Carbohydrate derivatives, pharmaceutical compositions on their basis

 

(57) Abstract:

The invention relates to a carbohydrate derivative of General formula I, where R1= H or CH2SO3-; R2and R3independently equal to N, (1-6C) alkyl or SO3-; R4= OSO3-; n= 0 or 1; p=1 or 2; or its pharmaceutically acceptable salt. Compounds according to the invention possess antithrombotic activity. Also proposed pharmaceutical composition for the treatment and prevention of diseases mediated by or associated with thrombin, including the specified carbohydrate derivative. 2 S. and 6 C.p. f-crystals.

The invention relates to carbohydrate derivatives having antithrombotic activity, to pharmaceutical compositions containing them and to the use of these carbohydrate derivatives to obtain drugs.

Currently known a number of carbohydrate derivatives having antithrombotic activity, in particular sulfated glycosaminoglycanes derived, disclosed in the patent EP 84999. Other carbohydrate derivatives related to the sulfated glycosaminoglycans described in EP 529715 and is characterized by an improved pharmacological his is, is such as a hydroxyl group, a N-sulfate and N-acetyl group.

It is found that the carbohydrate derivative of the present invention having the formula I,

< / BR>
where R1denotes N or CH2OSO3-;

R2and R3represent independently from each other H, (1-6C)alkyl or SO3-;

R4means OSO3-or NS3-;

n is 0 or 1;

p is 1 or 2;

or a pharmaceutically acceptable salt it has anti-XA activity, which is significantly higher than the activity of sugars without nevosstanovlenie the end of the 4th position glycerinate or glycolates group.

Factor XA plays an important role in the chain of reactions of blood coagulation. He is the catalyst for the formation of thrombin, which regulates the last stage in the chain of the coagulation process. The first function of thrombin is the cleavage of fibrinogen with the formation of fibrin monomers, which are due to cross-links to form an insoluble gel, fibrin clot.

Compounds of the present invention is suitable for treatment and prevention of diseases mediated by thrombin and associated walks activation of the coagulation process and which include, not limited to, deep vein thrombosis, pulmonary embolism, thrombosis, occlusion of the artery due to thrombosis or embolism, arterial reocclusion occurring during or after the plastic vessels or thrombolysis, restenosis, coming after damage to the arteries or invasive cardiological procedures, postoperative thrombosis or embolism veins, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, as well as neurodegenerative diseases. Carbohydrate derivatives of the present invention can also be used as inhibitors of proliferation of smooth muscle cells and for the treatment of angiogenesis, cancer and retroviral infections such as HIV infection.

In addition, the compounds of the present invention can be used as anticoagulants and antikoaguliruyuschee coatings in the extracorporeal circulation apparatus used in the process of dialysis and surgery.

Compounds of the present invention can also be used in vitro or ex vivo as anticoagulants.

Preferred derivatives of carbohydrates having the formula I, in accordance with the present invention I the/SUP>, R4represents OSO3-and R1n and p correspond to the previously given definitions; or their pharmaceutically acceptable salt.

More preferred such carbohydrate derivatives of the formula I, in which R1is stands. Especially preferred carbohydrate derivatives of the formula I, in which n is 1 and p is 1. And the most preferred such carbohydrate derivatives of the formula I, in which R1represents CH2S3-.

The term (1-6C)alkyl refers to a branched or unbranched alkyl group comprising from 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, t-butyl, isopentyl, hexyl, etc. Preferred alkyl groups are (1-4C)alkyl group such as methyl, ethyl, (ISO)propyl, n-butyl and t-butyl. The most preferred alkyl group is methyl.

Counterions, compensating charged part of the molecule, refers to pharmaceutically acceptable counterions, such as hydrogen or, more preferably, ions of alkali or alkaline earth metals such as sodium, calcium or magnesium.

Carbohydrate derivatives of the present invention can be obtained when the set out of the end is also protected tetrasaccharide, which can be obtained by the method described in the literature (Westerduin, P. , Bioorg. and Med.Chem., 1994, 2, 1267-1280). Further protecting groups are removed with subsequent sulfonation of the compound, leading to the formation of the carbohydrate derivative of formula I.

For the treatment of thrombosis or inhibition of proliferation of smooth muscle cells of the compounds of the present invention can be enterline or parenterally, in the case of people it is preferable to use a daily dose of 0.001-10 mg per 1 kg of body weight. Mixed with pharmaceutically acceptable additives (listed in the main guide Gennaro et al., Remington''s Pharmaceutical Sciences (18th ed. , Mack Publishing Company, 1990, see especially part 8: Pnarmaceutical Preparations and their Manufacture) these connections in case their activity in oral, transbukkalno or sublingual use can be pressed with the preparation of solid dosage forms such as pills, tablets, or may be subjected to other processing for the manufacture of capsules or suppositories. Using pharmaceutically acceptable liquids compounds can also be used in the form of a preparation for injection, representing a solution, suspension, emulsion or in the form of a spray, in particular a nasal spray.different additives, such as fillers, dyes, polymeric binders, etc. In General may be any pharmaceutically acceptable additive, which does not interfere with the action of the active compounds.

Suitable carrier materials, together with which can be considered compositions include lactose, starch, cellulose derivatives, etc. and their mixtures used in appropriate quantities.

The following examples illustrate the present invention.

(In the examples with references to schemes 1 and 2. Intermediate and final products have the designations referring to the corresponding number on the schema).

Example 1

The formation of compounds 7 and 8

Getting 2

To a cooled solution (0oC) 2-benzyloxyethanol 1 (2,84 ml) and chlorotrimethylsilane (1,59 ml) in dimethyl ether of ethylene glycol (25 ml) in an atmosphere of nitrogen was added sodium hydride as a 60% dispersion in mineral oil (1.2 g) and the resulting mixture was stirred for 20 h at room temperature. To the reaction mixture is added methanol and continue stirring for 15 minutes the mixture is diluted with ethyl acetate (100 ml), successively washed with aqueous solution of acid carbonate nroduct clean then chromatographytandem on a column of silica gel to obtain the result 2 in the amount of 2.5,

Getting 3

Synthesis of 3 described in the literature (Westerduin, P. et A1., Bioorganic and Medicinal Chemistry, vol. no. 11, pp. 1267-1280, 1994).

Getting 4

A mixture of 3 (125 mg), 2 (64 mg) and powdered molecular sieves (4) in dichloromethane (1.5 ml) is stirred for 15 minutes in a nitrogen atmosphere. The solution is cooled (5oWith) and make a freshly prepared solution containing N-jodatime (68 mg) and triftormetilfullerenov acid (2,7 μl) in 1.5 ml 1,2-dichloroethane-dioxane (1/1, vol/vol). After 10 min, red filter the reaction mixture was diluted with dichloromethane, washed sequentially with an aqueous solution of sodium thiosulfate and aqueous solution of acid sodium carbonate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The obtained residue clean pressure chromatography on Sephadex LH-20, suspended in a mixture of dichloromethane-methanol (2/1, vol/vol) to obtain the 4, 108 mg.

Getting 5

To a cooled (-5o(C) to a solution of 4 (105 mg) in tetrahydrofuran (7.3 ml) is added 30% aqueous hydrogen peroxide solution (3.8 ml), stirred for 10 minutes, then add a solution of lithium hydroxide (1.25 M, 1.7 ml). The mixture is stirred for 2 hours at a temperature of -5oWith, then lifting the with stirring for 24 hours Then the reaction mixture was cooled (0oC) and then add methanol (7.0 ml) and aqueous sodium hydroxide solution (4 M, 2.0 ml). Stir the mixture for 1 h, then increase the temperature to 20oWith and continue stirring for 20 hours then the mixture is cooled (0oC), acidified to pH 3 with hydrochloric acid (2 BC) and the extraction is carried out with dichloromethane. The organic layer was washed with aqueous solution of sodium sulfite (5%), dried over magnesium sulfate and concentrated in vacuo. The crude product is clean column chromatography on silica gel with getting 5, 80 mg.

Getting 6

To a solution of 6 (80 mg) in a mixture of water (7 ml) and 2-methyl-2-propanol (7 ml) is added 80 mg of palladium on coal (10%). The reaction mixture is placed for 16 hours in an atmosphere of hydrogen. The catalyst was removed by filtration and washed with a mixture of 2-methyl-2-propanol/water. The filtrate and the washing liquid was concentrated in vacuo, followed by lyophilization, which gives 6 in the amount of 38 mg.

Getting 7 and 8

A solution of 6 (38 mg) in water (0.8 ml) elute with water through a column of Dowex 50W8+and evaporated to dryness combined fractions. After evaporation with N, N-dimethylformamide, the residue is dissolved in N,N-Dimethylol the Mixture is stirred overnight at a temperature of 50oC, cooled to 0oAnd add an aqueous solution of acid sodium carbonate (533 mg). The mixture is stirred at a temperature of 20owithin 1 h, concentrated to a small volume and absoluut on a column of Sephadex G-25, suspended in a mixture of water : acetonitrile, 9 : 1 (volume/volume). The crude product to elute the column Dowex 50WX8Na+and clean anion-exchange chromatography on a column (HPLC, Mono-Q 5/5, gradient of sodium chloride) to obtain 12 mg of compound 7 {[]20D=+31,1 (C=1; water)} and 18 mg of compound 8 {[]20D=34,8 (=0,93; water)}.

Example 2

The connection 16

Receive 10

To a cooled (-20o(C) a mixture of glycerol (10 g) and pyridine (109 ml) is added dropwise over 1 h a solution of benzoyl chloride (26,3 ml) in dry dioxane (26 ml). The resulting mixture is stirred for 16 hours at a temperature of 0oWith, then add water. Stir the mixture for 15 min and then concentrate it to 1/5 of the volume, diluted with dichloromethane and washed with water, an aqueous solution of acid sodium carbonate and water. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The oil obtained is cleaned by chromatography on a column of silica gel with 10 in Kolichestvennaya metilsulfate (1,45 ml). The reaction mixture was cooled to 0oWith and add to it dropwise a mixture of dry benzoyl peroxide (3,63 g) in a mixture of acetonitrile: dichloromethane (1:1, vol/vol; 10 ml). After stirring for 16 hours at a temperature of 20oThe mixture is diluted with dichloromethane and washed with aqueous solution of acid sodium carbonate and water. The organic layer is dried over magnesium sulfate and concentrated in vacuo. After chromatography was carried out on a column of silica gel get 400 mg of compound (11).

Getting 12

Compound 12 was produced using the procedure similar to what was described in the work of Westerduin et al. (Westerduin, P. et al., Bioorganic and Medicinal Cnemistry, 1994, vol. 2, pp.1267-1280). At stages 12 uronic acid protecting benzyl groups, and not by methyl groups.

13

Connection 13 get method, similar to what was used to obtain 4 by combining 11 and 12.

Getting 14

To a solution of 1.3 (480 mg) in 2-methyl-2-propanol (60 ml) is added a suspension of acid sodium carbonate (142 mg) in water (2 ml) and Pd/C (400 mg). The mixture is placed in an atmosphere of hydrogen for 16 hours and Then the catalyst is removed by filtration and washed it with a mixture of 2-methyl-2-propanol/water. The combined filtrate ochistki.

Receive 15

Compound 14 (315 mg) was dissolved in 0,35 N. aqueous sodium hydroxide solution (10 ml). During the night stirred the reaction mixture, and then its pH adjusted to a value of 8.5 with 1 N. hydrochloric acid. The mixture is absoluut on a column of Sephadex G-25, suspended in a mixture of water : acetonitrile : triethylamine (90 : 10 : 0,1; volume/volume/volume). Combine appropriate fractions and concentrate them in a vacuum. The product is then again subjected to restoration by the method similar to that shown for the connection 14. After you complete the procedure and concentration of the filtrate and washing liquids mixture absoluut on a column of Sephadex G-25, suspended in a mixture of water:acetonitrile : triethylamine (90 : 10 : 0,1; volume/volume/volume). Combine the appropriate fractions, and concentrate them in a vacuum, applied to the column Dowex 50W8N+, elute with water, and in the end spend lyophilization to obtain 165 mg of compound 15.

Getting 16

A solution of 15 (165 mg) is evaporated together with N,N-dimethylformamide and dissolved in N,N-dimethylformamide (11,0 ml). Next, to the reaction mixture add complex of triethylamine and sulfur trioxide (1.31 g). The mixture is stirred at a temperature of 50oC for 16 h, and then aladejana 1 h at a temperature of 20oS, after which the solution was concentrated in vacuo. The obtained residue absoluut on a column of Sephadex G-25, suspended in a mixture of water : acetonitrile (9 : 1, volume/volume), combine appropriate fractions and concentrate them in a vacuum. The product is then applied to the column Dowex 50WX8Na+, elwira with it, and brush the product on a column of seasonal (Q-Sepharose High Load) using a gradient of sodium chloride, resulting in 160 mg of compound 16:

{[]20D=+24,0 (=0,77, N2O)}

Activated factor X (XA) is a coagulation cascade; its activity is slightly inhibited by antithrombin 111 (AT-111). Anticoagulants inhibit Ha directly or similar to heparin by increasing inhibitory activity AT-111. Anti-XA activity can be assessed by determining the degree of hydrolysis of the chromogenic substrate S-2222 in the presence of at-111.

This study is used to determine the anti-XA activity of a sample of human plasma containing at least 0.8 at-111 IU/mg (clinical sample).

Environment research: human plasma, diluted with 3 volumes of buffer cubie.

Connection compare: int. the standard is ü)

edetate disodium dehydrate 3,26 g (9.6 mmol)

tromethamine (tris) 6.11 g (of 50.4 mmol)

brought to 1 liter with distilled water.

the pH of the solution set to 8.4 using NS (0.10 mol/l).

2. Ha-solution

Bullish Ha-factor (CABI Diagnostics, Stockholm, Sweden) is dissolved in the buffer to obtain a solution containing 1 IU/ml (0.5 ncat/ml).

3. S-2222 solution

S-2222 (CABI Diagnostics) dissolved in distilled water to obtain a solution containing 0,374 mg/ml

4. Diluted pooled plasma samples. Plasma taken from healthy volunteers who had not taken any medication for 10 days (Bloedbank Nijmegen, The Netherlands). It was combined and stored at -20oC. Before using this plasma were diluted with 3 volumes of buffer cubie.

5. Standard solution calibration sample.

Standard heparin or Orgaran AK party is dissolved in diluted United plasma to obtain a standard solution containing approximately 0.1 anti-XA IU/ml

6. Control samples

The required number of standard heparin or Orgaran party AK dissolved in United plasma taken from healthy volunteers, obtaining the solution is CLASS="ptx2">

b) Orgaran: AK party: approximately 0.15 (low dose) and 0,60 (high dose) anti-XA IU/ml

The sample preparation

If you human AT-111 (CABI Diagnostics) add to clinical samples to obtain samples containing at least 0.8 at-111 IU/ml. Receive 4 the following sample:

Sample A: 1 volume clinical sample +volume 3 cubie

buffer (dilution factor 1/4)

Sample: 1 sample volume And + 0.5 volume of diluted United plasma (dilution factor 1/6)

Sample: 1 sample volume + 0.5 volume divorced

United plasma (dilution factor 1/9)

Sample D: 1 volume of sample + 0.5 volume of diluted United plasma (dilution factor 2/9)

Diluted samples b, C and D receive in order to limit the required number of clinical sample.

If you want all 4 test sample diluted in the same ratio diluted United plasma with obtaining samples containing 0,02-0,08 at-XA IU/ml

Peak control samples receive, using the same procedure as for clinical samples (diluted peak control samples).

Determination of Ha activity

Each you are at room temperature. To each well add Ha solution (0.05), using the shaker Cook.

After exactly 2 min in each well beetroot Ha solution, 0.1 ml of S-2222 solution and tablet again shaken. The remaining amount of Ha catalyzes the hydrolysis of S-2222, the extent of which is measured photometrically.

Subsequent periods of incubation 2 and 22 min, respectively, at room temperature, the absorbance of each sample is measured at 405 nm using a Microelisa Reader model 310 (Organon Teknika, Oss, The Netherlands) and calculated the increase in absorbance ( OD).

Each prototype/divorced peak control sample was determined twice. The control sample (0.05 ml diluted generalized plasma) was included along with all 10 samples.

The calibration curve

From aliquots of a standard solution calibration sample made a series of dilutions (dilution factor of 1.3 for samples of heparin or 1.4 for Orgaran samples). Received standard samples (approximately 10 samples) must contain 0,01-0,10 anti-XA IU/ml In each series of experiments were tested with 0.05 ml of each standard sample at least 3 times as specified in the definition of Ha activity. The calibration curve is obtained by fitting a straight line to

The
sky sample and control peak sample value of anti-XA activity in U/ml was determined, using the calibration curve. The value found for the clinical sample must be multiplied by a correction factor. Amendment to daily change test is performed using the control peak samples.

Correction factor:

a) low-dose standard heparin sample or Orgaran control sample is

< / BR>
or

< / BR>
C) high-dose standard heparin sample or Orgaran control sample is

< / BR>
or

< / BR>
The correction factor for the clinical sample represents the average value of the relevant (a) and (b).

1. Carbohydrate derivative having the formula I

< / BR>
where R1represents N or CH2OSO3-;

R2and R3represent independently from each other H, (1-6C) alkyl or SO3-;

R4represents OSO3-or NHSO3-;

n is 0 or 1;

p is 1 or 2;

or its pharmaceutically acceptable salt.

2. Carbohydrate derivative of the formula I under item 1, in which R2represents (1-6C) alkyl, R3represents the SO3-, R4performance is the one derived under item 2, in which R2represents methyl.

4. Carbohydrate derived under item 2 or 3, in which n is 1 and p is also equal to 1.

5. Carbohydrate derivative according to any one of paragraphs.2-4, in which R1represents CH2OSO3-.

6. The pharmaceutical composition intended for the treatment or prevention of diseases mediated and associated with thrombin, including derivatives of carbohydrates according to any one of paragraphs.1-5 and pharmaceutical additives.

7. Carbohydrate derivative according to any one of paragraphs.1-5 for the treatment or prevention of diseases mediated and associated with thrombin.

8. Carbohydrate derivative according to any one of paragraphs.1-5 to obtain drugs for treatment or prevention of diseases mediated and associated with thrombin.

 

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