,9±0,1420±9361,4±3,9
Example 32,9±0,13,3±0,2312±6141,3±7,4
Example 22,53±1,471,7±0,4299±7752,9±16,2
Example 5with 4.64±2,582,8±0,6285±6079,3±19,9
Example 45,9±0,72,5±0,330,9±3,727,1±10,1
Example 63,7±0,42,9±0,2of 160.4±3293,2±20,4

Concentrate for injection

Composition

Connection example 12 mg
Polyoxylene
oil527 mg
Digidrirovanny alcohol q.s.to 1.0 ml

Recipe for 100 ml solution

Digidrirovanny alcohol q.s.
Connection example 10.2 mg
Polyoxylene
oil52,7 mg
to 100 ml

Method of cooking

1. Added with vigorous stirring 30 g digidratirovannogo alcohol to 52.7 g Polyoxylene oil, continuing to mix until you obtain a transparent homogeneous solution.

2. Add 0.2 g of the compound of example 1 to the solution obtained in stage 1 and continue stirring for at least 60 minutes to obtain a transparent homogeneous solution.

3. To the resulting solution was added Digidrirovanny alcohol and stirred to obtain a transparent homogeneous solution.

4. Filter the solution obtained in stage 3, through a filter of 0.2 μm under pressure.

Liquid filling of hard gelatin capsules

Composition

Each hard gelatin capsule includes:

The compound of example 610 mg
Glycerylmonostearate390 mg
Glycerides lauromacrogol-32100 mg

Manufacturing composition for 500 hard gelatin capsules

Method of cooking

1. Mix 195 g glycerylmonostearate and 50 g of the glycerides of lauromacrogol-32 at 55-60°With, continuing to mix until you obtain a transparent homogeneous solution.

2. Add 5 g of compound of example 6 to a solution obtained in stage 1 and continue stirring at 50-60°C, to obtain a transparent homogeneous solution, does not contain suspended particles.

3. Fill capsules of size 0 with suitable equipment at 45-50°500 mg/capsule solution obtained in stage 2.

4. Leave the solution to cool at room temperature inside the capsule.

1. The compounds of formula (I)

where R is trifluoromethyl, phenyl, 2-furyl, 2-thienyl;

R1represents tert-butoxycarbonyl or benzoyl;

R2represents hydroxy;

R3is hydrogen or together with R2forms the residue of a cyclic carbonate of the formulaprovided that when R3is hydrogen, R is not phenyl.

2. The compounds of formula (I) according to claim 1, which are the following:

(2'R,3'R)-13-[N-benzoyl-3-(2-furyl)-2-methylisoborneol]baccatin III;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-furanyl)isuserinrole]baccatin III;

(2'R,3'S)-13-[N-Boc-2-methyl-3-phenylazomethine the l]-14β -hydroxyacetic III 1,14-carbonate;

(2'R,3'R)-13-[N-BOC-2-methyl-3-triftormetilfosfinov]-14β-hydroxyacetic III 1,14-carbonate;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-furanyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate;

(2'R,3'R)-13-[N-BOC-2-methyl-3-(2-thienyl)isuserinrole]-14β-hydroxyacetic III 1,14-carbonate.

3. Pharmaceutical composition having antitumor activity, containing one of the compounds of formula (I), together with pharmaceutically acceptable carriers and excipients.

4. The use of compounds of formula (I) for obtaining a medicinal product with antitumor activity.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemical, pharmaceuticals.

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

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

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

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, chemical technology, medicine, veterinary science.

SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.

EFFECT: improved preparing method, valuable properties of compound and composition.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diphenylazathedinone of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another (0-C30)-alkylene-L wherein one or some C-atoms of alkylene residue can be substituted with -O-, -(C=O)- or -NH- and, except for, R1-R6 can represent hydrogen atom (H), fluorine atom (F), and L represents compound of the formula: , and their pharmaceutically tolerated salts also. Compounds of the formula (I) elicit hypolipidemic effect and can be used in therapeutic aims. Also, invention describes a medicinal agent and its using.

EFFECT: valuable medicinal properties of compounds.

7 cl, 31 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

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

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino}-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate of the formula (1): . Also, invention relates to a method for preparing this compound by interaction of free compound of the formula (1) with maleic acid in the presence of organic solvent. This salt can be used as thrombin inhibitor.

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

4 cl, 2 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

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

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

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

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

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

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: pharmaceutical chemistry, medicine.

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

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

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

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes derivatives of 2-amino-1,3,5-triaziene of the formula (I): wherein R1 means phenyl or alkyl with from 1 to 6 carbon atoms that can be substituted with one or some radicals taken among halogen atom and cyano-group; R2 means unsubstituted cyclopropyl, cyclobutyl or cyclopentyl groups or substituted that with radical taken among halogen atom and alkyl with from 1 to 4 carbon atoms, or furyl, or tetrahydrofuryl; R3 means radical of the formula -N(B1-D1)(B2-D2); R4 means radical of the formula -B3-D3; A1 means direct alkylene with 1-5 carbon atoms or direct alkenylene with 2-5 carbon atoms; A2 means a direct bond or direct alkylene with 1-4 carbon atoms; B1, B2 and B3 mean a direct bond; D1, D2 and D3 mean hydrogen atom; (X)n means a number of X substitutes wherein X means independently halogen atom, nitro-group or unsubstituted alkyl with 1-6 carbon atoms or substituted that with one or some radicals taken among halogen atom and alkoxy-group with 1-6 carbon atoms; n = 0, 1 or 2 and wherein the total sum of carbon atoms in radicals A1 and A2-R2 is at least 6 carbon atoms. Also, invention describes the herbicide agent containing compound of the formula (I) and additives used usually for plants protection and a method for control of hazard plants and using the effective dose of compound of the formula (I) for treatment of plants or planting surface. Invention provides preparing effective herbicides.

EFFECT: valuable properties of compounds.

7 cl, 45 tbl, 4 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, a new chemical compound 2-isopropyl-4-[(furyl-2)metalinox] methylene-1,3-dioxolane exhibiting the properties of activator germination of wheat seeds and increases the resistance of seedlings to water stress

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their production

FIELD: organic chemistry of natural compounds, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 14β-hydroxybaccatin III-1,14-carbonate. Method involves the following steps: (a) treatment of 7-Boc-13-ketobaccatin III of the formula: with suitable bases and oxidizing agents to yield 7-Boc-13-keto-14-hydroxybaccatin III of the formula: ; (b) carbonization of hydroxy-groups in positions 1 and 14 to yield 14β-hydroxy-7-Boc-13-ketobaccatin III-1,14-carbonate of he formula: , and (c) reduction of ketone group in position 13 and removal of protecting group in position 7. Also, invention relates to new intermediate compounds of this method. Invention provides simplifying process based on using 13-ketobaccatin III as the parent compound.

EFFECT: improved method of synthesis.

11 cl, 7 ex

Up!
The compound of example 65 mg
Glycerylmonostearate195 mg
Glycerides lauromacrogol-3250 mg