Thrombocyte aggregation-inhibiting heteromeric peptides based on imidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane

FIELD: chemistry.

SUBSTANCE: thrombocyte aggregation-inhibiting heteromeric peptides based on imidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane are disclosed: , where R=Phe-Ile-Ala-Asp-Thr; Arg-Tyr-Gly-Asp-Arg; Lys-Ile-Ala-Asp-Asp; His-Ile-Gly-Asp-Asp.

EFFECT: improved properties.

1 dwg, 2 tbl, 4 ex

 

The invention relates to the pharmacy, in particular to the synthesis of pharmacologically active compounds.

Cardiovascular diseases are the leading cause of population mortality in Russia. Most often the basis for cardiovascular disease atherothrombosis is the pathological process of thrombosis, leading to myocardial infarction and stroke.

In thrombus formation play a significant role glycoprotein receptors on platelets. Namely fibrinogen binding to activated GP IIb/IIIa receptors of platelets is the final link in the aggregation of the latter. Inhibitors of GP IIb/IIIa receptors of platelets are powerful antiplatelet drugs, as well as the mechanism of their action is to block the final stage of platelet aggregation - the process of forming bridges from fibrinogen molecules between adjacent activated platelets. Antagonists of GP IIb/IIIa receptor of platelets is represented by different classes of chemical compounds, however, a considerable interest among antiplatelet agents are antagonists of GP IIb/IIIa receptor with a peptide nature.

It is also known that as a result of the interaction of nitric oxide (NO) with platelets and leukocytes reduced their aggregation and adhesion to the walls of blood vessels, leading to inhibition of processes thrombopathy�me. Disorders associated with the normal course of the above reactions are the basis of the pathophysiological processes specific to the development of various diseases of the cardiovascular system. When such diseases are observed multiple violations of the synthesis of endogenous NO, its reception soluble form of guanylyl cyclases (RGC), as well as the regulation of the level of cyclic nucleotides and calcium ions [With Dessy, O. Ferron Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature. Current Medical Chemistry - Anti-mflammatory & Anti-Allergy Agents in Medicinal Chemistry. 2004. Vol. 3. P. 207-216].

To date, proved the formation of nitric oxide as a result of the biotransformation of nitroglycerin and other nitrates, which are used for the treatment of cardiovascular diseases, as anti-ischemic and antianginal drugs. However, their significant drawback is the occurrence of tolerance and other side effects with long-term use [Granik V. G., Grigoriev N. B. Nitric oxide (NO). A new way to search for medicines: a monograph. - [Academic book. 2004, 360 p.].

In this regard, a search for new compounds able to form NO in vivo reanimations way. This approach is seen as relevant and promising direction of creating new, more effective in comparison with previously known anticipates�massive and antiplatelet medicines, having antianginal and anti-ischemic activity.

One of the classes of chemical compounds, derivatives of which are donors of nitric oxide - furoxone. Furoxone considered as a prodrug that implement its biological activity through the TWG-cGMP-path [Granik V. G., Grigoriev N. B. Nitric oxide (NO). A new way to search for medicines: a monograph. - [Academic book. 2004, 360; Granik, V. G., Kaminka M. E., Grigoriev, M. B., Severina I. S., Kalinkin M. A., Makarov V. A., Levin V. I. Furoquinoline as an exogenous donor of nitric oxide // Chem. Pharm. Log. 2002, Volume 36, No. 10, p. 7-11].

In the patent RU 2119354 1998 described the directed transport of drugs, which consists in binding in vivo of the carrier molecules pharmacoactive connections formed elements of the blood. For binding of the synthesized derivatives of pharmacological agents and peptide containing the RGD sequence. However, in the above patent is not considered antiaggregatory action of the peptide and it is used only as a carrier pharmacoactive connections.

In the patent US No. 2012/021007 2012 was held a screening of furoxans, but their antiplatelet activity has not been investigated.

In the patent RU 2123046 1998 and EN 2139932 1998 described furoxone as donors of nitric oxide and activators RHC, but the data on their antiplatelet activity not repre�aulani.

In the patent US No. 7838023 2010 mentioned that the biologically active derivatives of furoxone possess antiplatelet activity, but no information on the studies is not given.

The object of the present invention is to provide a new and effective inhibitors of platelet aggregation with two different mechanisms of action on platelet aggregation, consisting of two pharmacophore: peptide - inhibitors of GP IIb/IIIa receptors of platelets and purakanui donor of nitric oxide.

The problem is solved heterogenity peptides on the basis of imidazo[4,5-e]benzo[1,2-C;3,4-C']cefuroxine the General formula:

where R=Phe-Ile-Ala-Asp-Thr; Arg-Tyr-Gly-Asp-Arg; Lys-Ile-Ala-Asp-Asp; His-Ile-Giy-Asp-Asp.

The preliminary choice of these compounds as potential inhibitors of platelet aggregation is done on the basis of the results of mathematical modeling.

With the help of the program "Algolab" [Ramensky V., Sobol A., Zaitseva N. et al. A novel approach to local similarity of protein binding sites substantially improves computational drug design results // Proteins. - 2007; 69 (2): 349-357] we performed computer modeling of the binding heteromeric peptides with imidazo[4,5-e]benzo[1,2-C;3,4-C']cefuroximum fragment on the N-end with the protein integrin αIIb/β3. Calculation of estimates of binding [Keltie H.-D., Sippel V., Ranjan. Molecular modeling: theory and practice. - M.: BINOM. Laboratory�Riya knowledge 2009. - 318] with protein integrin αIIb/β3 were carried out for compounds of the type of Fur-A-B-C-Asp-D, where "Fur" - Methylenebis[4,5-e]benzo[1,2-C;3,4-C']Difenoxin; "A", "b", "C", "D" - L-amino acid residues, the structure of which was varied in the simulation process; as amino acid "C" was considered a glycine or alanine. Just generated 48000 molecules.

For docking from PDB database (open database PDB (Protein Data Bank) is a common source used in the calculations of information about the spatial structure of proteins) was selected complex protein integrin αIIb/β3 ID 2vdp. Docking started with the correct positioning of the acid fragment heteromera peptide to account for the presence of the ionic bond of the ligand with the magnesium ion in the active site. Also in the process of docking took into account the presence of two water molecules in the active site of the protein. Water molecules form hydrogen bonds with the C-terminal residue with oxygen and the third with C-end residue of the native ligand.

Selection of the above four compounds from the total quantity generated (48000 molecules) was determined by the good results of their evaluation of protein binding of the integrin αIIb/β3 (table 1).

The synthesis of target compounds.

Synthesis heteromeric peptides was performed on a solid phase under conditions of automatic�on peptide synthesizer ABI A PeptideSynthesizer (AppliedBiosystems, USA), using FastMoc 0.25-strategy. Strategy FastMoc 0.25 involves the consecutive addition of amino acid residues to an insoluble polymeric substrate. The base labile Fmoc group - 9-fluorenylmethoxycarbonyl - is used to protect the N-group of each amino acid residue. Residues that are potentially reactive side chains are protected kislotoneustoichiwami groups.

After removal of the Fmoc group with piperidine, the following protected amino acid is added, or using a coupling reagent, or pre-activated derivative of an amino acid.

As an activator of the first amino acid Fmoc-strategy in the reaction of accession to the resin acts as dicyclohexylcarbodiimide (DCC). The reaction proceeds in the presence of 4-dimethylaminopyridine (DCC/DMAP), which plays a catalytic role.

As an activator of the second and subsequent amino acids Fmoc-strategy acts 1-hydroxy-benzotriazole / dicyclohexylcarbodiimide (HOBt/DCC) in dimethylformamide. The reaction proceeds with the formation of the activated amino acid and N,N'-dicyclohexylamine (DCU).

All of these operations occur in a peptide synthesizer.

To relieve heteromeric peptides from the resin in the fume cupboard in a polypropylene test tube was prepared a mixture with the following ratio of components: 2.5% tanzola (TAN) 2.5% of triisopropylsilane (TIPS), 5.0% identicial (EDT), 90.0% trifluoroacetic acid (TFA). The prepared mixture was placed on ice to cool for 20-30 min. Then cool the mixture to remove heteromeric peptides were placed in the peptide-resin and stirred. Put the vial containing the peptide-resin in a polypropylene test tube, closed and kept on rocking for 4 hours.

Extraction heteromeric peptides from the resin was carried out on a glass filter funnel in a fume hood. Funnel pre-rinsed out twice with MTBE (methyl tertiary butyl ether). After removing the fused mixture with the resin and the peptide on the filter SCHOTT. Washed the test tube, which was the reaction of the TFA, the flush was leaking at the filter. Was filtered under a slight vacuum to the drying of the resin. Added cold MTBE, washed thoroughly with resin and filtered before drying. Washed the test tube, which was the peptide-resin three times with cold MTBE and added washout to the main drain. Thoroughly mixed, the slurry was left for not less than 1 hour at -20°C. the Precipitate was filtered and dried. The scheme of synthesis heteromeric peptides presented in figure 1, where Z = radicals of amino, Pr. Group (Protected Group) = a protective group of amino acids.

Cleaning heteromeric peptides was performed using a preparative high-performance liquid chromatograph PtiriFlash 450 (InterChim). Soda�the gether of the major substances after purification was not less than 95%.

The HPLC conditions: cartridge InterChim PF-C18 (20g), 15 μm. Can be used facing other cartridges C18 or C8.

a. The detector cell: preparative

b. Flow rate - 20.0 ml/min

c. Wavelength range: 200-400 nm

d. Range of detection: 2 AUFS

e. The value of the loop: 2 ml (injection volume 1.5-1.8 ml sample)

f. Eluent A: 5.0% acetonitrile, 0.1% trifluoroacetic acid in water

g. Eluent B: 0.1% trifluoroacetic acid in acetonitrile;

h. Gradient: 10-90% b for 12 min.

The structure of the synthesized compounds was confirmed by GC-mass spectroscopy.

Chromato-mass-spectrometric analysis was performed on a Waters instrument MSD SQD - ESI with UV and mass spectrometric detectors: wave length 220 nm, temperature probe 15°C, the temperature of the column thermostat at 40°C. MSD - parameters: source temperature 130°C, the gas temperature is 400°C, the voltage on the capillary 3kV; column Waters Acquity 1.7 μm 2.1·50 mm. A gradient from 5 to 100% b for 4 min (A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile).

Original amino acid derivatives containing protective groups, the polymer substrate and solvents for peptide synthesis produced by "Applied Biosystems", USA, N-carboxymethylamino[4,5-e]benzo[1,2-C;3,4-C']Difenoxin obtained by the method [V. V. Toporov, V. L. Korolev, V. P. Ivshin, V. M. Danilenko. Research of behavior of imidazo[,5]benzo[1,2-C; 3,4-C']cefuroxine in the reactions of nitration, alkylation and acidic hydrolysis. // Proc. Dokl. XVIII Mendeleev Congress on General and applied chemistry, Moscow, 23-28 September, 2007, 462].

Example 1. To 423.73 mg polymeric substrate Wang Resin (the number of active centers 0.59 mmol/g, the scale of the synthesis of 0.25 mol) was added to 10 ml of solution 1 mol Fmoc-Thr(tBu)-OH in dimethylformamide, 10 ml of a solution of dicyclohexylcarbodiimide (1 mol) / 4-dimethylaminopyridine (0.1 mol) in dimethylformamide stood for 1 hour, washed with 3×5 ml DMF. Added 10 ml of 20% solution of piperidine in dimethylformamide, stand 20 minutes, washed with 3×5 ml DMF. Added 10 ml of a solution of 1 mol of Fmoc-Asp(otBu)-OH in dimethylformamide, 10 ml of a solution of 1-hydroxybenzotriazole (0.1 mol) / dicyclohexylcarbodiimide (1 mol) in dimethylforamide, stand for 30 minutes, washed with 3×5 ml DMF. Added 10 ml of 20% solution of piperidine in dimethylformamide, stand 20 minutes, washed with 3×5 ml DMF. Similarly, Fmoc-Asp(otBu)-OH were successively sewn Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, followed by deprotecting 10 ml of 20% solution of piperidine in DMF after each cycle of joining amino acids. Added 10 ml of a solution of 0.1 mmol of N-carboxymethylamino[4,5-e]benzo[1,2-C;3,4-C']cefuroxime in dimethylformamide, 10 ml of a solution of 1-hydroxybenzotriazole (0.1 mol) / dicyclo�of oxycarbazepine (1 mol) in dimethylforamide, stand for 30 minutes, washed with 3×5 ml DMF, 3×5 ml of dichloromethane. All of these operations took place in a peptide synthesizer. To the polymer substrate with the attached heteromera peptide was added 10 ml of a chilled solution containing: 250 ál TAN, 250 ál TIPS, 500 ml EDT, 9 ml of TFA was stirred for 4 h, filtered on the filter SCHOTT (pores 40) in a vacuum. To uterine acid solution containing heteromeric peptide was added 50 ml of cold methyl tert-butyl ether (MTBE), mixed, cooled at -20°C for 1 hour, the precipitate was filtered on the filter SCHOTT (pores 14). Received 151,3 mg (yield 72%) of product. The mass spectrum of the [MS (ES)] m/z 840.6 [M+H]+, retention time 2.78 min.

Example 2. Under the conditions described in example 1, from 2 x 10 ml 1 mol of Fmoc-Arg(Pbf)-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Asp(otBu)-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Gly-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Tyr-OH in dimethylformamide, 10 ml of solution 1 mol no carboxymethylamino[4,5-e]benzo[1,2-C;3,4-C']Difenoxin in dimethylforamide received 152.9 mg (yield 65%) of product. The mass spectrum of the [MS (ES)] m/z 940.7 [M+H]+, retention time 1.81 min.

Example 3. Under the conditions described in example 1 from 2×10 ml of solution 1 mol Fmoc-Asp(otBu)-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Gly-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Ile-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-His(tt)-OH in dimethylformamide, 10 ml of solution 1 mol N-carboxymethylamino[4,5-e]benzo[1,2-C;3,4-C']cefuroxime in dimethylforamide received 141.2 mg (yield 68%) of product. The mass spectrum of the [MS (ES)] m/z 830.6 [M+H]+, retention time 2.16 min.

Example 4. Under the conditions described in example 1 from 2×10 ml of solution 1 mol Fmoc-Asp(otBu)-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Ala-HE's in dimethylformamide, 10 ml of solution 1 mol Fmoc-Ile-OH in dimethylformamide, 10 ml of solution 1 mol Fmoc-Lys(Boc)-OH in dimethylformamide, 10 ml of solution 1 mol N-carboxymethylamino[4,5-e]benzo[1,2-C;3,4-C']Difenoxin in dimethylforamide received 154.5 mg (yield 74%) of product. The mass spectrum of the [MS (ES)] m/z 835.6 [M+H]+, retention time 2.11 min.

The pharmacological action.

Assessment of specific activity antiaggregatory action heteromeric peptides was performed in vitro using the blood of healthy donors. Blood sampling was performed immediately before the study, using as anticoagulant sodium citrate (3.8%). The ratio of anticoagulant: blood corresponded to 1:9.

Antiplatelet activity of the obtained compounds was studied in platelet-rich plasma with the use of adenosine diphosphate (ADP) as an inducer of platelet aggregation.

For preparation of platelet rich plasma blood immediately after receiving centrifuged for 10 minutes at 1000 rpm, after which the top layer PL�of SMI transferred to another tube, and the residue was centrifuged for 20 min at 3000 rpm to obtain estramboticos plasma. All procedures were performed in polystyrene dishes with thromboresistant properties. During the entire study period is rich and estrambotica plasma was at room temperature, and the entry of platelet aggregation was performed at 37°C.

For the study of specific antiplatelet activity was guided by the requirements for pre-clinical pharmacological substances of this class, approved Pharmacological service on surveillance in healthcare and social development.

Platelet aggregation was studied by turbidimetric method of born (Born, 1962), based on the change of transmittance of light (540 nm) is studied using the plasma under constant stirring (1000 rpm). As a sample comparison, estrambotica plasma. Light transmission through estrambotica plasma was taken as 100%, and the light transmission through platelet-rich plasma was taken as 0%. The concentration of platelets was adjusted in platelet-rich plasma to 2.5·10-8cells/ml using dilution of platelet-poor plasma.

To conduct the study used a two-channel laser analyzer platelet aggregation/counter 230LA-2 SPC "Biola"). The sample volume was 300 μl. The measuring times - 8 minutes as the inductor used ADP at a concentration of 50 μm. Get agregarme represent the dependence of the degree of aggregation of the time elapsed after addition of the inducer of aggregation. The studied compounds (in aqueous solution, optionally containing DMSO 0.2%) in different concentrations was added to the sample prior to the introduction of aggregation inducer (ADP). Premaxillae inhibition (IC50) heteromeric peptides are presented in table 2.

Heteromera peptides on the basis of imidazo[4,5-e]benzo[1,2-C;3,4-C']Difenoxin, inhibiting platelet aggregation:

where R=Phe-Ile-Ala-Asp-Thr; Arg-Tyr-Gly-Asp-Arg; Lys-Ile-Ala-Asp-Asp; His-Ile-Gly-Asp-Asp.



 

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53 cl, 502 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.

EFFECT: disclosed are products of oxidative decomposition of an atorvastatin salt, which can be used to identify impurities or a product of decomposition of an atorvastatin salt in accordance with approved analytical procedures.

15 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.

EFFECT: new prodrugs.

14 cl, 1 tbl, 25(29) ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .

EFFECT: improved properties of the compound.

1 dwg, 1 tbl

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