Aminoisoquinoline thrombin inhibitor with improved bioavailability

FIELD: chemistry.

SUBSTANCE: invention relates to a N-(2-oxo-2-propoxyethyl)-β-phenyl-D- phenylalanyl-N-[(1-amino-6-isoquinolinyl)-methyl]-L-proline amide compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing said compound, as well as use of the compound to produce a medicinal agent for treating or preventing thrombin-mediated diseases. The invention also relates to a N-(carboxymethyl)-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolinyl)methyl]-L-proline amide compound of pharmaceutically acceptable salt thereof.

EFFECT: obtaining novel compounds possessing useful biological properties.

5 cl, 2 tbl, 5 ex

 

The invention relates to thrombin inhibitor, has aminoisoquinoline the group to its containing pharmaceutical compositions and to the use of this inhibitor for the manufacture of a medicinal product for the treatment of diseases mediated by thrombin.

Most peptidebinding of thrombin inhibitors reported in the literature contain a basic group in the so-called P1(R. Pfau, "Structure-based design of thrombin inhibitors", Current Opinion in Drug Discovery & Development6, 437-450, 2003). Examples of such major groups include the basic amino acids arginine and lysine, as well as guanidine and benzamide. I believe that is basically a fragment of such compounds is necessary for antithrombine activity. However, such highly basic groups are protonated at physiological pH and, consequently, such compounds are poorly absorbed through the gastrointestinal tract after oral administration and have a low oral bioavailability.

In General, therapeutic agents which can be administered orally, most preferred, and they have a high commercial potential due to their inherent ease of use.

In international patent application WO 98/47876 (Akzo Nobel N.V.) disclosed class of thrombin inhibitors, having as main group aminoisoquinolines frag is UNT, and these compounds possess improved properties transepithelial transport.

In particular, this patent application as an example, contains compounds N-(carboxymethyl)-D-i.e. phenylalanyl-[(1-amino-6-ethenolysis)methyl]-L-prolinamide (WO 98/47876, example77) and N-(carboxymethyl)-D-(4-methoxyphenyl)alanyl-[(1-amino-6-ethenolysis)methyl]-L-prolinamide (WO 98/47876, example111as), as well as their ester proletarienne derivatives.

It is desirable to develop inhibitors of thrombin with higher bioavailability, especially suitable for oral administration.

The present invention relates to new compounds - N-(2-oxo-2-propoxyethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide, which has high bioavailability when administered orally.

In another aspect the invention relates to N-(carboxymethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide, which is a selective inhibitor of thrombin generated onin situfrom N-(2-oxo-2-propoxyethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide by oral administration, which are useful as intermediate compounds in the synthesis ofn-through procarcinogen derived in accordance with the invention.

The compound of the present invention, i.e. N-(2-oxo-2-propoxyethyl)-β-phenyl--i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide, represented by the structural formula1A:

The present invention found thatn-through ester proletarienne derived1Ait has high bioavailability when administered orally compared with the bioavailability of the correspondingn-through ester proletarienne derivatives structurally closely related aminoisoquinolines of thrombin inhibitors, such as N-(carboxymethyl)-D-i.e. phenylalanyl-[(1-amino-6-ethenolysis)methyl]-L-prolinamide (2A) and N-(carboxymethyl)-D-(4-methoxyphenyl)alanyl-[(1-amino-6-ethenolysis)methyl]-L-prolinamide (3A), disclosed in WO 98/47876.

Thus, the introduction connections1Ain accordance with the invention leads to significantly higher concentrations in plasma thrombin inhibitor1B- derivative of the free acid1Athat quickly formedin vivoas soon as the connection gets into the bloodstream.

An unexpected increase in oral bioavailability of a new diphenylalanine derived1Acompared with the corresponding phenylalanine derived2Aor methoxyphenylalanine derived3Aallows you to develop an antithrombotic agent for oral administration, operating at a relatively low dosage.

The experimental the orbital part

General notes

The results of the analysis by LC-MS were obtained on a mass spectrometer Applied Biosystems API150EX. Spectra1H NMR were recorded on a spectrometer Bruker DPX 400 or DRX 400.

Example 1(Scheme I):

N-(2-oxo-2-propoxyethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide (1A)

A:N-[2-(1,1-dimethylmethoxy)-2-oxoethyl]-β-phenyl-D-phenylalanine (a)

To a stirred solution of D-diphenylalanine, H-D-Dpa-OH (20,0 g, to 82.9 mmol)and calcium carbonate (17,2 g, 125 mmol) in a mixture of dioxane/water (1:1 (vol./vol.), 100 ml) addedtert-butylbromide (12,2 ml, 83.0 mmol). After stirring overnight, water is added (100 ml) and the pH was adjusted to 5.5 by addition of 0.5 M citric acid solution. The precipitate is filtered off, washed with water, then with diethyl ether and dried in vacuum, to obtain 10.4 g specified in the connection headerand.

Scheme I

B:Hydrochloride 1,1-dimethylethylene ether (S)-2-[[[(1-amino-6-isothemal)methyl]amino]carbonyl]-1-pyrrolidinecarboxylic acid(b)

To a stirred solution of N-tert-butoxycarbonyl-L-Proline, Boc-Pro-OH (of 6.73 g, 31.25 mmol)in anhydrous N,N-dimethylformamide (100 ml) in an argon atmosphere add finely chopped hydrochloride of 1-amino-6-aminoethylethanolamine (10.0 g, 40,63 mmol) and N,N-diisopropylate the amine (16,17 g, 125,00 mmol). After stirring the suspension for 15 minutes at room temperature for 5 minutes servings add hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (17,67 g, 46,88 mmol), which eventually leads to the dissolution of the suspended hydrochloride of 1-amino-6-aminoethylethanolamine. The reaction mixture was stirred at room temperature in an argon atmosphere for another 90 minutes, after this time, the formed yellow precipitate of the hydrochloride 1,1-dimethylethylene ether (S)-2-[[[(1-amino-6-isothemal)methyl]amino]carbonyl]-1-pyrrolidinecarboxylic acid (b). The precipitate was separated by filtration, washed with dichloromethane (300 ml) before bleaching filtrate, and then dried in vacuum, gain of 7.8 g (56%) indicated in the title compound (purity 94% according to HPLC on a column Luna C18(2) 46×30 mm, gradient mobile phase acetonitrile:water, 5-100%/4 min, constantly contains 0,1% triperoxonane acid). The product is then isolated from the filtrate by evaporation in a vacuum to remove dimethylformamide and excess diisopropylethylamine with the addition of 500 ml of dichloromethane. The precipitate is removed by filtration, washed with dichloromethane (300 ml) and dried in vacuum, to obtain 4.6 g (33%) (purity 91% according to HPLC on a column Luna C18(2) 46×30 mm, gradient mobile phase acetonitrile:water, 5-100%/4 min, constantly contains 0.1% triperoxonane).

With:The hydrochloride of N-[2-(1,1-dimethylmethoxy)-2-oxoethyl]-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide (C)

To a suspension of the hydrochloride 1,1-dimethylethylene ether (S)-2-[[[(1-amino-6-isothemal)methyl]amino]carbonyl]-1-pyrrolidinecarboxylic acid (b) (4,14 g, 9,34 mmol) in dichloromethane (20 ml) is added triperoxonane acid (8 ml). After stirring the solution for 2 hours, the solvent and excess triperoxonane acid is removed in vacuo. The residue is then dissolved in N,N-dimethylformamide (41 ml) and add 2-(tert-butoxy-carbonylmethyl-amino)-3,3-diphenyl-propionic acid (Boc-D-Dpa-OH) (3,30 g, 9.3 mmol), hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (5.31g, a 13.9 mmol) and N,N-diisopropylethylamine (9.75 ml, 56 mmol). The mixture is stirred at room temperature for 1 hour, then add water to sediment. The wet precipitate was separated by filtration, and then transferred into ethyl acetate, dried (MgSO4), filtered and evaporated to dryness, to obtain the crude product (7.2 g). Purification of column chromatography (silica, mode gradient elution with mixtures of dichloromethane and methanol (0-10%)) gives 4.6 g specified in the connection headerwithin the form of resin.

D:The hydrochloride of N-(carboxymethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide (1V)

To dissolve the hydrochloride of N-[2-(1,1-dimethylmethoxy)-2-oxoethyl]-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide ( with) (4.6 g, 7.1 mmol) in dichloromethane (25 ml) add triperoxonane acid (4.6 ml). After standing overnight the solution is evaporated to dryness, dissolved in dichloromethane and add an excess of hydrogen chloride in diethyl ether. The product precipitated by addition of anhydrous diethyl ether, then separated by filtration and dried in vacuum, get the 2.8, Additional 0.8 g obtained by precipitation from the mother liquor.

1H NMR δ (CD3OD) of 1.32 (m, 1H)and 1.83 (m, 3H), of 2.86 (m, 1H), 3,53(m, 1H), 3,68 (DD, 2H; J=17,1 Hz), 3,80 (d, 2H; J=17,1 Hz) (4,15 (m, 1H), to 4.52 (d, 1H; J=16.6 Hz), 4,59 (d, 1H; J=11.5 Hz), 4,69 (d, 1H; J=16.1 Hz), 5,3 (d, 1H; with 11.5 Hz), 7,2-7,6 (m, 10H), 7,66 (d, 2H; J=7.5 Hz), 7,72 (DD, 1H, J=1.5 and 8.0 Hz), 7,89 (c, 1H), scored 8.38 (d, 1H; J=9 Hz); MC m/z552,2 (M+H)+.

E:The hydrochloride of N-(2-propoxy-2-oxoethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide (1A)

To a suspension of the hydrochloride of N-(carboxymethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide (1B; 300 mg, 0.5 mmol) inn-propanol (5 ml) was added dropwise thionyl chloride (0.4 ml). After stirring for 3 days the solution was diluted with dichloromethane, washed with 5% aqueous sodium bicarbonate solution and evaporated to dryness. The crude product is purified obremeniaet HPLC, and then turn to cleaners containing hydrochloride salt by dissolving in a small amount of methanol and depositing a 1M solution of hydrogen chloride in diethyl EF the re. After adding an additional quantity of anhydrous diethyl ether, the resulting precipitate was separated by filtration and dried in vacuum, to obtain 185 mg specified in the title compound as a white powder.

1H NMR δ (CD3OD) δ of 0.85 (t, 3H, J=7.5 Hz), 1,33 (m, 1H), 1.57 in (Sextus, 2H; J=7 Hz)and 1.83 (m, 3H), 2,88 (m, 1H), 3,51 (m, 1H), of 3.73 (d, 1H; J=17.6 Hz), 3,84 (d, 1H; J=17.6 Hz), 4,07 (m, 2H), 4,16 (DD, 1H, J=5.0 and 8.0 Hz), a 4.53 (d, 1H; J=16.6 Hz), 4,56 (d, 1H,; J=13,6 Hz), 4,70 (d, 1H; J=16.6 Hz), 5,20 (d, 1H; J=11 Hz), 7.23 percent-7,44 (m, 7H), to 7.50 (t, 2H, J=7.5 Hz), 7,56 (d, 1H; J=7,0 Hz), the 7.65 (d, 2H; J=7.5 Hz), 7,72 (DD, 1H; J=1.5 and 8.0 Hz), of 7.90 (c, 1H), 8,39 (d, 1H; J=8,5 Hz); MC m/z594,4 (M+H)+.

Using methods similar to those disclosed above and depicted in scheme I in terms of D-phenylalanine or O-methyl-D-tyrosine instead of D-diphenylalanine, were obtained from the corresponding derivatives. Connection2Band3Bwere selected and used for subsequent studies in the form of trifenatate salts.

Example 2

2B: Triptorelin N-(carboxymethyl)-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide

1H NMR δ (CD3OD) δ of 1.41 (m, 1H), of 1.85 (m, 2H), 1,99 (m, 1H), 2,47 (m, 1H), 3,35 (DD, 1H; J=5,0, 13.1 Hz), 3,40 (DD, 1H; J=10,6, 13.1 Hz), of 3.45 (m, 1H), of 3.73 (d, 1H; J=16.6 Hz), 3,80 (d, 1H; J=16.6 Hz), 4,34 (DD, 1H; J=4,5, 8,1 Hz), and 4.5 (DD, 1H; J=5,0, a 10.6 Hz), 4,51 (d, 1H; J=16.1 Hz), 4.72 in (d, 1H; J=16.6 Hz), of 7.23 (d, 1H; J=7,1 Hz), 7,27-the 7.43 (m, 5H), 7,52 (d, 1H; J=7,1 Hz), 7,71 (DD, 1H, J=1.5 and 8.6 Hz), of 7.90 (c, 1H), 8.34 per (d, 1H; J=8.6 Hz); MCm/z 476,0 (M+H)+.

2A: Hydrochloride of N-(2-propoxy-2-oxoethyl)-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide

1H NMR δ (CD3OD) δ of 0.89 (t, 3H, J=7,6 Hz)of 1.41 (m, 1H), 1,62 (Sextus, 2H; J=7,6 Hz)and 1.83 (m, 2H), 2,00 (m, 1H), 2,44 (m, 1H), and 3.16 (DD, 1H; J=1,5, a 10.6 Hz), 3,37 (DD, 1H; J=5,5, 13.1 Hz), 3,47 (m, 1H), 3,93 (d, 1H; J=17,1 Hz), 4,06 (d, 1H; J=17,1 Hz), 4,14 (m, 2H), 4,36 (DD, 1H; 5,0, 9.1 Hz), of 4.54 (m, 2H), 4,71 (d, 1H; J=17,1 Hz), 7,26 (d, 1H; 7,1 Hz), 7,29-7,44 (m, 5H), 7,56 (d, 1H; J=7,1 Hz), 7,73 (d, 1H; J=8.6 Hz), 7,92 (c, 1H), scored 8.38 (d, 1H; J=8.6 Hz); MCm/z518,2 (M+H)+

Example 3

3B: Triptorelin N-(carboxymethyl)-O-methyl-D-tyrosine-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide

1H NMR δ (CD3OD) δ of 1.46 (m, 1H), 1,87 (m, 2H), 2,02 (m, 1H), has 2.56 (m, 1H), is 3.08 (DD, 1H; J=10,6, and 12.6 Hz), with 3.27 (DD, 1H; J=5,5, to 13.6 Hz), 3,47 (m, 1H), 3,71 (d, 1H; J=16.1 Hz), with 3.79 (d, 1H; J=15.6 Hz), 3,79 (c, 3H), 4,36 (DD, 1H; J=4,0, 8.6 Hz), 4,46 (DD, 1H; J=4,0, 8,66 Hz), 4,51 (d, 1H; J=16.6 Hz), 4.72 in (d, 1H; J=16.6 Hz), 6,92 (d, 2H, J=8.6 Hz), 7,21 (d, 2H, J=8.6 Hz), 7,24 (d, 1H; 7,1 Hz), 7,52 (d, 1H; J=7,1 Hz), 7,71 (d, 1H; J=8,1 Hz), of 7.90 (c, 1H), 8,35 (d, 1H; J=9.1 Hz); MC m/z506,3 (M+H)+.

3A: Hydrochloride of N-(2-propoxy-2-oxoethyl)-O-methyl-D-tyrosine-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide

1H NMR δ (CD3OD) δ to 0.88 (t, 3H, J=7,1 Hz), 1,47 (m, 1H), 1,61 (Sextus, 2H; J=7,1 Hz)to 1.86 (m, 2H), 2,04 (m, 1H), 2,54 (m, 1H), 3,10 (DD, 1H; J=10,6, 15.1 Hz), and 3.31 (m 1H), 3,49 (m, 1H), 3,79 (c, 1H), 3,91 (d, 1H; J=16.6 Hz), Android 4.04 (d, 1H; J=16.6 Hz), 4,13 (m, 2H), to 4.38 (DD, 1H; 5,0, 9.1 Hz), 4,48 (DD 1H; J=5,0, a 10.6 Hz), of 4.54 (d, 1H; J=16.1 Hz), 4,71 (d, 1H; J=16.1 Hz), 6,93 (d, 2H, J=8.6 Hz), 7,22 (d, 2H, J=8.6 Hz), 7,26 (d, 1H; 7,1 Hz), 7,55 (d, 1H; J=7,1 Hz), 7,73 (DD, 1H; J=2,0, 8.6 Hz), 7,92 (c, 1H), scored 8.38 (d, 1H; J=8.6 Hz); MCm/z548,3 (M+H)+.

Example 4

The study of the activity of thrombin

Activity inhibition of thrombin appreciate preincubating the compounds at various concentrations with α-thrombin human at 37°C. After 10 minutes, to the mixture add chromogenic substrate H-D-Phe-Pipecolinic-Arg-p-nitroanilide (S-2238) and measure the change of absorption through the next 8 minutes. Both compounds1Aand1Bare effective inhibitors of α-thrombin human dependent on the concentration of the image with values IC50equal 13,0 nm and 12.6 nm, respectively (for both n=5; figure 1). In subsequent experiments, in which also alter the concentration of S-2238, dependency graphs [S]/V against [S] parallel used for each concentration of S-2238, indicating the competitive nature of the inhibition. The analysis of these data Haines-wolf allowed to determine the values of Ki, equal to 0.9 nm (n=5) for1Band 1.0 nm (n=3)1A. Comparison with indicators of the activity of compounds2and3conducted in table 1.

Table 1
Indicators of activity of inhibition of thrombin
ConnectionIC50(nm)Ki (nm)
1A13,01,0
1B12,60,9
2A57334,5
2B86445,5
3A1971,8
3B358of 5.4

Example 5

Determination of bioavailability of compounds 1A, 2A and 3A in rats

Animals

Male Wistar rats Ola (~250 g). During the study had free access to food and water.

Surgical preparatory actions

For intravenous pharmacokinetic studies in the right jugular vein under isoflurane anesthesia were introduced catheters (Portex polythene inner diameter 0.58 mm, outer diameter of 0.96 mm, ending in a nozzle, made from a tube of medical grade silicone SF, SFM-1350). Tubes were withdrawn in the back of the neck, filled GE is kinesiology saline (100 u/ml) and plugged. Animals were given a period to recover at least 48 hours prior to administration of the compounds.

Introduction connections

Connection1A,2Aand3Aadministered orally (PO). Connection1B,2Band3Binjected intravenously (IV). Serial blood samples (for plasma) was collected from the lateral veins in time from 3 minutes to 24 hours (final sample taken by cardiac puncture) in accordance with the Protocol in the form of a matrix (3 samples at each time point). Plasma samples prior to analysis were stored at -20°C.

Analysis of plasma samples

In the plasma samples was determined appropriate thrombin derivative of the free acid1B,2Band3Busing the method LC-MS. Cmax (maximum plasma concentration) and AUC values were determined from the profiles of the average plasma concentration - time.

Experiments

Performed the following experiments:

Connection1Bin saline was injected intravenously (IV) 5 to rats at a rate of 5 mg/kg (5 mg/ml, dosed at 1 ml/kg).

Connection1Bin saline solution was administered orally (PO) 4 rats at the rate of 10 mg/kg (2 mg/ml, dosed at 5 ml/kg).

Connection1Ain a solution containing 5% of alipogene/95% saline, was administered orally 5 rats at the rate of 10 mg/kg (2 mg/ml, dosed at 5 ml/kg).

Connection2Bin saline was injected intravenously 4 rats at the rate of 2 mg/kg (2 mg/ml, dosed at 1 ml/kg).

Connection2Ain saline solution was administered orally 4 rats at the rate of 10 mg/kg (2 mg/ml, dosed at 5 ml/kg).

Connection3Bin saline was injected intravenously 4 rats at the rate of 2 mg/kg (2 mg/ml, dosed at 1 ml/kg).

Connection3Ain saline solution was administered orally 4 rats at the rate of 10 mg/kg (2 mg/ml, dosed at 5 ml/kg).

Results

Compartmental pharmacokinetic analysis was performed using WinNonlin Professional 3.1 and 4.1. The obtained pharmacokinetic parameters are presented in table 2.

It was found that the bioavailability, expressed as AUC(IV)/AUC(PO)×100%, forn-through ester derivative (1A) diphenylalanine derived hydrochloride N-(carboxymethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethanolic)methyl]-L-prolinamide is extremely high (58%) compared with biodostupnostthew corresponding phenylalanine (2A) and p-methoxyphenylalanine (3Ainhibitors of thrombin.

Table 2
Pharmacokinetic parameters
Connection 1Band1Bb1Bb
with the subsequent introduction1A
2B2B
with the subsequent introduction2A
3B3B
with the subsequent introduction3A
Dose (mg/kg)51010210210
PathIVPOPOIVPOIVPO
MediaSalinemultigen/
saline
SalineSalineSalineSaline
AUC(IV) (ng/ml·h)48646591008
T1/2 (h)0,320,610,16
Clearance (ml/min/kg)175434
Vss (l/kg)0,482,40,46
Cmax (ng/ml) 352130462
Tmax (h)1,210,0671,6
AUC(RO) (ng/ml·h)1195647n/a97
Bioavailability (%)1,358bminor1,9
n/a = not determined.
a = data are the average of two experiments.
b = bioavailability1Bafter the introduction of1Avaries from 30 to 60%of that measured in several experiments on Wistar rats Ola with different media type (suspension in a mixture of gelatin/mannitol or mannitol solution/phosphate buffered saline, or a mixture of 5% multigen/95% soleve the solution), used for the connection1A.

1. The Union, representing N-(2-oxo-2-propoxyethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide, or its pharmaceutically acceptable salt.

2. The compound according to claim 1 in the form of the dihydrochloride.

3. Pharmaceutical composition for treatment or prevention of diseases mediated by the thrombin-containing compound according to claim 1 and pharmaceutically acceptable excipients.

4. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment or prevention of diseases mediated by thrombin.

5. The Union, representing N-(carboxymethyl)-β-phenyl-D-i.e. phenylalanyl-N-[(1-amino-6-ethenolysis)methyl]-L-prolinamide, or its pharmaceutically acceptable salt.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is haemostimulating medicine, representing immobilised on polymer recombinant erythropoietin, characterised by the fact that recombinant erythropoietin is immobilised by electron-emitting impact by its introduction into solution of low-molecular water-soluble polymer (PEG, polyvinyl pyrrolidone, hydroxyethyl starch with molecular weight 400-4000 Da), preliminarily subjected to impact of ionising irradiation in dose 1-5 Mrad, to final concentration 500-5000 IU in 1 ml of solution. Shown is more expressed specific activity of medication in case of parenteral and per oral intake in comparison to medication "Mircera".

EFFECT: claimed medication does not possess immunogenic properties and does not demonstrate signs of allergenic action.

4 tbl

Material // 2437650

FIELD: chemistry.

SUBSTANCE: granular material contains (a) at least 50 wt %, in terms of the weight of granular material, of a solid water-insoluble inorganic mixed compound of layered double hydroxides of metals capable of binding phosphate, and which contains iron (III) and at least one of the following metals: magnesium, calcium, lanthanum or cerium; (b) 3-10 wt % chemically bound water in terms of the weight of granular material; (c) not more than 47 wt % filler in terms of the weight of granular material. The granular material is obtained via wet granulation. The disclosed granular material is meant for use in therapy for a condition or disease associated with unfavourable content of phosphate in the body.

EFFECT: invention enables to maintain physical integrity of granules and batches during storage, good phosphate binding after ingestion of the granules without their excessive breakdown in the mouth.

22 cl, 8 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and disaster medicine, and can be used in case of necessity to stop hemorrhage caused by injury of parenchymatous organs in case of polytraumas. For this purpose at the stage of sorting out wounded people with symptoms of continuing intra-abdominal hemorrhage are detected, delivered to operation room, where in cause of taking anti-shock measures, intra-abdominal hemorrhage is diagnosed. After that, laparotomy is performed and source of hemorrhage is detected. On detected injuries of parenchymatous organs applied is hydrophilic powder two-component hemostatic preparation in form of mixture of synthetic zeolites of CaA and CaX types, synthesized in kaolin granules. CaA zeolites correspond to formula mCaO·nNa2O·2SiO2·Al2O3·0.5H2O in volume amount within the interval 70÷80 wt %. CaX type zeolites correspond to formula mCaO·nNa2O·2.5SiO2·Al2O3·0.5H2O in volume amount within the interval 30÷20 wt %. Crystal matrices of said zeolites contain calcium ions in quantity 8÷10 wt %. After that, gauze tampon is applied and pressed by hand for 5-7 min until stable hemostasis is achieved. Simultaneously detection of other injuries is continued by revision of abdominal cavity organs which results in determination of further patient treatment tactics.

EFFECT: method makes it possible to ensure efficient stable primary hemostasis in case of multiple hemorrhages.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula in which R1 means hydrogen or alkyl with 1-4 carbon atoms, R2 means hydrogen and L means an alkandiyl group with 1-4 carbon atoms, one CH2-group in which can be substituted by with oxygen atom or a group of formula: or in which * means a conjunction with nitrogen atom, R3 means hydrogen, methyl, propane-2-yl, propane-1-yl, imidazol-4-ylmethyl, hydroxymethryl or 4-aminobutan-4-yl, or R3 is connected with R1 together with which forms (CH2)3- or (CH2)4- -group, R4 means hydrogen or methyl, R5 means alkyl with 1-4 carbon atoms, and R6 means hydrogen or alkyl with 1-4 carbon atoms, and also to its salt and to a method of preparing it.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing diseases, first of all thromboembolic diseases.

5 cl, 4 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is an agent enhancing thrombocyte adhesion properties, representing cyclophilin A. It is shown that cyclophilin A not changing thrombocyte count increases collagen-induced thrombocyte aggregation without thrombin, and does not have an effect on ADP-induced and ristocetin-induced thrombocyte aggregation.

EFFECT: cyclophilin A provides an adhesive effect, and does not promotes development of thromboembolic complications.

3 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and can be used for treatment of distal postmastectomy lymphedema. For this purpose at the background of standard treatment 6 procedures of retrograde lymphotropic introduction of drug mixture are carried out. Lymphotropic introduction is performed in the following way: in area of middle third of forearm applied is cuff, with creating in it pressure of 60 mm Hg, after which in two points on internal surface in area of wrist introduction of mixture of medications is performed. Composition of introduced mixture alternates every second day: 1, 3, 5 days - actovegin 80 mg, ketonal 1 ml, marcaine 0.5% 4 ml; 2, 4, 6 days - chymotrypsin 100 mg, marcaine 0.5% 4 ml.

EFFECT: method ensures efficient treatment of postmastectomy lymphedema due to enhancing of lymphatic drainage of distal parts of extremity.

3 tbl, 2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology, and can be applied for treatment of hereditary anemias, associated with failure of porphyrine synthesis. For this purpose per orally introduced is 5-aminolevulinic acid or its hexyl ether in doses, which insure compensation of insufficient biosynthesis of 5-aminolevulinic acid by organism.

EFFECT: method insures fast and effective increase of hemoglobin level in treatment of said pathology in experiment.

3 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: polypeptide, which is used in composition of pharmaceutical composition and in sets for screening of adhesion inhibitors of platelet adhesion or aggregation, is obtained in recombinant way applying matrix of cDNA of Anopheles stephensi salivary gland.

EFFECT: invention makes it possible to obtain polypeptide which possesses inhibiting activity with respect to platelet aggregation or inhibiting activity with respect to platelet adhesion.

10 cl, 4 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: described is a novel compound of general formula (I): oligosaccharide-spacer-antagonist GpIIb/IIIa (1), where the oligosacharride is a negatively charged pentasaccharide residue of formula (B) (B), where R1 denotes OCH3 or OSO3-. The charge is compensated for by positively charged counterions; the spacer is essentially a pharmacologically inactive binding residue having length of 10-35 atoms; the GpIIb/IIIa antagonist is a tirofiban residue (MK 383). The spacer includes a covalent bond with a biotin analogue of formula -(CH2)4-X-BT, where X=NH, N(1-4C)alkyl, -N-CH(CH2OH)-CH2-C(O)-NH-, -NH-CH(CH3)-CH2-C(O)-NH-, -NH-CH(COOH)-CH2-C(O)-NH- or -NH-CH(CH2COOH)-CH2-C(O)-NH-, and BT is a label ; or pharmaceutically acceptable salt thereof.

EFFECT: compounds have antithrombotic activity and can be used to treat or prevent thrombotic diseases.

8 cl, 7 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

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