Substance showing combined antiagregant, anticoagulant and vasodilator activities, n,n'-substituted piperazines and method for preparing them (versions)

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely new organic compounds, namely N,N'-substituted piperazines of general formula (I), wherein R1, R2: linear or branched alkoxy (C1÷C4), CH3C(=O)O; n=1-5; m=0-3; Z: C=O, SO2; X:C(=NH)NH2, C(=NH)NHC(-NH)NH2, G is low-molecular organic or mineral acid, sodium, potassium, ammonium cations or water influences the haemostasis system, showing antiagregant, anticoagulant and vasodilator properties, and to a method for preparing N,N'-substituted piperazines of formula 1 by reaction of N-substituted piperazines of general formula wherein R1, R2; linear or branched alkoxy (C1÷C4), CH3C(=O)O; n=1-5; m=0-3; Z: C=O, SO2; and 1H-pyrazole-1-carboxamidine, dicyane diamide and their salts in organic solvents or water at temperature 10-50°C in the presence of bases.

EFFECT: new substance are promising for prevention and treatment of the disturbed haemostasis system.

12 cl, 10 tbl, 14 ex

 

The technical field

The invention relates to the field of pharmaceutical chemistry, namely to new organic compounds that affect the hemostatic system, manifesting antiplatelet, anticoagulant and vasodilatory properties, and the way they are received.

In particular, the invention relates to N,N'-substituted the piperazines with combined antiplatelet, anticoagulant and vasodilatory effects on the body, the General formula (I) and (II):

where R1, R2linear or branched alkoxy (C1÷C4), CH3C(=O)O;

n=1÷5; m=0÷3; Z: C=O, SO2;

X: C(=NH)NH2C(=NH)NHC(=NH)NH2,

G - low molecular weight organic or mineral acid, sodium cations, potassium, ammonium or water,

and

where R1, R2linear or branched alkyl (C1÷C4), linear or branched alkoxy (C1÷C4);

n=1÷5; m=0÷3; Z: C=O, SO2;

X: CH2(SNON)CH2SO3H;

G - low molecular weight organic or mineral acid, sodium cations, potassium, ammonium or water

Prior art

Diseases of hemostasis, in particular thrombosis, vasoconstriction, are a key element in the pathogenesis of disorders of the coronary and cerebral circulation, which makes the treatment at azannyh diseases is quite relevant. Advances in the treatment and prevention of disorders of hemostasis are largely connected with the use of medicines on the basis of physiologically active compounds of different chemical nature and mechanism of pharmacological action.

The purpose of antithrombotic drugs reduces the overall risk of cardiovascular events in the quarter, non - fatal myocardial infarction by one third, nonfatal stroke by one quarter, and vascular death - one-sixth [H. McConnel // Br. Med. J. 2002. V.324. R-86]. The main directions of antithrombotic therapy are: inhibition of platelet aggregation, targeted impact on the system gemokoagulyatsii, reducing trombotsitnoy activity of the endothelium. Despite the large number of drugs that have the ability to suppress the activity, and the aggregation capacity of platelets, their clinical efficacy in diseases of the cardiovascular system, requiring antiplatelet therapy, proved only in respect of the three groups of assets - acetylsalicylic acid (ASA), thienopyridines (ticlopidine, clopidogrel, prasugrel) and antagonists of glycoprotein receptors of platelets.

Aspirin (acetylsalicylic acid - ASA) is considered to be almost the only drug used for primary prevention of a heart condition is about-vascular diseases [ANN Intern. Med. 2002. V.136. P.161-172], the efficacy and safety of which is confirmed by the results of numerous studies [Circulation. 2004. V.110. R-2367; 30thInternational Stroke Conference. 2005, Abstr. P87].

The disadvantages of ASC should be attributed to suppression of the synthesis of prostacyclins, the risk of bleeding, ASC-induced gastropathy, deteriorating the portability and reduce the adherence of patients to treatment, resistantanti patients to the drug [J. Thromb. Haemost. 2003. N1. R-1713; BMJ 2004. V.328. P.477-479; Brit. J. Clin. Pharmacol. 2008. V.66. N2. P.222-232].

Known inhibitor of phosphodiesterase - Dipyridamole to reduce the incidence of transient ischemic attacks, stroke, and mortality in cerebrovascular disease. Dipyridamole similar therapeutic effect to the ASC; together use the effectiveness of treatment increases [Future Medicine. 2005. V.1. N1. P.19-26]. However, the use of Dipyridamole may cause unwanted side effects. So, when stenocereus atherosclerosis of the arteries and the presence of a significant number of collaterals the drug can cause the syndrome victimize. Therefore, the purpose of Dipyridamole in acute coronary syndrome and myocardial infarction is contraindicated [Int. Med. J. 2008. V.1. N1. P.8-14].

Representatives of the group thienopyridines in a series of antiplatelet agents are Ticlopidine, Clopidogrel, Prasugrel. Drugs are poleca the problem that is, therapeutic effect is achieved due to the pharmacological action of the active metabolites. The advantages of the drug Ticlopidine is a 20% reduction in the likelihood of stroke, and 10% of its adverse outcomes, cerebral ischemia, or vascular death [Ann. Intern. Med. 1998. V.129. N5. R-405]. The disadvantages of this drug are low portability and frequent skin (4-15%) and gastrointestinal (20%) reactions, which are the reasons for stopping treatment ticlopidina. In addition, there are known cases of thrombocytopenic purpura fatal [Bennett C., Weinberg p, Rozenberg-Ben-Dror K., et al. Thrombocytopenic purpura associated with ticlopidine. Ann Intern Med 1998; 128: 541-44].

The drug Clopidogrel, CAPRIE data [Lancet. 1996. V.348. R-39] in many cases more effective than aspirin in long-term use in patients with high risk of ischemic events. The advantages can be considered to be better than ticlopidine, tolerability, including the lower the incidence of hematological complications, a more rapid onset of therapeutic effect when using the stress doses (300 and 600 mg), compatible with most drugs used in cardiology. The disadvantages of Clopidogrel are resistant (to 14% of the population) in patients with the polymorphism of CYP450, especially 2C19 [JACC. 2007. V.49. P.1505; FDA Drug Safety Communication. March 12, 2010]; significant is the decline in the efficiency with coadministration with proton pump inhibitors - Omeprazole, Rabeprazole [FDA Public health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009], a suboptimal response to the drug in the presence of acute coronary syndrome, diabetic patients, and in patients with metabolic syndrome [JACC. 2007. V.49. R].

The drug Ticagrelor is characterized by a relatively rapid onset of therapeutic effect, a pronounced inhibition of the aggregation activity of platelets. Treatment ticagrelor compared with Clopidogrel reduces the rate of death from vascular abnormalities, myocardial infarction, stroke, without increasing the overall frequency of major bleeding, but with increased frequency of bleeding not associated with invasive procedures, which is a significant disadvantage of this drug, limiting its use [N. Engl. J. Med. 2009. V.361. 11. P.1045-57].

In medical practice also apply direct thrombin inhibitors - atrani [Am. Heart J. 2009. V.157. R-810]. So, Dabigatran demonstrates the reduction in the risk of stroke, including hemorrhagic, bleeding, including life-threatening and intracranial and reducing death from cardiovascular events. therapy does not require monitoring [N. Engl. J. Med. 2009. V.361. N12. P.1139-1151]. Significant disadvantages of the representatives of this group are hepatotoxicity and intragastric it is avoteinu [NHS. 2009. N8], and the absence of concomitant antiplatelet, anticoagulant and vasodilating effects on the body.

The most similar effect achieved by the claimed invention are preparations antagonists, thromboxane - Ridogrel, Ozagrel, Permagrin, which have antihypertensive and vasodilating properties. Drugs are safe and effective in myocardial infarction [Cardiovascular Drug Reviews. 2008. V18. N3. R-231], can reduce bronchospasm [Life Scinece. 1997. V.60. N18. P.1583-88].

The disadvantages of this group of drugs are the low efficiency of the oral application.

The task of the authors was to create a more effective and safer drugs with combined antiplatelet, anticoagulant and vasodilatory effects on the body.

The invention

The technical result was achieved by applying as a tool with combined antiplatelet, anti-thrombotic agents and vasodilatory activity, N,N'-substituted piperazines of General formula (I) and (II):

where R1, R2linear or branched alkoxy (C1÷C4), CH3C(=O)O;

n=1÷5; m=0÷3; Z: C=O, SO2;

X: C(=NH)NH2C(=NH)NHC(=NH)NH2,

G - low molecular weight organic or mineral acid, sodium cations,potassium, ammonium or water,

and

where R1, R2linear or branched alkyl (C1÷C4), linear or branched alkoxy (C1÷C4);

n=1÷5; m=0÷3; Z: C=O, SO2;

X: CH2(CHOH)CH2SO3H;

G - low molecular weight organic or mineral acid, sodium cations, potassium, ammonium go in the water.

As low molecular weight organic acid is used, as a rule, organic acids with carbon chain length of C2-C4such as acetic, succinic, fumaric, etc. the nature of the organic acids on the main pharmacological properties of the compounds (1) significant value has not.

These compounds can be used both in pure form and in the form of a solvate, or salt - salts of low molecular weight (C2-C4) organic or mineral acids, sodium, potassium, ammonium.

Currently, substituted nitrogen-containing heterocyclic compounds known as drugs, promising to antiplatelet therapy.

Thus, in U.S. patent No. 4,370,330 proposed to stimulate the blood circulation of the new N-trimetoksi-benzylpiperazine and their pharmaceutically acceptable salts of the General formula:

where

R: CF3, OH, NO2, halogen, alkyl - or is laxi-; R': N, CF3, halogen, alkyl - or alkoxy-Deputy; R: H or alkoxy substituents.

In U.S. patent No. 4,574,156 protected as a means of improving blood circulation, derived polymethoxysilanes General formula:

where R: H; OMe; n=2÷5.

In U.S. patent No. 4,368,199 proposed to be used for the treatment of vascular and heart failure derivatives 3,4,5-trimethoxycinnamic-oilpipeline General formula:

where X: is(CH2)nn=1÷3, or-CH2-CO-, n=1, 2; Ar: substituted phenyl - or phenylcyclohexyl - radicals and other

In European patent No. 284359 described 1,4-disubstituted piperazines of the General formula:

where: pentalene-, indenyl, indanyl-, naphthyl-, azulene and other radicals; R: phenyl radical substituted by 1÷5 alkoxy group; X: CH2, CO or thiocarbonyl; m=2, 3, and their salts. Mainly described substituted 3,4,5-trimethoxybenzyl - and 3,4,5-trimethoxybenzylamine and the method of obtaining them, which consists in the interaction of the intermediate compounds with the acid of General formula A-COOH or galogenangidridy General formula A-COW, where A: as stated above, W: halogen. Compounds or their salts in the form of pharmaceutical compositions can be used for inhibition of platelet activating factor as antiplatelet agents.

N,N'-C is displaced piperazines of General formula:

where AL: H, OH, halogen, CN, alkoxy and others; n=0÷2; Y: C, N, O; X: H, alkyl, COOR, and others;

for treatment or prevention of vascular inflammation and thrombosis (European patent No. 1783115).

Substituted N-benzylpiperidine, their pharmaceutically acceptable salts or hydrates are used to regulate heart rhythm (European patent No. 416581, U.S. patent No. 5,210,090):

where R1: benzofuranyl radical; n=0÷10; R2: H, alkyl, O; R3: H, carboxyethyl: X: H, pyridinyl, phenyl (mono - and polyamidine on alkyl, halogen, alkoxy-Deputy).

Known compounds (M.Protiva et all. Collection Czechoslov. Chem. Commun. Vol.41, p.1035-1041 (1976); CS 151752. 15.01.1974), compounds of General formula

where R is methyl, and

where R1, R2, R3-H, OCH3, SCH3C6H5, halogen, phenylthio-, and at least one of these radicals is H as substances with anti-hypertensive effect.

The last of the compounds obtained by addition of sulfate S - methylisothiazoline to the boiling solution of connections

where X, R1, R2, R3same as in the target connection.

General shortcomings of the above compounds is the limited range of effects on the body, because in the literature there is no information on this issue is, such compounds have combined antiplatelet, anticoagulant and vasodilatory properties.

The closest structure to the claimed compounds is (M.Protiva et all. Collection Czechoslov. Chem. Commun. Vol.40, p.3904-3923(1975), the compound of General formula:

where R, R1=H, CH3F, NO2CI, OCH3, SCH3

However, a significant difference in the structure of the inventive compounds for the substance marked with a narrow range of possible applications - as a matter of hypotensive action.

A review of the literature showed the presence of a wide spectrum of biological activity inherent in N,N'-substituted the piperazines, and that compounds that affect the hemostatic system, not well understood, and therefore more in-depth study of derivatives of N,N'-substituted piperazines is relevant.

In this regard, as well as for the development of effective and safe drugs of interest is the synthesis of new derivatives of N,N'-substituted piperazines with combined antiplatelet, vasodilatory and antithrombotic activity, high security, promising for the treatment of diseases of hemostasis.

Embodiments of the inventions

To solve this task we have synthesized new N,N'- someseni the piperazines, biological tests which demonstrated their high efficiency.

The compounds are classified according to their structure into two groups of substances of the General formula (II) and (III).

The first embodiment include N,N'-substituted piperazines of General formula (II):

where R1, R2linear or branched alkoxy (C1÷C4), CH3C(=O)O;

n=1÷5; m=0÷3; Z: C=O, SO2;

X: C(=NH)NH2C(=NH)NHC(=NH)NH2,

G - low molecular weight organic or mineral acid.

These compounds can be used both in pure form and in the form of a solvate, or salt of low molecular weight (C2-C4) organic or mineral acids.

Compounds of General formula (II) are obtained by reacting N-substituted piperazines of General formula (IV)

where R1, R2linear or branched alkoxy (C1÷C4), CH3C(=O)O;

n=1÷5; m=0÷3; Z: C=O, SO2;

with carboxymethyloxime agents or their salts in organic solvents or water in the presence of bases. The process was performed at room or elevated temperatures. As carboxamidine agents may be used a substance from the group of: 1H-pyrazole-1-carboxamidine or dicyandiamide, for example 1H-benzotriazol-1-carboxamide, 1H-pyrazole-1-ka who backslidin, 3,5-dimethyl-1H-pyrazole-1-carboxamides, dicyandiamide or substances forming these compounds during hydrolysis, for example salts of dicyandiamide, salt 1H-pyrazole-1-carboxamidine. As organic solvents can be used lower aliphatic alcohols, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dichloromethane, or a mixture thereof, as the bases of sodium or potassium hydroxide, carbonates or bicarbonates. The reaction is expediently carried out at a pH no higher than 9.0±0.5, for optimum yield N,N'-substituted piperazines of formula II;

The second group of compounds (2) include N,N'- substituted piperazines of General formula (III):

where R1, R2linear or branched alkyl (C2÷C4), linear or branched alkoxy (C1÷C4);

n=1÷5; m=0÷3; Z: C=O, SO2;

X: CH2(CHOH)CH2SO3H;

G - cations of sodium, potassium, ammonium or water.

Instead of these compounds for the same purpose can be used their hydrates or pharmaceutically acceptable salt.

The method of obtaining compounds of General formula (III) is in the interaction of N-substituted piperazines of General formula (V), as well as their hydrates or salts:

where R1, R2linear or branched alkyl (Csub> 1÷C4), linear or branched alkoxy (C1÷C4);

n=1÷5; m=0÷3; Z: C=O, SO2;

2-hydroxy-3-chloropropanesulfonyl or its salts in organic solvents or water in the presence of bases.

The process was performed at room or elevated temperatures. As organic solvents can be used lower aliphatic alcohols, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dichloromethane, or a mixture thereof, as the bases of sodium or potassium hydroxide, carbonate or hydrogen carbonate, triethylamine. The reaction is expediently carried out at a pH no higher than 9.0±0.5, and to achieve optimum yield N,N'-substituted piperazines of the formula III.

After the reaction, the selection of the final product from the reaction mixture by using conventional methods of organic synthesis, selected depending on the composition of the mixture by distillation of the solvent, recrystallization, presidenial, chromatography and the like, the Purity of the compounds obtained according to RP HPLC was not less than 98%.

Monitoring the progress of the reaction, as well as the assessment of the purity of the final products was performed by the method OF HPLC on a chromatograph Alliance (Waters), column Eclipse Bond C18, 3.5 μm, 3*100 mm (Agilent Technologies), the mobile phase is a mixture of buffer solution containing 0.01 M sodium octanesulfonate and 0.02 M sodium of digid is apostate (pH 3.0) - acetonitrile, detection - at 230 nm.

The structure of the obtained compounds was confirmed by the data of NMR spectroscopy1H,13C, mass spectrometry, elemental analysis. Elemental analysis performed for C, H, N, S analyzer Leco-932 (Leco Corporation).

Determination of molecular weight of the performed mass spectrometry on time-of-flight mass reflectron MX-5303 with the ion source of the type "Electrospray".

During farmakologicheski studies it was shown that the synthesized N,N'-substituted piperazines have good solubility in water as compared with the known analogues - derived nitrogen-containing heterocyclic compounds and aspirin, a wider therapeutic range and high security that can be used as antiplatelet agents and drugs affecting hemostasis system.

In particular, in the treatment of abnormalities of hemostasis, as studies have shown, the introduction of N,N'-substituted piperazines in the body at a dose of 0.005 mm/kg or more leads to the reduction of pathological platelet aggregation, has a positive effect on the fibrinolysis system, provides vasodilatation of blood vessels.

N,N'-substituted piperazines may be introduced into the body in compositions containing a mixture of physiologically-active (current) substances with accessories is mi substances. As auxiliary substances are allowed Pharmacopoeia substances that improve conditions for the receipt, storage or use of a medicinal product, such as solvents, fillers, fragrances, flavors, stabilizers, etc.

Antiplatelet, antithrombotic properties of N,N'-substituted piperazines are confirmed below are examples.

Industrial applicability

Example 1

Synthesis of 4-(3,4,5-trimethoxybenzoyl)piperazine-1-carboximidic fumarata of hemihydrate.

1) Synthesis of 3,4,5-trimethoxybenzoyl chloride.

In odnogolosy flask with a capacity of 100 ml equipped with a reflux condenser with a gas exhaust tube immersed in a solution of NaOH, placed 20 g (94 mmol) of 3,4,5-trimetoxybenzoic acid and 45 ml of absolute benzene. Then add 0.5 ml of DMF and 10.8 ml (150 mmol) thionyl chloride. After cessation of gas evolution, the mixture is refluxed for 2 hours the Solution is cooled to a temperature of 20°C, poured into a beaker with 50 ml of hexane. Precipitated white crystals of the product is filtered off, the filtrate is evaporated to 1/3 volume under vacuum at 50°C. Upon cooling allocated second portion of the product, which is filtered and combined with the first. The product is dried in vacuum at a temperature of 50÷60°C for 1 h

Output 3,4,5-trimethoxybenzyl the sludge chloride - 19.6 g (90%), TPL 77°C.

2) Synthesis of 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride.

In a three-neck flask with a capacity of 500 ml, equipped with a mechanical stirrer, addition funnel and thermometer, is placed 20.0 g (232 mmol) of piperazine in 50 ml of acetic acid and 60 ml of water. To the mixture was added dropwise a solution of 13 g (56 mmol) of 3,4,5-trimethoxybenzoyl chloride in 15 ml of THF over 20 min, keeping the temperature of the reaction mixture in the range of 10÷15°C, then stirred for 1 h and left overnight. The solution is filtered, evaporated to dryness, under vacuum at a temperature of 50÷60°C. To the residue was added 100 ml of abs. ethanol is heated to boiling with stirring. The mixture is cooled to a temperature of 20°C, filtered. The mother liquor evaporated to dryness in a vacuum of ~20 mm Hg and a temperature of 50÷60°C, add 100 ml of acetone and stirred on a magnetic stirrer for 30 min at a temperature of 40÷50°C. the Precipitate is filtered off, washed with twice 50 ml of acetone and dried for 12 h at 40°C.

Output 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride - 7.8 g (44%).

The PMR spectrum of 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (Bruker 400MHz; solution in DMSO-d6): 3.35 USS (4H; pieperazinove ring); 3.58-3.78 ush. (4H; pieperazinove ring); 3.69 S. (3H; CH3O); 3.81 S. (6H; two CH3O); 6.75 S. (2N; aromatic.); 9.57 USS (2H; NH2+).

3A) Synthesis of 4-(3,4,5-trimethoxybenzoyl)piperazine-1-carboxamidine fumarata p and pH of the reaction mixture 9±0.5.

To 4.5 g (14.2 mmol) of 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride was added 1.7 g (16 mmol) of Na2CO3, 40 ml of water, 2.1 g (14.3 mmol) of 1H-pyrazole-1-carboxamidine of monohydrochloride, the pH of the reaction mixture is 9±0.5. The mixture is stirred at 20°C for 24 hours the Solution is evaporated in vacuum by heating on a water bath and the temperature of 50÷80°C. To the residue was added 60 ml of abs. alcohol and refluxed for 20 minutes the Solution is filtered, the filtrate evaporated in vacuum at a temperature of 50÷80°C. the Residue is triturated in a mortar with 50 ml diethyl ether, then with 50 ml of acetone, then with 50 ml of dichloromethane, dissolved in 50 ml of 1 M NaOH, extracted twice with 50 ml dichloromethane. The combined organic extracts dried over sodium sulfate, evaporated in vacuum at room temperature, dissolved in 100 ml of ethanol, was added 1.65 g (14.2 mmol) of fumaric acid, boiled for 2 h, the hot solution is filtered, evaporated to 1/4 volume, incubated at 4°C for 3 h, the product is separated by filtration, dried in vacuum at 40°C until constant weight, recrystallized from isopropanol and dried in vacuum at 40°C until constant weight.

The output of C15H22N4O4*C4H4O4*0.5H2O, 4-(3,4,5-trimethoxybenzoyl)-piperazine-1-carboxamidine fumarata is hemihydrate - 2.3 g (35%). Elemental analysis of C15H22N4O4*C4H4O4*0.5H2O. Calculated, %: C 51.00; N, 6.08; N, 12.52. Found, %: C 51.08; H 6.18; N, 12.44. Mass spectrum, Foundation, found: m/z 322.32. Calculated: M 322.36.

3b) Synthesis of 4-(3,4,5-trimethoxybenzoyl)piperazine-1-carboxamidine fumarata when the pH of the reaction mixture 12±0.5

To 4.5 g (14.2 mmol) of 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride was added 2.07 g (37 mmol) of KOH, 40 ml of water, 2.1 g (14.3 mmol) of 1H-pyrazole-1-carboxamidine of monohydrochloride, the pH of the reaction mixture is 12±0.5. The mixture is stirred at 20°C for 24 hours the Solution is evaporated in vacuum by heating on a water bath and the temperature of 50÷80°C. To the residue was added 60 ml of abs. alcohol and refluxed for 20 minutes the Solution is filtered, the filtrate evaporated in vacuum at a temperature of 50÷80°C. the Residue is triturated in a mortar with 50 ml diethyl ether, then with 50 ml of acetone, then with 50 ml of dichloromethane, dissolved in 50 ml of 1 M NaOH, extracted twice with 50 ml dichloromethane. The combined organic extracts dried over sodium sulfate, evaporated in vacuum at room temperature, dissolved in 100 ml of ethanol, was added 1.65 g (14.2 mmol) of fumaric acid, boiled for 2 h, the hot solution is filtered, evaporated to 1/4 volume, incubated at 4°C for 3 h, the product is separated by filtration, dried by the vacuum at the temperature of 40°C to constant weight, recrystallized from isopropanol and dried in vacuum at 40°C until constant weight.

The output of C15H22N4O4*C4H4O4*0.5H2O, 4-(3,4,5-trimethoxybenzoyl)-piperazine-1-carboxamidine fumarata of hemihydrate - 1.4 g (21%). Mass spectrum, Foundation, found: m/z 322.32. Calculated: M 322.36.

Example 2

Synthesis of N-carbamimidoyl-4-(2,3,4-trimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride

1) Synthesis of 2,3,4-trimethoxybenzoyl chloride.

In odnogolosy flask with a capacity of 100 ml equipped with a reflux condenser with a gas exhaust tube immersed in a solution of NaOH, placed 25 g (118 mmol) of 2,3,4-trimetoxybenzoic acid and 50 ml of absolute benzene is added 0.5 ml of DMF and 10.8 ml (150 mmol) thionyl chloride. After cessation of gas evolution, the mixture is refluxed for 2 hours the Solution is cooled to a temperature of 20°C, poured into a beaker with 50 ml of hexane. The precipitate is filtered off, the filtrate is evaporated to 1/3 volume under vacuum at a temperature of 50÷80°C. When cooling is allocated a second portion of the product, which is filtered and combined with the first. The product, a white powder is dried in a vacuum at a temperature of 50÷60°C for 1 h

Output 2,3,4-trimethoxybenzoyl chloride - 23.1 g (85%), TPL 42°C.

2) Synthesis of 1-(2,3,4-trimethoxybenzoyl)piperazine hydrochloride.

In a three-neck flask with a capacity of 500 ml, equipped with a mechanical stirrer, addition funnel and thermometer, is placed 30.0 g (348 mmol) of piperazine, 75 ml of acetic acid and 90 ml of water. To the mixture was added dropwise a solution of 19.5 g (85 mmol) of 2,3,4-trimethoxybenzoyl chloride in 25 ml of THF over 30 min, maintaining the temperature of the reaction mass in the range 10÷15°C. Then stirred for 1 h and left overnight. Light yellow solution is evaporated to dryness in a vacuum at a temperature of 50÷60°C. the Residue is treated with 450 ml of 2.5 N. HCl (1.125 mol) with ice cooling and stirred for 15 minutes the Solution is filtered. The filtrate is evaporated to dryness in a vacuum of 20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 150 ml of abs. ethanol and heated to boiling with stirring. The mixture is cooled to a temperature of 20°C and the precipitate is filtered off piperazine dihydrochloride. The mother liquor evaporated to dryness in a vacuum of ~20 mm Hg and a temperature of 50÷60°C. To the residue was added 150 ml of acetone and stirred on a magnetic stirrer for 30 min at a temperature of 40÷50°C. the Precipitate is filtered off, washed twice with acetone 50 ml, dried for 12 h at 40°C.

Output 1-(2,3,4-trimethoxybenzoyl)piperazine hydrochloride - 12.1 g (45%).

3) Synthesis of N-carbamimidoyl-4-(2,3,4-trimethoxybenzoyl)piperazine-1-Carbo-xylidide hydrochloride.

In odnogolosy flask with a capacity of 100 ml was placed 6.3 g (20 mmol) 1-(2,3,4-trimethoxybenzoyl)is piperazin hydrochloride, 1.77 g (21 mmol) of dicyandiamide and 50 ml of 1-butanol. The mixture is refluxed for 10 h, evaporated in vacuum at a temperature of 50÷80°C. To the residue was added 100 ml of ethanol and refluxed for 0.5 hours, the Hot mixture is filtered, the precipitate is dried at 45°C for 2 days.

The output of C16H24N6O4*HCl, N-carbamimidoyl-4-(2,3,4-trimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride - 4.3 g (53%). Elemental analysis of C16H24N6O4*HCl. Calculated, %: 47.94; N, 6.29; N 20.96. Found, %: C 48.63; N, 6.47; N 21.03. Mass spectrum, Foundation, found: m/z 364.38. Calculated: M 364.40.

The PMR spectrum of the N-carbamimidoyl-4-(2,3,4-trimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride (Bruker 400MHz; solution in DMSO-d6): 3.17-3.70 ush. the singlets (8H; pieperazinove ring); 3.75 C. (3H; CH3O); 3.76 S. (3H; CH3O); 3.80 S. (3H; CH3O); 6.83 S. and 6.91 S. (1H and 1H; aromatic.); 6.98 OSS and 7.38 USS (4H, and 2H; 2NH, NH2(+), NH2).

Example 3

Synthesis of 4-(4-atomic charges-3,5-dimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride

1) Synthesis of 1-(4-atomic charges-3,5-dimethoxybenzoyl)piperazine hydrochloride.

In a three-neck flask with a capacity of 500 ml, equipped with a mechanical stirrer, addition funnel and thermometer, is placed 20.0 g (232 mmol) of piperazine in 50 ml of acetic acid and 60 ml of water, was added dropwise a solution of 13 g (50 mm the l) 4 atomic charges-3,5-dimethoxybenzoyl chloride in 15 ml of THF over 20 min, maintaining the temperature of the reaction medium in the range of 10÷15°C, stirred for 1 h, left overnight. The solution is evaporated to dryness in a vacuum at a temperature of 50÷60°C. the Residue is treated with 300 ml (750 mmol) of 2.5 N. HCl under ice cooling, stirred for 15 minutes the Solution is filtered, the mother liquor evaporated to dryness in vacuum at ~20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 100 ml of absolute ethanol and heated to boiling with stirring. The mixture is cooled to a temperature of 20°C and filtered. The mother liquor evaporated to dryness in a vacuum of ~20 mm Hg and a temperature of 50÷60°C. To the residue was added 100 ml of acetone and stirred on a magnetic stirrer for 30 min at a temperature of 40÷50°C. the White precipitate is filtered off, washed with twice 50 ml of acetone, dried for 12 h at 40°C.

Output 1-(4-atomic charges-3,5-dimethoxybenzoyl)piperazine hydrochloride - 7.6 g (44%).

2) Synthesis of 4-(4-atomic charges-3,5-dimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride.

To 4.52 g (13.1 mmol) of 1-(4-atomic charges-3,5-dimethoxybenzoyl)piperazine hydrochloride was added 1.6 g (14.8 mmol) of Na2CO3and 40 ml of water, 1.92 g (13.1 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride. The mixture is stirred at 30°C for 24 hours the Solution is evaporated in vacuum at a temperature of 50÷80°C. To the residue was added 60 ml of isopropanol and refluxed for 20 minutes the Solution is altroot, the mother liquor evaporated in vacuum at a temperature of 50÷80°C. the Residue is triturated in a mortar with 50 ml diethyl ether, then with 50 ml of acetone, and then triturated with 50 ml of dichloromethane and dried. The resulting product is a white powder is recrystallized from isopropanol, dried for 12 h at 40°C.

The output of C16H22N4O5*HCl, 4-(4-acetoxy-3,5-dimethoxybenzoyl)piperazine-1-carboxamidine hydrochloride - 2.0 g (35%). Elemental analysis of C16H22N4O5*HCl. Calculated, %: C at 49.68; N, 5.99; N, 14.48. Found, %: C 49.79; H 5.86; N, 14.43. Mass spectrum, Foundation, found: m/z 350.42. Calculated: M 350.36.

Example 4

Synthesis of 3-(1-(2,3,4-trimethoxybenzoyl)piperazine-4-yl)-2-hydroxy-1-propanesulfonic acid sodium salt

In odnogolosy flask with a capacity of 100 ml was placed 6.3 g (20 mmol) 1-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride and 30 ml of water, add portions of 5.5 g (65 mmol) of NaHCO3. After cessation of gas is added a solution of 4.10 g (20 mmol) 2-hydroxy-3-chloropropanesulfonyl in 30 ml of water and 0.1 g of potassium iodide, pH of the reaction mixture is 9±0.5.

The mixture is refluxed for 5 hours the Solution is evaporated to dryness in vacuum at ~20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 100 ml of abs. ethanol and refluxed for 0.5 h at peremeci the years. The hot solution was filtered from inorganic salts and soak in the day. White precipitate is filtered off and dried at 45°C for 2 days.

The output of C17H27N2NaO7S, sodium salt 3-(1-(2,3,4-trimethoxybenzoyl)-piperazine-4-yl)-2-hydroxy-1-propanesulfonic acid, 4.1 g (46%).

Elemental analysis of C17H25N2NaO8S. Calculated, %: 46.36; H 5.72; N, 6.36. Found, %: 46.33; N, 5.74; N, 6.41

Example 5

Synthesis of 4-(2,3,4,5-tetramethoxybenzene)piperazine-1-yl)-carboxamide acetate

1) preparation of 2-bromo-3,4,5-trimetoxybenzoic acid

1 litre flat-bottomed flask with reflux condenser with a trap for hydrogen bromide, addition funnel, magnetic stirrer, to a solution of 24.2 g (106 mmol) of 3,4,5-trimetoxybenzoic acid in 200 ml of chloroform was added 2.5 ml of water and the reaction mass is brought to a boil and added dropwise 5.9 ml (18.4 g, 115 mmol) of bromine in 40 ml of chloroform for 30 minutes and boil until the discoloration of the solution ~10 hours. After that the reaction mixture is transferred into a separating funnel, washed with 2 times 100 ml of water, the organic phase is dried with 5 g of anhydrous sodium sulfate, filtered from the drying agent, the chloroform evaporated on a rotary evaporator to yield 30.3 g (86%) of a light yellow precipitate.

The PMR spectrum of 2-bromo-3,4,5-trimetoxybenzoic acid (Bruker 300 MHz; actor in CDCl 3): 3.91 (3H; CH3O); 3.93 (3H; CH3O); 3.99 (3H; CH3O); 7.44 (1H, CH-Ar), 11.4 ush. the singlet (1H, CO2H)

2) Obtaining 2,3,4,5-tetramethoxybenzene acid:

1 litre flat-bottomed flask on a magnetic stirrer with a reflux condenser fitted with potassium chloride tube, prepare a solution of sodium methylate, by dissolving 7.4 g (32 mmol) of sodium in 480 ml of absolute methanol, then added 30.4 g (105 mmol) of 2-bromo-3,4,5-trimetoxybenzoic acid, after it is dissolved add 10 g (52 mmol) of copper iodide and the reaction mixture is boiled for 10 hours, select a sample, determine the completeness of the completion of the reaction by TMR, if the sample is not the source of the acid, the reaction is allocated, if not, continue heating until it the end.

After the reaction from the reaction mixture (distilled methanol, the residue is dissolved in 200 ml of water, filtered precipitated copper salt, the residue is acidified with concentrated hydrochloric acid to pH 1-2, and extracted with methylene chloride h ml), the organic phase is washed with water 2×50 ml), dried with 5 g of anhydrous sodium sulfate, filtered from the drying agent, the methylene chloride evaporated on a rotary evaporator to yield m=23.5 g of light yellow oil. The oil is recrystallized from 150 ml of a mixture of hexane/ethyl acetate (5/1), after cooling to +4°C the precipitate was filtered, dried in vacuum 10 Torr, 40°C, m=21,5 g (84%).

PMR-spectrum 2,3,4,5-tetramethoxy what Noynoy acid (Bruker 300 MHz; solution in CDCl3): 3.87 (3H; CH3O); 3.92 (3H; CH3O); 3.98 (3H; CH3O); 4.07 (3H; CH3O); 7.45 (1H, CH-Ar), 11.5 ush. the singlet (1H, CO2H).

3) Obtain the acid chloride 2,3,4,5-tetramethoxybenzene acid

In a round bottom flask of 250 ml with a reflux condenser with a trap for hydrogen chloride on a magnetic stirrer, a solution of 8.6 g (35.5 mmol) of 2,3,4,5-tetramethoxybenzene acid in 20 ml of methylene chloride was added 3.6 ml (5.95 g, 50 mmol) chloride tiomila and three drops of dimethylformamide, and boil until the termination of allocation hydrogen chloride ~3 hours, and then methylene chloride evaporated in vacuo, the residue oil was dissolved in 30 ml of heptane at room temperature, filtered from the precipitate, the mother liquor evaporated obtain 8.5 g (92%) of yellow oil, which is used in the following stage without purification.

4) to Obtain tert-butyl 4-(2,3,4,5-tetramethoxybenzene)piperazine-1-carboxylate

In a three-neck round bottom flask of 250 ml with reflux condenser, dropping funnel and thermometer, magnetic stirrer in a cooling bath, to a solution of 5.8 g (31 mmol) of BOC-piperazine, 4.1 g (40 mol) of triethylamine in 70 ml of methylene chloride and cooled to -5°C, was added dropwise a solution of 7.8 g (0.03 mol) of acid chloride of 2,3,4,5-tetramethoxybenzene acid in 50 ml of methylene chloride with such speed, that the temperature did not rise above +5°C, after that the OHL is a discussion removed and the reaction mixture was stirred at room temperature 1 hour. Next, the reaction mixture was transferred into a separating funnel and washed with 2×30 water, 2×30 saturated solution of sodium bicarbonate, 2×30 saturated solution of ammonium chloride and 2×30 water, methylene chloride evaporated, and the remaining yellow oil is dissolved in 40 ml of ethanol and planted the product 200 ml of water. The precipitate is filtered off, dried in vacuum, a white precipitate 10 g (81%).

PMR-spectrum 2,3,4,5-tetramethoxybenzene acid (Bruker 300 MHz; solution in CDCl3): 1.4 (S, tert-butyl); 3.0-3.7 m (8H, pieperazinove ring); 3.8 (6N, 2 CH3O); 3.9 (3H, CH3O); 3.95 (3H, CH3O); 7.3 (1H, CH-Ar).

5) Obtaining 4-(2,3,4,5-tetramethoxybenzene)-piperazine-1-carboximidic of acetate

In flat-bottomed flask 100 ml) under reflux on a magnetic stirrer boil 4.1 g (10 mmol) of tert-butyl 4-(2,3,4,5-tetramethoxybenzene)piperazine-1-carboxylate in 20 ml of methylene chloride and 2.3 g (20 mmol) triperoxonane acid, ~5 hours (control by TLC methylene chloride/ethyl acetate 6/4), then the solvent and excess triperoxonane acid is evaporated in vacuo on a rotary evaporator.

The residue analysis used in the next stage.

The connection with the previous stage is dissolved in 40 ml of water and portions added 2.12 g (20 mol) of sodium carbonate, after you cease to be allocated carbon dioxide, is added 1.61 g (11 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride, reactio the ing the mixture is stirred at room temperature for 24 hours. Then the water is evaporated in vacuo on a rotary evaporator with a bath temperature of not higher than 5°C, the residue zamalchivaut 20 ml of 20% sodium hydroxide solution and extracted with 4×40 ml of methylene chloride, the organic phase is washed with 10 ml of water, dried with magnesium sulfate, and after filtering off the desiccant, the evaporated methylene chloride, the residue is dissolved in 20 ml of water and passed through an anion-exchange column with 100 ml of sorbent Dowex 1×8, 200 in the main form, collecting ~100 ml of the eluate, which zachisliaut 10 ml of acetic acid. After evaporation the residue is boiled with 20 ml of acetone, the precipitate is filtered, washed with 10 ml of acetone and 10 ml of diethyl ether, to obtain 3.3 g (66%) of 4-(2,3,4,5-tetramethoxybenzene)-piperazine-1-carboximidic of acetate.

The PMR spectrum of 4-(2,3,4,5-tetramethoxybenzene)-piperazine-1-carboximidic of acetate (Bruker 300 MHz; solution in CDCl3): 1.6 (3H, CH3COOH), 3.25 m (2N, pieperazinove ring); 3.37 m (2N, pieperazinove (ring); 3.50 m (2N, pieperazinove ring); 3.67 m (2N, pieperazinove ring); 3.7 (3H; CH3O); 3.75 (3H; CH3O); 3.79 (3H; CH3O); 3.85 (3H; CH3O), 6.55 (1H, CH-Ar); 9.0 ush. the singlet (4H, the guanidine group).

Elemental analysis of C18H28N4O6. Calculated, %: C 54.53; H 7.12; N, 14.13. Found, %: C 54.48; N, 7.18; N, 14.21.

Example 6

Synthesis of 4-(3,4,5-trimethoxyphenylacetic)piperazine-1 Il-carboximide hydrochloride

1) is intes 3,4,5-trimethoxybenzaldehyde

In a beaker of 500 ml with a thermometer, magnetic stirrer with a cooling bath (water/ice) was placed a solution of 19.6 g of sulfur dioxide (306 mmol) in 60 ml of acetic acid and CuCl 4 g (40 mmol), stirred for 15 minutes. To this solution was added in portions over 5 min at 0°C a solution of diazonium salts (obtained standard diazotization of 8.2 g (44.8 mmol) of 3,4,5-trimethoxyaniline in a mixture of 15 ml of concentrated hcl and 40 ml of acetic acid with a solution to 3.36 g (48.7) of sodium nitrite in 5 ml of water at +5°C), observed foaming and evolution of nitrogen. After the addition of all solution of diazonium salts, the reaction mixture is stirred for 1 hour at room temperature, then poured into 200 ml of water and ice and extracted with 3×100 ml of methylene chloride, washed with 2×100 ml of water, dried with anhydrous sodium sulfate, filtered from the drying agent and evaporated methylene chloride. The remainder of the 10 g chromatographic on a column filled with silica gel (90 g, 40-60µ), elwira methylene chloride, collecting 1 fraction (TLC eluent methylene chloride, Rf=0.48), after evaporation crystallized light yellow oil, m=7.4, According to the PMR spectrum contains 25% impurity - 3,4,5-trimetoksi-1-chlorobenzene. Output 3,4,5-trimethoxybenzaldehyde - 46%. Used without further purification in the next stage.

2) Obtain tert-butyl 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxylate

Kruglomordoe flask of 500 ml addition funnel on a magnetic stirrer with a cooling bath (ice/water) to a solution of 9.3 g (50 mmol) of BOC-piperazine in 200 ml of dichloromethane and 10.1 g (100 mmol) of triethylamine was added dropwise a solution of 9.75 g (48.7 mmol) 3,4,5-trimethoxybenzaldehyde in 50 ml of dichloromethane, so that the temperature of the reaction mixture did not exceed +5°C, then remove the cooling and the reaction mixture is stirred at room temperature for 2 hours, washed 3·100 ml water, dried with Na2SO4, evaporated in vacuum, get a white powder. It is dissolved in 60 ml of boiling benzene, add 60 ml of hexane. After cooling to 20°C after 1 hour, the white precipitate was filtered, air-dried. Obtain 12.4 g (81%) of tert-butyl 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxylate.

The PMR spectrum of tert-butyl 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxylate (Bruker 300 MHz; solution in CDCl3): 1.45 (S, tert-butyl), 3.05 m (4H, pieperazinove ring); 3.62 m (4H, pieperazinove ring); 3.92 (S, CH3O); 6.95 (2H, CH-Ar).

3) Obtaining 4-(3,4,5-trimethoxyphenylacetic)piperazine-1 hydrochloride

In a round-bottom flask 500 ml with reflux condenser, magnetic stirrer, mix 12.4 g (29.7 mmol) of tert-butyl 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxylate, 150 ml of ethanol and 10 concentrated hydrochloric acid and boiled for 1 hour (control by TLC). The reaction mixture is evaporated in vacuum, obtain 10.5 g (100%) of the white light powder - 4-(3,4,5-trimethoxyphenylacetic)piperazine-1 hydrochloride.

4) to Obtain 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxamidine hydrochloride

p> 4-(3,4,5-trimethoxyphenylacetic)piperazine-1 receive a base by processing) 7.0 g (19.8 mmol) of 4-(3,4,5-trimethoxyphenylacetic)piperazine-1 hydrochloride 20%aqueous NaOH solution and extracted 2·100 ml of CH2Cl2. The extract was dried, evaporated. The residue was dissolved in 50 ml of DMF, was added 2.93 g (20.0 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride and stirred at 20°C for 20 hours. Then the solvent was evaporated in vacuo, the residue was treated with 2·40 ml of warm acetone. The resulting white powder was dried at 40°C. was Obtained 5.5 g (70%) of 4-(3,4,5-trimethoxyphenylacetic)piperazine-1-carboxamidine hydrochloride.

PMR-spectrum (Bruker 400 MHz; solution in DMSO-d6): 3.02 m (4H, pieperazinove ring); 3.39 m (4H, pieperazinove ring); 3.75 (6N, CH3O); 3.87 (6N, CH3O); 6.96 (1H, CH-Ar); 7.71 (4H, the guanidine group).

Elemental analysis of C14H23ClN4O5S. Calculated, %: 42.58; N, 5.87; N, 14.19. Found, %: 42.61; N, 5.91; N, 14.17.

Example 7

3-(4-(3,4-dimethoxyphenylacetone)piperazine-1-yl)-2-hydroxy-1-propanesulfonic acid sodium salt

1) preparation of tert-butyl 4-(2,3,4,5-tetramethoxybenzene)piperazine-1-carboxylate

In a round bottom flask 100 ml addition funnel on a magnetic stirrer with a cooling bath (ice/water) to a solution of 2.6 g (14 mmol) of BOC-piperazine in 40 ml of dichloromethane and 2.5 g (25 mmol) triethylamine is added dropwise a solution of 3.3 g (14 mmol) of 3,4-dimethoxybenzenesulfonamide in 20 ml of dichloromethane, so that the temperature of the reaction mixture did not exceed +5°C, then remove the cooling and the reaction mixture is stirred at room temperature for 2 hours, washed 3·100 ml water, dried with Na2SO4, evaporated in vacuum, get a white powder. It is dissolved in 60 ml of boiling benzene, add 60 ml of hexane. After cooling to 20°C after 1 hour, the white precipitate was filtered, air-dried. Obtain 4.4 g (81%) of tert-butyl 4-(3,4-dimethoxyphenylacetone)piperazine-1-carboxylate.

The PMR spectrum of the tert-butyl 4-(2,3,4,5-tetramethoxybenzene)-piperazine-1-carboxylate (Bruker 300 MHz; solution in CDCl3): 1.45 (S, tert-butyl); 2.85 m (4H, pieperazinove ring); 3.42 m (4H, pieperazinove ring); 3.98 (6N, CH3O); 7.12 (1H, CH-Ar); 7.23 (1H, CH-Ar); 7.35 (1H, CH-Ar).

2) Obtain 1-(3,4-dimethoxyphenylacetone)piperazine hydrochloride

In a round bottom flask of 50 ml with reflux condenser, magnetic stirrer, mixed 4.4 g (11.3 mmol) of tert-butyl 4-(3,4-dimethoxyphenylacetone)piperazine-1-carboxylate, 20 ml of ethanol and 10 concentrated hydrochloric acid and boiled for 1 hour (control by TLC). The reaction mixture is evaporated in vacuum, obtain 3.6 g (100%) of white powder - 4-(3,4-dimethoxyphenylacetone)piperazine-1-carboxamidine hydrochloride.

3) Obtain 3 -(4-(3,4-dimethoxyphenylacetone)piperazine-1-yl)-2-hydroxy-1-propanesulfonic acid sodium salt

Odnogolosy flask with a capacity of 100 ml was placed 3.0 g (9.4 mmol) of 1-(3,4-trimethoxyvinylsilane)piperazine hydrochloride and 30 ml of water, add portions of 2.8 g (33 mmol) of NaHCO3. After cessation of gas is added a solution of 1.88 g (9.1 mmol) of 2-hydroxy-3-chloropropanesulfonyl in 10 ml of water and 0.1 g of potassium iodide, pH of the reaction mixture is 9±0.5.

The mixture is refluxed for 5 hours the Solution is evaporated to dryness in vacuum at ~20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 60 ml of abs. ethanol and refluxed for 0.5 h with stirring. The hot solution was filtered from inorganic salts and soak in the day. White precipitate is filtered off and dried at 45°C for 2 days.

The output of C15H24N2NaO8S2sodium salt of 3-(4-(3,4-dimethoxyphenylacetone)piperazine-1-yl)-2-hydroxy-1-propanesulfonic acid sodium salt of 2.4 g (57%).

The PMR spectrum of 3-(4-(3,4-dimethoxyphenylacetone)piperazine-1-yl)-2-hydroxy-1-propanesulfonic acid sodium salt (Bruker 300 MHz; solution in D2O): 2.4-2.6 m (6N, 3CH2, pieperazinove ring and propanesulfonic acid); 2.8-3.1 m (6N, 3CH2, pieperazinove ring and propanesulfonic acid); 3.82 (6N, CH3O); 4.25 m (1H, CH from propanesulfonic acid); 7.05 (1H, CH-Ar); 7.18 (1H, CH-Ar); 7.34 (1H, CH-Ar).

Elemental analysis of C15H23N2NaO8S2. Calculated, %: 40.35; N, 5.19; N, 6.27. Found, %: C 40.44; N, 5.21; N, 6.25.

Example 8

p> Synthesis of 4-(3,4-trimethoxyvinylsilane)piperazine-1-yl)carboxamide hydrochloride

In odnogolosy flask with a capacity of 100 ml was placed 3.75 g (9.4 mmol) of 1-(3,4-trimethoxyvinylsilane)piperazine hydrochloride was dissolved in 40 ml of water, and portions added 1.8 g (17 mmol) of sodium carbonate, after you cease to be allocated carbon dioxide, is added 1.52 g (10.4 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride and the reaction mixture stirred at room temperature for 24 hours. Then the water is evaporated in vacuo on a rotary evaporator with a bath temperature not exceeding 50°C, the residue is dissolved by heating in 50 ml of absolute ethanol, filtered off from nerastvorim inorganic salts, zachisliaut 2 ml of concentrated hydrochloric acid and evaporated. The residue after evaporation is boiled in 50 ml of acetone for 20 minutes, filtered, the filter cake washed with 20 ml of acetone. Dried in vacuum at 50°C.

Obtain 1.72 g (66%) of 4-(3,4,5-tetramethoxypropane)-piperazine-1-carboxamidine hydrochloride.

The PMR spectrum of 4-(3,4-trimethoxyvinylsilane)piperazine-1-yl)carboxamide hydrochloride (Bruker 300 MHz; solution in DMSO-d6): 2.96 m (4H, 3CH2, pieperazinove ring); 3.5 m (4H, CH3, pieperazinove ring); 3.95 (6N, CH3O); 7.1-7.2 m (2H, CH-Ar); 7.18 (1H, CH-Ar); 7.34 (1H, CH-Ar).

Elemental analysis of C13H21CN 4O4S. Calculated, %: 42.80; N, 5.80; N, 15.36. Found, %: 42.82; N, 5.83; N, 15.33.

Example 9

Synthesis of 4-(2,3,4-triethoxysilyl)piperazine-1-carboximidic fumarata

1) Synthesis of 2,3,4-triethoxysilyl chloride.

In odnogolosy flask with a capacity of 100 ml equipped with a reflux condenser with a gas exhaust tube immersed in a solution of NaOH, placed 30 g (118 mmol) of 2,3,4-triethoxysilane acid and 50 ml of absolute benzene is added 0.5 ml of DMF, and 11 ml (150 mmol) thionyl chloride. After cessation of gas evolution, the mixture is refluxed for 2 hours the Solution is cooled to a temperature of 20°C, poured into a beaker with 50 ml of hexane. The precipitate is filtered off, the filtrate is evaporated to 1/3 volume under vacuum at a temperature of 50÷80°C. When cooling is allocated a second portion of the product, which is filtered and combined with the first. The product, a white powder is dried in a vacuum at a temperature of 50÷60°C for 1 h

Output 2,3,4-triethoxysilyl chloride 25 g (90.5%), TPL 48°C.

2) Synthesis of 1-(2,3,4-triethoxysilyl)piperazine hydrochloride.

In a three-neck flask with a capacity of 500 ml, equipped with a mechanical stirrer, addition funnel and thermometer, is placed 30.0 g (350 mmol) of piperazine, 75 ml of acetic acid and 90 ml of childbirth. To the mixture was added dropwise a solution of 24 g (85 mmol) of 2,3,4-triethoxysilyl chloride in 25 ml of THF for 30 min, to support the Wai temperature of the reaction mass in the range 10÷15°C. Further stirred for 1 h and left overnight. Light yellow solution is evaporated to dryness in a vacuum at a temperature of 50÷60°C. the Residue is treated with 450 ml of 2.5 N. HCl (1.125 mol) with ice cooling and stirred for 15 minutes the Solution is filtered. The filtrate is evaporated to dryness in a vacuum of ~20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 150 ml of abs. ethanol and heated to boiling with stirring. The mixture is cooled to a temperature of 20°C and the precipitate is filtered off piperazine dihydrochloride. The mother liquor evaporated to dryness in a vacuum of ~20 mm Hg and a temperature of 50÷60°C. To the residue was added 150 ml of acetone and stirred on a magnetic stirrer for 30 min at a temperature of 40÷50°C. the Precipitate is filtered off, washed twice with acetone 50 ml, dried for 12 h at 40°C.

Output 1-(2,3,4-triethoxysilyl)piperazine hydrochloride and 15 g (50%).

3) Synthesis of 4-(2,3,4-triethoxysilyl)piperazine-1-carboxamidine fumarata.

In odnogolosy flask with a capacity of 100 ml was placed 7.2 g (20 mmol) 1-(2,3,4-triethoxysilyl)piperazine hydrochloride, 1.8 g (21 mmol) of dicyandiamide and 50 ml of 1-butanol. The mixture is refluxed for 10 h, evaporated in vacuum at a temperature of 50÷80°C. To the residue was added 100 ml of ethanol and refluxed for 0.5 hours, the Hot mixture is filtered, the precipitate is dried at 45°C for 2 days.

The output of C16H24N6O4 *HCl, 4-(2,3,4-triethoxysilyl)piperazine-1-carboxamidine hydrochloride - 5.5 g (70%).

5.9 g (15 mmol) 4-(2,3,4-triethoxysilyl)piperazine-1-carboxamidine hydrochloride dissolved in 50 ml of 1 M NaOH, extracted twice with 50 ml dichloromethane. The combined organic extracts dried over sodium sulfate, evaporated in vacuum at room temperature, dissolved in 100 ml of ethanol, was added 1.7 g (15 mmol) of fumaric acid, boiled for 2 hours, the hot solution is filtered, evaporated to 1/4 volume, incubated at 4°C for 3 hours, the Product is separated by filtration, dried in vacuum at 40°C until constant weight, recrystallized from isopropanol and dried in vacuum at 40°C until constant weight.

The output of C18H28N4O4*C4H4O4, 4-(2,3,4-triethoxysilyl)piperazine-1-carboximidic fumarata - 3 g (42%). Elemental analysis of C18H28N4O4*C4H4O4. Calculated, %: 54.99; H 6.71; N, 11.66. Found, %: C 54.92; H 6.75; N, 11.63. Mass spectrum, Foundation, found: m/z 364.43. Calculated: M 364.45.

Example 10

Synthesis of potassium salt of 3-(1-(3-tert-butyl-4-methoxybenzoyl)piperazine-4-yl)-2-hydroxy-1-propanesulfonic acid

1) Synthesis of N-(tert-butyloxycarbonyl)-N'-(3-tert-butyl-4-methoxybenzyl)-piperazine.

In a three-neck round the bottom of the flask, 250 ml, under reflux, drip funnel and a thermometer, magnetic stirrer in a cooling bath, to a solution of 2 g (10.7 mmol) of N-barefoot-piperazine and triethylamine in 20 ml of dichloroethane was added dropwise a solution of 2.06 g (10.7 mmol) of chlorin-hydride 3-tert-butyl-4-methoxybenzoic acid in 20 ml of dry dichloromethane with such a rate that the temperature did not rise above +5°C, then cooling is removed and the reaction mixture stirred at room temperature for 1 hour. Next, the reaction mixture was transferred into a separating funnel and washed with 2×30 water, 2×30 saturated solution of sodium bicarbonate, 2×30 saturated solution of ammonium chloride and 2×30 water, methylene chloride evaporated, and the residue, a yellow oil 3.5,

Sediment - 3.5 g used in the next stage.

2) Synthesis of (3-tert-butyl-4-methoxybenzoyl)piperazine dihydrochloride.

To 3.5 g of N-(tert-Butylochka-carbonyl)-N'-(3-tert-butyl-4-methoxy-benzoyl)piperazine was added 30 ml of 10%HCl and 5 ml of ethanol, the mixture is stirred for 5 h at 20°C, evaporated to dryness in a vacuum at a temperature of 50÷80°C. To the residue is added 20 ml of dry acetone, boiled with stirring for 20 min, cooled to a temperature 10°C. After 1 h the product filters, washed with 10 ml of acetone and dried on the air. Output (3-tertbutyl-4-methoxybenzoyl)piperazine hydrochloride 2.1 g (68%).

3) Synthesis of potassium salt of 3-(1-(3-tert-butyl-4-methoxime the zoilus)piperazine-4-yl)-2-hydroxy-1-propanesulfonic acid

In odnogolosy flask with a capacity of 100 ml was placed 2.2 g (6.6 mmol) (3-tert-butyl-4-methoxybenzoyl)piperazine hydrochloride and 30 ml of water, add portions 5 g KHCO3. After cessation of gas, was added a solution of 1.4 g (6.6 mmol) of sodium salt of 2-hydroxy-3-chloropropanesulfonyl in 30 ml of water and 0.1 g of potassium iodide. The mixture is refluxed for 5 hours the Solution is evaporated to dryness in vacuum at ~20 mm Hg and a temperature of 50÷60°C. the Residue is treated with 50 ml of abs. ethanol and refluxed for 1 h under stirring. The hot solution was filtered from inorganic salts and soak in the day. White precipitate is filtered off and dried at 45°C for 2 days.

The output of C19H29KN2O6S, sodium salt (3-tert-butyl-4-methoxybenzyl)-piperazine-4-yl)-2-hydroxy-1-propanesulfonic acid, 1.3 g (45%).

Elemental analysis of C19H29KN2O6S. Calculated, %: C 50.42; N, 6.46; N, 6.19. Found, %: C 50.61; N, 6.52; N, 6.21. Mass spectrum, found: m/z 452.14. Calculated: M 453.14.

Example 11

The study of antiplatelet and anticoagulant properties of N,N'-substituted piperazines for example, donated human blood

Blood was obtained by puncture of the cubital vein of the donor dry sharp needle without syringe. 7÷10 days before the study was canceled taking drugs that affect the function of the Yu platelets.

In dimensional plastic centrifuge tube was placed 1 ml of 3.8% solution translesanas primary sodium citrate with a pH of 7.4. Was punctilobula cubital vein, collected freely flowing blood up to the mark with 10 ml, the mixture was immediately stirred by preventing formation of air bubbles. The obtained stable blood poured into 2 tubes, 5 ml each.

To obtain platelet-rich plasma is stabilized, the blood was centrifuged for 8 min at room temperature and 1000 rpm (150 g). Repeated centrifugation of the blood for 20 min at 3200 rpm (2300 g) and 22°C were obtained platelet-poor plasma.

The study of anticoagulant activity was performed within 2 h after receiving platelet-rich plasma. Plasma was standardized to obtain the concentration of platelets 200-250×109/l, adding estrambotica plasma. The concentration of platelets was determined on the analyzer SOLAR AR 2110.

Antiplatelet properties of N,N'-substituted piperazines were evaluated for their effect on platelet aggregation tests with ADP-, collagen - and ristocetin-induced aggregation. For dissolving N,N'-substituted piperazines and cultivation of reagents used Tris-HCl buffer, pH 7.4.

As the main characteristics of the aggregation activity of platelets adopted the maximum amplitude of aggregation (MA) - the maximum is the value of the transmittance of the sample after adding an aggregating agent, in % to the transmission estramboticos plasma. The reaction was recorded in straight lift curve aggregation for 16 C.

The measurements were carried out on 4-channel analyzer CHRONO-LOG 490-4D (CHRONO-LOG, USA). The temperature in the cell - 37°C, the rotation speed of the magnetic stirrer is 1200 R/min

0.5 ml of N,N'-substituted piperazine was made in the cuvette was added standardized platelet plasma (0.4 ml)were mixed, incubated at 37°C for 5 minutes Cuvette was placed in aggregometer, was added 0.05 ml of a solution of the inductor aggregation (ADP, or collagen, or ristocetin) and registered platelet aggregation within 3 minutes.

In the test of ADP-induced reversible aggregation of platelets was used reagent CHRONO-PAR ADP REAGENT (CHRONO-LOG, USA) with a concentration of 10 μm. Primary (reversible) platelet aggregation was assessed by response to the Addendum to the plasma threshold doses of ATP (concentration of ADP - 1 μm).

In the test, the collagen-induced platelet aggregation reagent CHRONO-PAR COLLAGEN (CHRONO-LOG, USA) was diluted with buffer to a concentration of 10 μg collagen/ml

To study ristocetin-induced platelet aggregation reagent CHRONO-PAR RISTOCETIN (CHRONO-LOG, USA) was diluted with buffer to a concentration of ristocetin 12 mg/ml was Measured amplitude of platelet aggregation after 60 s after start of the reaction.

The study of antiplatelet properties of N,N'-what ameenah of piperazines with inductor arachidonic acid (CHRONO-LOG, USA): 450 µl platelet plasma was added 50 μl of a solution of N,N'-substituted piperazine, incubated for 15 min at 36°C in a ditch of aggregometer CHRONO-LOG. The concentration of arachidonic acid in the sample is 0.2 mm, N,N'-substituted piperazines, drug compare aspirin - 4÷5 mm/l

It was shown that N,N'-substituted piperazines have expressed aspirin-like activity, inhibiting platelet aggregation induced by arachidonic acid (table 5).

For studies of anticoagulant properties of N,N'-substituted piperazines were determined by activated partial thromboplastin time (APTT) is the ability of N,N'-substituted piperazines to prolong the clotting time platelet-poor plasma compared with control. Used set of reagents for the determination of the APTT (Rhosneigr health Ministry on THE 9398-214-01966456-99) and coagulometer COAG-A-MATE ® HM (ORGANON TEKNIKA, USA).

The solutions of N,N'-substituted piperazines were mixed with platelet-poor plasma in a ratio of 1:1, was added 0.1 ml of APTT reagent, the mixture is incubated in a cuvette at 37°C, 5 min, was added 0.1 ml of 0.277% CaCl2. Determined the clotting time in seconds.

The results of the study of the properties of N,N'-substituted piperazines are presented in tables 1-5 (Appendix). As follows from these data, N,N'-substituted piperazines are compounds with selective effects on coagulation factors helmet is as high antiplatelet and anticoagulant activity. Antiplatelet and anticoagulant activity of the compounds of the present invention exceeds the activity of drugs

Table 1
Antiplatelet properties of N,N'-substituted piperazines and the comparison drug - ozagrel. ADP-induced platelet aggregation.
Parameters aggregationC, mm/l
00.20.51.252.505.07.5
(control)
Ozagrel (n=10)
MA, % (n=10)13.2±2.6--12.9±2.110.6±2.59.6±2.54.2±1.2
Y %* ---2.319.763.668.2
N,N'-substituted piperazine in example 8
MA, % (n=10)17.9±2.517.3±2.812.3±1.18.2±1.82.05±1.1-
Y%-3.431.354.298.9-
N,N'-substituted piperazine in example 5
MA, % (n=10)15.3±1.115.0±2.011.2±1.45.0±2.11.8±0.2--
Y %-2.026.896.798.7- -
N,N'-substituted piperazine in example 1
MA, % (n=5)13.7±2.16.4±1.15.0±1.14.1±0.73.0±12.11.3±0.5-
Y %-53.363.570.178.190.5
N,N'-substituted piperazine according to example 2
MA, % (n=10)19.3±2.0--15.0±1.88.7±2.23.1±0.8-
Y%---21.155.084.2-
N,N'-substituted piperazine according to example 2
MA, % (n=5)18.3±3.4 --10.6±2.05.7±1.11.7±0.5-
Y %---42.168.990.7-
N,N'-substituted piperazine in example 3
MA, % (n=10)15.8±2.014.2±1.011.1±1.35.0±1.22.1±0.4--
Y %-10.129.796.898.7--
* - Y=(MA0-MAx):MA0*100%

Table 2
Antiplatelet properties of N,N'-substituted piperazines. Collagen-induced aggregation.
C, mm/l
aggregation0 (control)0.20.51.252.55.07.5
Ozagrel (similar action)
MA, % (n=10)76.7±9.1-74.3±7. 964.1±12.060.0±2.554.0±12.934.2±11.2
Y%*--3.116.421.829.655.4
N,N'-substituted piperazine in example 8
MA, % (n=10)76.3±3. 5-72.0±3.263.0±1.855.4±4.650.1±1.9-
Y%-5.617.427.434.3-
N,N'-substituted piperazine in example 5
MA, % (n=10)78.7±4. 8-74.5±4.363.7±2.223.9±0.3--
Y %--5.319.169.8--
N,N'-substituted piperazine in example 1
MA, % (n=5)74.0±1. 7-70.0±5.160.7±7.718.4±3.12.1±0.4-
Y %--5.4.18.875.197.2-
N,N'-substituted piperazine according to example 2
MA, % (n=10)79.3±2. 0-73.0±7.365.10±1.858.7±2.924.1±0.8-
Y%--7.917.926.069.6-
N,N'-substituted piperazine in example 4
MA, % (n=5)77.7±1. 4--57.0±2.850.2±3.524.1±1.5-
Y %---26.435.469.0-

Table 3
Antiplatelet properties of N,N'-substituted piperazines. Ri is tieten-induced platelet aggregation.
OptionsC, mm/l
aggregation0 (control)0.20.51.252.55.0
Ozagrel (similar action)
MA (60), % (n=10)63.7±10. 2--58.6±9.145.6±9.535.6±8.5
Y %*---8.02844
N,N'-substituted piperazine in example 8
MA (60), % (n=10)60.7±4.560.2±6.150.0±8.745.0±3.839.5±7.733.04±2.8
Y %-- 18263546
N,N'-substituted piperazine in example 3
MA (60), % (n=10)68.8±4.8-63.7±5.159.9±8.950.0±1.223.1±3.2
Y %--682478
N,N'-substituted piperazine in example 1
MA (60), % (n=5)71.3±2.1-70.0±10.562.1±7.755.1±11.133.3±4.5
Y %--2132353.3
* - Y=(MA0-MAx):MA0*100%

The APTT, with (n=5)
Table 4
Anticoagulant properties of N,N'-substituted piperazines.
The parameters coagu-C, mm/l
0 (con-1.72.54.16.38.312.5
ablationcontrol)
Ozagrel (similar action)
The APTT, with (n=5)48.3±4.0-51.8±1.753.1±3.0-57.9±2.562.7±2.1
Z %*-710-20 30
N,N'-substituted piperazine in example 4
The APTT, with (n=5)53.2±2.155.5±3.058.0±2.064.1±2.173.8±1.787.01±2.2111.1±14.0
Z %-49203964109
N,N'-substituted piperazine in example 5
The APTT, with (n=5)56.4±9.553.7±7.069.2±5.976.5±9.898.9±9.9>150-
Z %--5233675--
N,N'-substituted piperazine in example 1
44.9±7.350.4±7.063.3±5.770.4±5.2-139.1±9.5-
Z %124057-210-
N,N'-substituted piperazine in example 10
The APTT, with (n=5)55.0±4.658.0±4.065.2±5.084.2±2.2-149.0±2.5-
Z %61953-171-
* Z=(APTTx-APTT0):APTT0*100%

Table 5
Antiplatelet properties of N,N'-substituted piperazines and the comparison drug - aspirin - standard inhibitor of platelet aggregation induced by arachidonic acid. The platelet aggregation induced by arachidonic acid.

No.SubstanceC, mm/lMAMaximum speed for 16% Inhibition of aggregation
1Buffer (control)0881390
2N,N'-substituted piperazine in example 54.021100
3N,N'-substituted piperazine in example 84.3704567
4N,N'-substituted piperazine in example 14.52060

Example 12. The study of antiplatelet and anticoagulant properties of N,N'-substituted piperazines in vivo

Water
Table 6
The compositions for biological studies
No.Component nameThe quantity g
1Composition 1
N,N'-substituted piperazine in example 433 mm or 8.3 mm or 3.3 mm or 1.7 mm
Sodium chloride9.0
Sodium hydroxide 0.1 M solutionto pH 7.2
Waterto 1 l
2Composition 2
N,N'-substituted piperazine in example 13.3 mm or 1.7 mm
Sodium chloride9.0
Sodium hydroxide 0.1 M solutionto pH 7.2
to 1 l
3Composition 3
N,N'-substituted piperazine in example 88.3 mm or 3.3 mm
Sodium chloride9.0
Sodium hydroxide 0.1 M solutionto pH 7.2
Waterto 1 l
4Composition 4
Ozagrel (similar action)33 mm or 8.3 mm or 3.3 mm
Sodium chloride9.0
Sodium hydroxide 0.1M solutionto pH 7.2
Waterto 1 l
5Composition 5
N,N'-substituted piperazine in example 18.3 mm or 3.3 mm
Sodium chloride9.0
Sodium hydroxide 0.1 M solutionto pH 7.2
Waterto 1 l
6Composition 6
Ozagrel (similar action)0.067 mm (0.017 g)
Lactose0.053 g
Microcrystalline cellulose0.129 g
Sodium fumarate0.001 g
TOTAL0.200 g
7Composition 7
N,N'-substituted piperazine in example 10.067 mm (0.025 g)
Lactose0.053 g
Microcrystalline cellulose0.121 g
Sodium fumarate0.001 g
TOTAL0.200 g
8Composition 8
N,N'-substituted piperazine in example 1433 mm or 8.3 mm or 3.3 mm
The three who chloride 9.0
Sodium hydroxide 0.1M solutionto pH 7.2
Waterto 1 l
9Composition 9
N,N'-substituted piperazine (example 733 mm or 8.3 mm or 3.3 mm
Sodium chloride9.0
Sodium hydroxide 0.1 M solutionto pH 7.2
Waterto 1 l

Studies of N,N'-substituted piperazines in vivo were performed on rats male Wistar rats weighing 300±30 g (age 15-25 weeks). The animals were kept on an unlimited consumption of food and water.

Studied the effect of N,N'-substituted piperazines on the performance of ADP-induced platelet aggregation and fibrinolytic activity of blood.

Intravenous (in/in): 1 ml of N,N'-substituted piperazine or 1 ml of a solution of a drug comparison of ozagrel was injected bolus into the tail vein of generalizirovanny rats.

Oral administration (b/W): 0.2 g of the composition containing N,N'-substituted piperazine or comparator drug ozagrel (table 6), was mixed with 1.5 ml of water, the suspension vvodili/W hard metal tip.

The dose of the active substance was calculated in mm per 1 kg of body weight of the rat. In the control similarly injected with saline (1.5 ml).

Immediately after injection, animals were placed in individual standard cells for observation.

Blood samples stabilized with heparin (50 u/ml), was carried out for 40÷60 of bedranol vein under General anesthesia (thiopental sodium, 50 mg/kg intraperitoneally, in 1 ml of physiological solution). The ratio of blood and stabilizer was 9:1. The blood was placed in siliconized tubes and gently mixed.

The study of the aggregation activity of platelets produced in whole blood within 30 min after blood collection.

The determination was conducted on the impedance aggregometry AI-300 (NGOs to them. The Comintern and the scientific research Institute of cardiology health Ministry to them. Government institution Almazov) was performed at 37°C and constant speed mixing (1100 rpm) in an intact environment (V.I. Ivanov and others; inventor's certificate SU 1504591 A1, 1989, bull. N32). The electrodes of the sensors in contact with the mixed blood covered first by platelets in a single layer. When making the inductor develops the aggregation of platelets, resulting in platelet count on the electrodes increases. Thickening covering the electrode layer when platelet aggregation leads to an increase in impedance between the electrodes.

In a cuvette containing a magnetic stir bar was placed 0.55 ml of whole blood of rats and were preincubation at 37°C for 2-3 min in a thermostat. Then in the cuvette was placed sensor, was transferred to a special chamber of the device and after stirring contributed aggregation inductor - solution of disodium salt of ATP with a concentration of 0.25 mm. The ratio of the volume of aggregation inductor and a sample of whole blood was 1:12. Determination of the intensity of aggregation produced the impedance method after 5 min from the moment you enter the field (table 7).

Table 7
The effect of intravenous N,N'-substituted piperazines on ADP-induced platelet aggregation
MedicationControl (fisr-R)Impedance, Ohm*
0.1 mm/kg0.025 mm/kg0.01 mm/kg0.005 mm/kg
Composition 4 (Ozagrel), in/at5.0±0.53.0±0.63.5±0.64.3±0.2
% pin is Olya -607086
Composition 1/5.7±0.25.9±0.24.2±0.33.0±0.2-
% of control-1047453
Composition 2/5.8±0.3--3.3±0.44.4±0.3
% of control--5776
Composition 3/5.0±0.5-3.4±0.83.5±0.8-
% of control--6670-
Composition 6 (Ozagrel)/W5.7±0.34.1±0.2---
% of control-72---
Track 7,/W5.7±0.33.7±0.2---
% of control-65---
* - p<0.05 compared to control

The study of the influence of N,N'-substituted piperazines on fibrinolytic activity in the blood of rats was estimated by the time of spontaneous lysis of the clot derived from euglobulin fraction of plasma. Method is one of the integral methods of assessment of fibrinolytic system.

Selection of stable sodium citrate (3.2%) blood was taken under General anesthesia (thiopental sodium (50 mg/kg, intraperitoneally with 1 ml of physiological solution), 60 seconds from the femoral vein.

Soothes is the blood and the stabilizer was 9:1. Stable blood was centrifuged for 10 min at a speed of 1200 g. Investigated platelet-poor plasma with a reagent for the study of spontaneous euglobulin fibrinolysis company LLC "Technology standard" (Russia, Barnaul). Before defining the reagents were diluted with distilled water to a concentration of reagents: calcium chloride - 0.277%, acetic acid - 1%.

To obtain euglobulin fraction of plasma in vitro was consistently mixing 8 ml of water d/and 0.18 ml of 1% acetic acid and 0.5 ml of plasma. The mixture is incubated at a temperature of 4÷8°C for 30 min, centrifuged at 600 g for 5 minutes the Supernatant was decanted, the tube was overturned on filter paper for 1 min left on the bottom of the tube sediment euglobulin was dissolved in 0.5 ml of assay buffer.

To 0.5 ml euglobulin in a test tube was added 5 ml of 0.277% solution of CaCl2gently stirred, avoiding shaking, incubated in a water bath at 37°C.

Recorded time (min) from the moment of addition of the solution of CaCl2to dissolve the clot. In healthy rats spontaneous lysis euglobulin is 90-180 minutes. Shortening the time of lysis indicates activation and elongation is about the inhibition of fibrinolysis (table 8).

Table 8
Fibrinolytic activity of N,N'-substituted piperazines
MedicationControl (fisr-R)Spontaneous lysis of the clot, min*
0.10 mm/kg0.025 mm/kg0.01 mm/kg
Composition 4 (Ozagrel, similar in action), in/at129±12-203±31173.8±36
% of control--157134
Composition 1/128±11-155±11176±15
% of control--121138
Composition 3/129±12-158±8223±24
% of control -122172
Composition 5 in/in129±12-212±8230±24
% of control-164178
Composition 6 (Ozagrel)/W122±10190±21--
% of control-156--
Track 7,/W122±10199±17--
% of control-163--
* - p<0.05 compared to control

Example 13. The study of the influence of N,N'-substituted piperazines on the hemostatic system. The model of experimental thrombosis

The study was performed nekrich male Wistar rats weighing 230±30 g (kennel laboratory animals "Rapolano",). The animals were kept on an unlimited consumption of food (standard diet for rats To 120 company "inform-feed", Russia) and water.

The drug was administered bolus into the tail vein of generalisierungen animals. In the control were administered saline (5 ml/kg). Immediately after injection, animals were placed in individual standard cells for observation.

Modeling of thrombosis: 50 min after drug injection in the left femoral vein was injected 1 ml of photosensitizer rose Bengal A (Acros Organic, USA) at a dose of 17 mg/kg [Boselli 2007, Petrishchev 2009], made an incision about 2 cm on the inner surface of the right thigh of the animal. The site of the femoral artery about 5 mm in length were freed from surrounding tissues, was isolated from the neurovascular bundle. Under this area of the artery and brought a strip of opaque black plastic with a width of 3 mm, thereby isolating the vein and surrounding tissue from the radiation. Irradiation was carried out using a diode laser, DPSS laser (Diode Pumpd Solid State Laser, South Korea). The wavelength of 532 nm, 60 mW, the exposed area is 1 mm2the exposure time of 40 minutes. The blood flow in the femoral artery was measured using high-frequency ultrasound dopplerography (device "minimax-Doppler-K"), the probe frequency 20 MHz). Measured change in blood flow velocity in the irradiation process, arteri the (table 9).

Table 9
The effect on the change in velocity of blood flow in experimental photothrombosis
Drug; DoseV, cm/s*
0 min10 min20 min30 min40 min
N,N'-substituted
piperazine in example 6;7.1±3.27.00±2.47.5±2.26.4±1.96.6±1.5
0.01 mm/kg
N,N'-substituted piperazine in example 7;6.9±3.27.00±2.06.8±2.06.9±1.30.01 mm/kg
The composition according to example 6. Ozagrel(similar action); 0.01 mm/kg10.9±2.95.7±1.8The absence of blood flow
N,N'-substituted piperazine in example 3;8.5±1.78.4±1.28.4±3.08.9±1.68.5±1.2
0.025 mm/kg
N,N'-substituted
piperazine in example 10;8.3±1.88.1±1.38.3±2.08.0±1.38.2±1.2
0.025 mm/kg
The composition according to example 6. Ozagrel (similar action); 0.025 mm/kg9.0±2.75.1±1.73.8±1.05.5±1.45.8±1.7
* - p<0.05 (n=6)

Example 14. The study vasodilatory properties of N,N'-substituted piperazines

Vasodilatory properties of N,N'-substituted piperazines aanlysis their influence on the reactivity of the blood vessels of the microvasculature.

The study was performed on rats male Wistar rats weighing 300±30 g (kennel laboratory animals "Rapolano RAMS). The animals were kept on an unlimited consumption of food (standard diet for rats To 120 company "inform-feed", Russia) and water.

The solutions of N,N'-substituted piperazines and saline (control) was administered bolus over 1 min into the tail vein of generalizirovanny animals from the calculation of 5.0 ml per 1 kg Immediately after introduction of the solution of the animals were placed in individual standard cells for observation.

After 30 min after injection the animals were narcoticyou (thiopental sodium, 60 mg/kg subcutaneously). Through Nizhneserginsky access took a loop of the small intestine, premikudu is to mesoappendix to study the microcirculation in venules and arterioles of the mesentery in the transmitted light, and placed the rat on thermostatted sample table of the microscope. The application of a solution of noradrenaline (Ageton, 2 mg/ml, Laboratoire AGUETTANT, France) produced directly on the mesentery (Fumess J.B., J.M. Marshall, 1974; Antaria LI, 2004).

Study of microcirculatory vessels was carried out on the basis of microscope LUMAM I1 (LOMO, Russia). Using the camera Optics and Electronics ISTA Ltd) made the video data on a personal Computer, the processing of results was performed by Video-Test 4.0 (ISTA Ltd., Russia). Defined: the diameter of the vascular wall (D, μm) before and after application of noradrenaline, the start time of the deceleration of blood flow in the vessels under the action of norepinephrine (the observation was carried out for 1 min after application).

Table 10
Vasodilatory properties of N,N'-substituted piperazines
The slowing of blood flow**
Drug; DoseWithON* g/ml% stenosisThe latent period of deceleration, S.
Venules
Saline (control)10-7 7029±4
N,N'-substituted piperazine in example 7; 0.025 mm/kg10-722The blood flow is not slowed down
The composition according to example 6. Ozagrel (similar action); 0.025 mm/kg10-727The blood flow is not slowed down
Saline (control)10-67827±6
N,N'-substituted piperazine in example 7; 0.01 mm/kg10-63341±6
The composition according to example 6. Ozagrel (similar action); 0.01 mm/kg10-64432±4
Arterioles
Saline (control)10-78034±5
N,N'-substituted piperazine in example 7; 0.025 mm/kg10-728 The blood flow is not slowed down
The composition according to example 6. Ozagrel (similar action); 0.025 mm/kg10-727The blood flow is not slowed down
Saline (control)10-68520±4
N,N'-substituted piperazine in example 7; 0.01 mm/kg10-65843±4
The composition according to example 6. Ozagrel (similar action); 0.01 mm/kg10-68027±6
* - CONthe concentration of norepinephrine.
** - p<0.05 compared to control (n=6).

Conducted pharmaco-biological tests have shown that N,N'-substituted piperazines have antiplatelet, anticoagulant and vasodilator properties. Compositions based on N,N'-substituted piperazines have a positive effect on the restoration of hemostasis.

1. N,N'-substituted piperazines of General formula (I):

where R1, R2- frost the first or branched alkoxy (C 1÷C4), CH3C(=O)O;
n=1-5; m=0-3;
Z is C=O, SO2;
X - C(=NH)NH2C(=NH)NHC(NH)NH2;
G - low molecular weight organic or mineral acid, sodium cations, potassium, ammonium or water.

2. The method of obtaining N,N'-substituted piperazines according to claim 1, by reacting N-substituted piperazines of General formula

where R1, R2- linear or branched alkoxy (C1÷C4), CH3C(=O)O;
n=1-5; m=0-3; Z is C=O, SO2;
with 1H-pyrazole-1-carboxamidine, dicyandiamide and their salts in organic solvents or water at a temperature of 10-50°C in the presence of bases.

3. The method of obtaining N,N'-substituted piperazines according to claim 2, wherein the N-substituted piperazines use their hydrates.

4. The method of obtaining N,N'-substituted piperazines according to claim 2, wherein the N-substituted piperazines using their salts.

5. The method of obtaining N,N'-substituted piperazines according to claim 2, characterized in that as a reason to use the hydroxides or carbonates of alkali metals and their organic basis.

6. The method of obtaining N,N'-substituted piperazines according to claim 2 characterized in that the organic solvents used lower aliphatic alcohols, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dichloromethane or the x of the mixture.

7. N,N'-Substituted piperazines of General formula (II)

where R1, R2- linear or branched alkyl (C1÷C4), linear or branched alkoxy (C1-C4);
n=1-5; m=0-3; Z is C=O, SO2;
X - CH2(CHOH)CH2SO3H,
G - low molecular weight organic or mineral acid, sodium cations, potassium, ammonium or water.

8. The method of obtaining N,N'-substituted piperazines according to claim 7 by reacting N-substituted piperazines of General formula

where R1, R2- linear or branched alkyl (C1÷C4), linear or branched alkoxy (C1-C4);
n=1-5; m=0-3; Z is C=O, SO2;
2-hydroxy-3-chloropropanesulfonyl or its salts in organic solvents or water at a temperature of 10-100°C in the presence of bases.

9. The method of obtaining N,N'-substituted piperazines of claim 8, wherein the N-substituted piperazines use their hydrates.

10. The method of obtaining N,N'-substituted piperazines of claim 8, wherein the N-substituted piperazines using their salts.

11. The method of obtaining N,N'-substituted piperazines of claim 8, wherein as the organic solvents used lower aliphatic alcohols, acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl shall sulfoxide, dichloromethane, chloroform or mixtures thereof.

12. The method of obtaining N,N'-substituted piperazines of claim 8, characterized in that as a reason to use ammonia, sodium hydroxide, or potassium hydroxide, or sodium carbonate, or sodium bicarbonate, or potassium carbonate, or potassium bicarbonate.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: description is given of amides of piperazinyl- or piperidinylaminesulphoamic acid with genera formula (I) , in which R1 and R2 together with a nitrogen atom, to which they are bonded, represent a 6-member aliphatic heterocyclyl, containing two atoms of nitrogen as heteroatoms. The indicated extra atom of nitrogen is substituted with radical R, where R represents COOR', and R' represents (C1-C6)alkyl or benzyl, or phenyl, substituted with trifluoromethyl and aminocarbonyl, or R1 represents hydrogen, and R2 represents a group with formula , in which R9 represents (C1-C8)alkoxycarbonyl or phenyl, substituted with haloid(C1-C6)alkyl or aminocarbonyl; R3 represents phenyl or phenyl(C1-C4)alkyl, containing two substitutes, chosen from halogen and haloid(C1-C6)alkyl. Description is given of the use of formula (I) compounds as inhibitors of steroid sulphatase.

EFFECT: compound has inhibition effect to steroid sulphatase.

7 cl, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

FIELD: medicine.

SUBSTANCE: invention refers to a compound which represents a biphenyl derivative of formula . What is also described is a pharmaceutical composition for treating or relieving HCV on the basis of said compound.

EFFECT: higher efficacy of the composition.

3 cl, 265 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I) where Q represents a bond, CH-NR3 R4, NR5 or oxygen atom; X represents CH or nitrogen atom; Y represents a bond, CH2, oxygen atom or NR6; Z represents CH or nitrogen atom; R1, R2 represent, independently, hydrogen, halogen; R3, R4 represent, independently, hydrogen, (C1-C6)-alkyl; R5 represents hydrogen, (C1-C6)-alkyl, (CO)R7, SO2- (C1-C6)-alkyl or benzyl; R6 represents hydrogen, (C1-C6)-alkyl; R7 represents (C1-C6)-alkyl, phenyl, benzyl, OR8 or NR9R10; R8 represents (C1-C6)-alkyl; R9 represents hydrogen, (C1-C6)-alkyl; R9 represents hydrogen, (C1-C6)-alkyl; R11, R12 represent, independently, hydrogen or (C1-C6)-alkyl; and to their pharmaceutically acceptable salts; provided when X represents nitrogen atom, Y cannot represent oxygen atom or NR6; and except for the compounds (E)-N-hydroxy-3-(4-{(E)-3-[4-(4-methylpiperazine-1-yl)phenyl]-3-oxopropenyl}phenyl) acrylamide; (E)-N-hydroxy-3-{4-[(E)-3-(4-moropholine-4-ylphenyl)-3-oxopropenyl] phenyl}acrylamide; (E)-3-(3-flour-4-[(E)-3-(4-morpholine-4-ylphenyl)-3-oxopropenyl]phenyl}-N-hydroxyacrylamide. Also, the invention refers to a method for producing the compounds of formula (I), to a pharmaceutical composition, as well as to application of one or more compounds of formula (I), (la), (lb), (Ic).

EFFECT: producing new biologically active compounds which exhibit histone deacetylase inhibitor activity.

21 cl, 53 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula , where X is -O-; values of Ar, R1-R5, R11 are given in the formula of invention. The said compounds have inhibitory effect on HIV reverse transcriptase. The invention also relates to a pharmaceutical composition containing the invented compounds or their pharmaceutically acceptable salts.

EFFECT: obtaining new compounds and a pharmaceutical composition containing said compounds.

8 cl, 61 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of substituted N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein R represents methyl or mesyl, or its salt. Also, invention describes methods for synthesis of these compounds, pharmaceutical compositions containing thereof and their using for increasing activity of PDH in warm-blooded animal. Proposed compounds are useful in treatment of diabetes mellitus in warm-blooded animals.

EFFECT: valuable medicinal properties of compounds, improved methods for synthesis.

10 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with polar residues of the general formula (I):

wherein R means a polar residue; G means a trifunctional residue, a perfluorinated carbon chain; K means a metal complex; Z means a linker group. Proposed complexes can be used for intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis. Also, invention describes a method for synthesis of these complexes.

EFFECT: valuable medicinal properties of complexes.

16 cl, 1 tbl, 26 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention describes perfluoroalkyl-containing complexes with residues of sugars of the general formula (I): wherein R means mono- or oligosaccharide residue added through 1-OH- or 1-SH-position; Rf means perfluorinated carbon chain; K means the metal complex of the formula (II) wherein R1 means hydrogen atom (H) or equivalent of metal ion with order number 21-29 or 58-71 under condition that at least two radicals of R1 represent metal ions; R2 and R3 mean independently hydrogen atom (H), (C1-C6)-alkyl, benzyl, phenyl; U means the group C6H4-O-CH2-ω- or (C2-C8)-alkylene, or (C6-C9-C6H4-O-group optionally broken with one oxygen atom (O), 1,2-NHCO-groups or 1,2-CONH-group wherein ω means a point of addition to -CO-; Y and Z represent linker-groups useful for using in intravenous lymphography, tumor diagnosis and for visualization of infarctions and necrosis.

EFFECT: valuable medicinal properties of complexes.

11 cl, 1 tbl, 2 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely, to method of obtaining N,N,N1,N1-tetrasubstituted di[4-(aminomethylsulfanyl)]phenyl ethers of general formula (1): , which lies in the following: di-(4-sulfanyl)phenyl ether is subjected to interaction with water formaldehyde and secondary amines (N-benzylanilin, piperidine, morpholine) in presence of catalyst samarium nitrate crystallohydrate Sm(NO3)3·6H2O with mole ratio di-(4-sulfanyl)phenyl ether : CH2O : RR'NH : Sm(NO3)2·6H2O - 10 : 20 : 20 : (0.3-0.7), at room temperature (20°C) and atmospheric pressure for 0.5-1.5 h.

EFFECT: elaborated is method of obtaining said phenyl ethers, which can be applied as novel modified means for protection of plants against root rots and means, increasing productivity of crops.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining N,N-disubstituted N-{[alkyl(benzyl)sulfanyl]methyl} amines, which can be applied as novel modified means of plant ptotection against root rot and means, increasing productivity of crops. Essence of method lies in interaction of secondary amines of general formula RRNH with N,N-dimethyl-N-{[alkyl(benzyl)sulfanyl)methyl}- amines of general formula Me2N-CH2-SR' in presence of catalyst zinc chloride crystallohydrate ZnCl2-H2O at temperature 20 °C and atmospheric pressure in chloroform as solvent for 5-7 h. Output of N,N-disubstituted N-{[alkyl(benzyl)sulfanyl]methyl} amines is 82-98%.

EFFECT: increased output of suitable product.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amine compound of formula (I), pharmaceutically acceptable addition salts, hydrates or solvates thereof, having immunodepressive effect , where R - H or P(=O)(OH)2; X - O or S; Y denotes -CH2CH2- or -CH=CH-; Z denotes C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene; R1 denotes CF3, R2 denotes C1-4-alkyl, substituted with OH or halogen; R3 and R4 independently denotes H < or C1-4-alkyl; A denotes optionally substituted C6-10-aryl, heteroaryl containing 5-10 ring atoms, where 1 or 2 atoms are selected from N, O and S, C3-7-cycloalkyl optionally condensed with optionally substituted benzene, or heterocycloalkyl containing 5-7 ring atoms, where 1 or 2 atoms are selected from N and O, where said substitutes are selected from C1-4-alkylthio, C1-4-alkylsulphanyl, C1-4-alkylsulphonyl, C2-5-alkylcarbonyl, halogen, cyano, nitro, C3-7-cycloalkyl, C6-10-aryl, C7-14-aralkyloxy, C6-10-aryloxy, optionally substituted with oxo or halogen, C2-3-alkyleneoxy, C3-4-alkylene or C1-2-alkylenedioxy, optionally substituted with halogen C1-4-alkyl or C1-4-alkoxy.

EFFECT: novel compound which is effective in reducing the level of lymphocytes in peripheral blood, suppresses tissue breakdown and exhibiting less side effects, such as bradycardia, is disclosed.

20 cl, 237 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claimed invention described are phenoxiacetic acids of formula I: where X is selected from S and SCH2, X1 represents O, R1 represents C1-C6alkyl, R2 represents -C≡C-R2a, R2a represents C1-C4alkyl, substituted with morpholinyl, R3 is selected from chlorine and methyl, R4a represents H, R4b represents H, R4c represents H, R5a represents H, R5b represents H, R5c represents H, R5d represents H and R5e represents H, and pharmaceutical compositions containing them.

EFFECT: phenoxiacetic acids are PPAR-δ activators and can be used for treatment of mediated by them conditions.

6 cl, 48 ex

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