Method of intensifying antiaggregant activity

FIELD: chemistry.

SUBSTANCE: method of intensifying antiaggregant activity in an experiment involves use of a chemical compound which is a conjugate of beta-cyclodextrin with acetylsalicylic acid.

EFFECT: wider range of agents for increasing antiaggregant activity.

1 tbl

 

The invention relates to medicine, namely to experimental pharmacology.

To date, the known method antiplatelet activation using acetylsalicylic acid (aspirin)with antiplatelet and anti-inflammatory properties [1], but at present this drug is outdated and has a number of side effects.

The purpose of the invention is the expansion of the means to increase antiplatelet activity.

This goal is achieved by the use of the new synthesized compound, which is the conjugate beta-cyclodextrin with acetylsalicylic acid.

Synthesis of applicable connection

Conjugate beta-cyclodextrin with acetylsalicylic acid synthesized in the research laboratory of organic chemistry Department of Moscow state pedagogical University.

To a solution of 0.50 g (0.441 mmol) of β-cyclodextrin in 8 ml of pyridine under stirring was bury 0.44 g (2.20 mmol) of the acid chloride acetilsalicilico acid in 2 ml of benzene was kept at 20°C 24 h of the pyridine Hydrochloride was filtered, the filtrate was evaporated, the residue was rubbed out in ethyl alcohol (10 ml), precipitated precipitate was filtered, washed with ethanol (2×5 ml) and dried in vacuum.

The yield of compound (I) 0.47 g (63%), TPL 203-205°C, Rf0.78 (n is the aluminum plates with a fixed layer of silica gel, in the system acetonitrile-water 5:2). An NMR spectrum1N (d6-DMSO), δ, M. D.: 2.05-2.35 m (10.5H, C(O)CH3), 3.13-4.08 m (42H; C2H-C5H, C6H2), 4.23-4.59 m (3.5H, C6OH), 4.81 ush. (7H, C1H), 5.60-6.04 m (14H; C2OH, C3OH), 7.05-8.11 m (14H, CHarene.). NMR13C (d6-DMSO), δ, M. D.: 20.8 (C(O)CH3), 59.4 (C6OH), 63.9 [C6OC(O)], 68.9 [C5C6OC(O)], 71.5-74.0 (C2C3C5), 80.1-83.0 (C4), 101.0-103.1 (C1), 122.1-135.0 (Carene.), 150.1 [COC(O)], 169.2 [C(O)]. Found, %: C, 51.11; H, 5.45. C73.5H91O45.5. Calculated, %: C, 51.85; H, 5.39.

The formula of the obtained compound

In the experiment in vitro was tested antiplatelet activity against platelet plasma rich. Drug comparison served as acetylsalicylic acid (aspirin).

To study the functional status of platelets by the photometric method used platelet-rich plasma (PRP) and a suspension of washed platelets. In the morning, before feeding laboratory animals (white outbred rats), took the blood from the jugular vein into a plastic syringe containing anticoagulant (3.8% (0.11 M) solution of sodium citrate in the ratio of 9:1. All manipulations with blood, plasma, platelet-rich, and a suspension of washed platelets was carried out in a plastic container. Received what I platelet-rich plasma, the blood was centrifuged in plastic tubes at room temperature for 10 minutes for sedimentation of erythrocytes and leukocytes. The platelet count of PRP was counted in the Goryayev camera on the microscope MBI-15 with a phase-contrast console and brought to 2×1011-2.5×1011platelets/l using plasma poor in platelets (PPP). PRP was obtained by repeated centrifugation of the blood within 10 minutes. PRP was stored at 4°C.

Assessment of platelet aggregation was performed on aggregometry PICA (model 330, USA), as well as dual aggregometry LaborAPACT (USA) with graphic recording and automatic calculation of the amplitude and maximum velocity of the aggregation. Agregatogramme analyzed the amplitude (maximum value drop optical density, expressed in %); the maximum rate of aggregation (expressed in %/min). All the experiments were carried out in six parallel test, where experimental sample was compared with a control sample. As inducers of platelet aggregation used thrombin at a final concentration of 0.5 units/ml of Blood were incubated 5 min with samples at 37°C.

As an example, in table 1 the data antiaggregatory activity of the conjugate beta-cyclodextrin with acetylsalicylic acid obtained in the experiment in vitro.

Antiplatelet activity of the conjugate beta-tsiklodestrina with acetylsalicyl the howling acid
SampleThe concentration of anti-inflammatory drugs in the sample (mm)Amplitude (%)Speed (% / min)
Control-38±8.748±6.5
Acetylsalicylic acid0,0524.7±4.927.9±6.5
Conjugate beta-cyclodextrin with acetylsalicylic acid0,0213.0±3.5*13.0±6.1*
* p<0.05 compared with control

Sources of information

1. Mashkovsky PPM Medicines. M.: Izd. "New wave", 2005, 1206 S.

2. Manual on experimental (preclinical) study of new pharmacological agents. Under the General editorship Rugarama. M.: 2005. 829 S.

3. K.Uekama, F.Hirayama, T.Irie, Chem. Rev, 98(5), 2045-2076 (1998).

4. M.E.Davis, M.E.Brewster, Nature Rev. Drug Discovery, 3, 1023-1035 (2004).

5. Cyclodextrins and their complexes. Chemistry, analytical methods, applications. // Ed. H. Dodziuk, Wiley-VCH, Weinheim. 2006. 489 p.

6. K.Uekama, Campam, F.Hirayama, J. Med. Chem, 40 (17), 2755-2761 (1997).

A way to enhance the antiplatelet activity in the experiment, characterized by the fact that h is about as antiplatelet tools used chemical compound, representing conjugate beta-cyclodextrin with acetylsalicylic acid when the degree of substitution of 3.5.



 

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