Thrombocyte aggregation-inhibiting n-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane

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


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

Cardiovascular diseases are the leading cause of deaths in Russia. Most often the basis for cardiovascular disease atherothrombosis is the pathological process of thrombosis, leading to myocardial infarction and stroke. Therefore, the development of new classes of drugs with antiplatelet activity is relevant.

The antiplatelet agents are drugs with different mechanism of action, belonging to different groups of chemical compounds.

It is 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 the processes of thrombosis. 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 (RGD), as well as the regulation of the level of cyclic nucleotides and calcium ions [Dessy S., Ferron O. Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature. Current Medical Chemistry - Anti-Inflammatory &Anti-Allergy Aents 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 antihypertensive and antiplatelet medicines that possess anti-anginal 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 p.; Granik, V. G., Kaminka M. E., Grigoriev, M. B., Severina I. S., M. A. Kalinkina, �akirov V. A., Levin V. I. Furoquinoline as an exogenous donor of nitric oxide // Chem. Pharm. Log. 2002, Volume 36, No. 10, pp. 7-11].

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 is not presented.

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.

The problem is solved N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxine, inhibiting platelet aggregation.

The synthesis of the target compounds

Synthesis of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime was performed on the solid phase under the conditions of automated 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 OST�TKA. 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 in dicyclohexylcarbodiimide (HOBt/DCC). 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.

For removal of the peptide from the resin in the fume cupboard in a polypropylene test tube was prepared a mixture with the following ratio of components: TAN - 2.5%, TIPS - 2.5%, EDT - 5%, TFA - 90%. The prepared mixture was placed on ice to cool for 20-30 min. Then cool the mixture to remove the peptide was 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 of the peptide from the resin was carried out n� 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 peptide purification was performed using preparative high-performance liquid chromatograph PuriFlash 450 (InterChim).

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 over 12 min

The structure of synthesized compounds was confirmed by NMR1H and chromatography-mass spectroscopy. The NMR spectra of1H were recorded on the instrument Brker Avance 600 mhz; chemical shifts were measured relative to the solvent signal (DMSO-d6that δH2.5 M. D.).

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 of 1.7 µm 2.1·50 mm. A gradient from 5 to 100% B over 4 min (A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile).

The NMR spectrum1H (δ, M. D.) of 1.52 (m, 2H, C(22)H2); 1,74 (m, 2H, C(21)H2); 3,10 (m, 2H, C(23)H2); to 4.28 (m, 1H, C(20)H); 5,31 (s, 2H, C(16)H2); 7.23 percent (ush. d, 5H, N(19)H, N(24)H, N(26)H, N(29)H2); 8,89 (m, 1H, C(11)H); 9,02 (s, 1H, COOH).

The mass spectrum of the [MS (ES)] m/z 449.35 [M+H]+

The pharmacological action.

Estimation of specific activity of antiplatelet action of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin conducted 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 inducer of platelet aggregation.

The date of preparation of platelet-rich plasma blood immediately after receiving centrifuged for 10 minutes at 1000 rpm, after which the top layer of plasma was 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 of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime 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 end�centration 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. Studying the connection (in the form of an aqueous solution, optionally containing DMSO 0.2%) in different concentrations (0.1·10-6, 0.2·10-6, 0.3·10-6, 0.4·10-6, 0.5·10-6M) was added to the sample prior to the introduction of aggregation inducer (ADP). The results of studies on the blood of healthy donors are presented in table 1.

Table 1. The results of the study specific antiplatelet activity of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime

The concentration of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin, M% aggregation in the presence of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime
0.1·10-6 39.2

In the study of the inhibitory action of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin on platelet aggregation in healthy donors was discovered the effect of inhibition of ADP-induced platelet aggregation. The dependence of platelet aggregation on the concentration of the compounds is presented in Fig.1.

The compound inhibited ADP-induced platelet aggregation with IC500.25 μm, which shows a pronounced antiplatelet effect. Shown by the connection antiplatelet activity of higher antiplatelet activity of similar compounds described in patent RU 2502739 2012 (IC500.41 µm).

N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin formula

inhibits platelet aggregation.


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51 cl, 34 tbl, 44 ex

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1 dwg, 1 tbl

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53 cl, 502 ex, 11 tbl

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7 cl, 1 tbl, 12 ex

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2 cl

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5 cl, 7 ex, 8 dwg

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9 tbl

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17 cl, 11 dwg, 6 ex

FIELD: medicine, pharmaceutics.

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25 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for treating trophic ulcers and purulonecrotic involvements of lower extremities in diabetic patients. That requires a baseline therapy and a regional fibrinolytic therapy. Conducting the regional fibrinolytic therapy following applying a rubber bandage on the lower one-third of the shin is accompanied by administering Urokinase medac in a dose of 100 thousand units into the heel bone once a day within 5 days.

EFFECT: in the setting of reducing the total dosage of the preparation, the invention enables providing the high concentration of Urokinase medac in a pathological centre, improving microcirculation and metabolic processes in the involved tissues, accelerating the wound healing and reducing the length of hospital admission of the patients suffering from diabetic foot syndrome.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition containing a thrombosis inhibitor. Active substances of the above inhibitor are Triflusal and clopidogrel bisulphate with Triflusal:clopidogrel bisulphate ratio of (100-650):(30-150), preferentially (1-20):1, more preferentially (3-6):1, and most preferentially 3:1 or 6:1. The composition is applied in treating cardiovascular and cerebrovasacular disorders.

EFFECT: inhibiting thrombosis and thrombocyte aggregation using the combination has been more effective, than using Triflusal and clopidogrel bisulphate individually; six-month monitoring has shown that the stability of the combined drug preparation of Triflusal and clopidogrel bisulphate is higher than that of the combined drug preparation of Triflusal or clopidogrel bisulphate.

20 cl, 2 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and concerns using tetrapeptide Pro-Gly-Pro-Val as an agent for preventing or treating lipid storage disease; a method for preventing or treating lipid storage disease involving the intranasal administration of a therapeutic agent containing tetrapeptide Pro-Gly-Pro-Val in an effective amount; to a pharmaceutical composition for preventing or treating lipid storage disease, containing peptide Pro-Gly-Pro-Val with the anticholesteremic and triglyceridemic action as an active substance, and an auxiliary substance as a preserving agent.

EFFECT: group of inventions provides the more effective prevention and treatment of lipid storage disease as compared to natural tripeptide Pro-Gly-Pro.

6 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.

EFFECT: compounds of formula (I) as PDE10 inhibitors.

39 cl, 13 ex, 2 tbl, 77 dwg