Gel-forming mixed dextran ester phosphates and carbamates, method for preparing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents gel-forming mixed dextran esters containing phosphate and carbamate groups of general formula: {C6H7O2(OH)3-x-y{[(OP(O)ONa)mONa)]xl[(O2P(O)ONa)k]x2}x(OCONH2)y}n, wherein x=x1+x2 is a degree of substitution in phosphate groups (mono- and diesters), x=0.47-1.09; X1 is a degree of substitution in monoesters, X1=0.01-0.48; m is a number of phosphates in monoesters, m=1-2; x2 is a degree of substitution in diesters, x2=0.01-1.09; k is a number of phosphates in diesters, k=1-2; y is a degree of substitution in carbamate groups, y=0.39-1.23; n is a degree of polymerisation, 20≥n≤1000.

EFFECT: invention provides producing low-toxic low- and high-substituted dextran phosphates in the form of hydrogels containing additionally carbamate groups and possessing antiproliferative activity with respect to cancer cells.

2 cl, 3 dwg, 14 ex

 

The invention relates to medicine, in particular to high-molecular compounds, specifically, esters of dextran containing phosphate and urethane groups, having biological activity and designed to create a prolonged medicines.

Dextran is a polysaccharide composed of glucopyranose units linked mainly by α-1,6 bond, and, to a lesser extent, α-1,2 and α-1,3 linkages. Dextran soluble in water, has biocompatibility and ability to biodegradation in the tissues of a living organism without toxic substances. It is known that the introduction of part of the acid functional groups of a certain type (sulfate, carboxyl, aldehyde, phosphate and others) tells him a set of additional physico-chemical and biomedical properties [1-9]. For example, [1], the dextran sulfate has anticoagulant activity, low toxicity and finds application in the clinic. In addition, it is known [2]that the dextran sulfate have antiproliferative activity against various viruses, and HIV infection. Unlike dextran sulfate synthesis and study of the biomedical properties of dextran phosphate devoted to a relatively small number of studies [3, 6-8]. In [3] describes a method of obtaining niscota imennyh phosphate dextran by the esterification of a solution of polyphosphoric acid in formamide and installed, the dextran phosphate (phosphorus content of 1.7%) has immunomodulatory activity and can induce immunomodulatory effects of interferon (IL - 10 and γ-IFN).

The dextran phosphate is a derivative of dextran, which by the esterification of a part of the hydroxyl groups of the polysaccharide substituted phosphate groups, mainly with the formation of mono - and diesters. The formation of diesters determines the cross-linking of dextran macromolecules, i.e. the possibility of obtaining not only in the form of solutions and hydrogels.

Obtaining hydrogels capable of absorbing significant amounts of water (or other liquid) and hold it without dissolution, is one of the most promising and rapidly developing areas in the chemistry of high molecular compounds. Hydrogels are used in the development of compositions for the manufacture of soft contact lenses, dosage forms with prolonged release of the active substance, transdermal therapeutic systems, sorbent materials for the manufacture of implants, etc. the reason for the wide and varied applications of hydrogels is their unique porous structure, providing a high rate of swelling in water, a high permeability for low - and high-molecular compounds, as well as good biocompatibility [10, 11].

The ratio of mono - and di is ameenah phosphate dextran depends on the type and composition of tarifitsiruemih mixture, the reaction conditions phosphorylation. The literature describes various methods of esterification of dextran. It is known [3, 7-9]that to obtain highly-substituted PCB phosphate dextran (degree of substitution of hydroxyl groups of phosphoric acid in one glucopyranose level equal to or greater than 0.8) is used, as a rule, highly toxic and corrosive reagents such as phosphorus oxychloride, phosphorus oxide (V). The use of less aggressive reagents, for example, phosphates of sodium or potassium polyphosphates, phosphoric, polyphosphoric acids, and others, contributes to obtaining nitrosamine phosphate dextran. Nitrosamine phosphates dextran obtained above methods are water-soluble compounds.

The prototype of the invention are mixed esters of starch in the form of hydrogels containing phosphate and urethane groups, the retrieval method [12, 13]. Received mixed esters of starch can be used as sorbents for water purification from polyserena cations of metals, such as thickening agents. The inclusion of urethane groups in the structure of the phosphate polysaccharide contributes to additional intermolecular interactions (hydrogen bonds, chemical crosslinking) and, as a consequence, obtaining products of the esterification reaction in the form of hydrogels in a wide range and the changes in the degree of substitution for phosphate groups. Known phosphorylation of starch is carried out with phosphoric acid in the molten urea at a temperature of 110-140°C. under a vacuum of 0.01 to 0.13 ATM) for 1-3 hours. After cooling, to the reaction mass add distilled water to swell the obtained hydrogels, washed 3 times with a solution of methanol (80%solution), dried under vacuum at 50°C for three hours.

This method cannot be used to produce hydrogels phosphate dextran for the following reasons:

- intensively flowing the process of degradation of dextran leads to the production of phosphate esters dark in colour only in the form of viscous solutions;

the unsuitability of this method of esterification to obtain hydrogels polysaccharides having a low degree of polymerization.

The task of the invention to provide a low-toxicity low - and highly-substituted PCB phosphate dextran in the form of hydrogels, additionally containing urethane groups and exhibiting antitumor activity.

The problem is solved by the fact that as low-toxic anticancer molecular compound proposed ethers of dextran containing phosphate and urethane groups according to the formula:

{C6H7O2(OH)3-x-y{[(OP(O)ONa)m(ONa)]x1[(O2P(O)ONa)k x2}x(OCONH2)y}nwhere

x=x1+x2the degree of substitution for phosphate groups (mono - and diesters), x=0,47-1,09;

x1the degree of substitution on monoethers, x1=from 0.01 to 0.48;

x2the degree of substitution on the diesters, x2=0,01-1,09;

m is the number of phosphates in monoufia, m=1-2;

k is the number of phosphate diesters, k=1-2;

y is the degree of substitution by urethane groups, y=0,39-1,23;

n is the degree of polymerization, 20≥n≤1000.

The method of producing dextran phosphate, including phosphorylation of dextran orthophosphoric acid in the melt of urea at 110-140°C. and residual pressure, adding water until pasty state of the reaction mixture followed by washing and drying of the final product, characterized in that the source dextran before modification optionally dried, the phosphorylation is carried out at a higher residual pressure of 0,05-0,27 ATM with subsequent treatment of the reaction mixture of 0.75 M solution of sodium chloride in 70%ethanol solution, bringing the pH of the solution to values of 11.0 to 12.0, obtained by washing the precipitate with 70%ethanol solution.

Method of obtaining esters of dextran containing phosphate and urethane groups, compared with the method of [13] modified as follows:

for primary education diphosphonates ethers of dextran and is Holocene products in the form of hydrogels source dextran before the esterification reaction is dried at 50°C. and residual pressure of 0.1 ATM for 5-16 hours;

- phosphorylation of dextran orthophosphoric acid in the urea melt is carried out at a residual pressure of 0,05-0,27 ATM. This option phosphorylation process has a significant influence on the yield of dextran phosphate in the form of gel-fraction. At a residual pressure of 0.5 ATM output of gel-fraction is significantly reduced (about 2 times). At atmospheric pressure can be obtained only nitrosamine water-soluble samples of phosphate dextran;

to replace the toxic solvent (methanol) in the process of leaching of phosphates dextran, reducing its period, and receive the Na-form phosphate esters product modification after cooling the reaction mass, adding distilled water precipitated 0,75M solution of sodium chloride in a mixture of ethanol - water (70%solution), the pH is increased by a solution of sodium hydroxide to a value of 11.0 to 12.0. The precipitate is washed in to conventional Soxhlet extractions 70%ethanol solution and dried at 50°C. in a vacuum Cabinet at a residual pressure of 0.1 ATM.

As starting material for obtaining the claimed compounds are used dextran with a molecular weight in the range 40-1000 kDa.

The method allows to obtain low-toxic gel-forming phosphates dextran with antitumor activity. If the pH of the swollen hydrogels content is designed in the range of 7.2 to 7.4, which corresponds to the pH of the blood.

The output products of the reaction, calculated from theoretically possible, quantitative.

The invention is illustrated by the figures, tables, examples.

Figure 1. Electron micrographs of pellets source (1) and phosphate (2, 3) dextrans: 2 - SzP=0,48, NWN=0,42; 3 - NWP=0,68, NWN=0,47.

Figure 2. The dependence of the amount of absorbed water, 1 g of dextran phosphate (SzP=1,09; SzN=1,23) time (Q, g/g).

Figure 3. Dynamics of growth of Sarcoma M-1 (V, cm3) in rats in the control and after intraperitoneal administration of dextran phosphate (SzP=0,48, NWN=0,42) at a dose of 2.0 g/kg

Example 1. To 20 g of pre-dried at 50°C. and residual pressure of 0.1 ATM for 16 hours dextran (Mw=40000 Da) with constant stirring add 29,76 g of urea (CHP) and 5.2 ml of 85% orthophosphoric acid. The molar ratio of d-anhydroglucose link (GTF): orthophosphoric acid (H2RHO4): urea [(NH2)2CO] is 1.0:0,6:4,0. Maintained at a temperature of 125°C. and a residual pressure of 0.06 to 0.25 psi for 3 hours after the phosphorylation reaction, the reaction mixture was cooled to room temperature. Then add distilled water to produce a pasty mass, poured 400 ml (module baths (g/ml) - 1:20) solution of NaCl (30 g per 1 l of a solution of 70% ethanol, pH to the who adjusted with sodium hydroxide to a value of 11.5) and leave at room temperature for 24 hours The precipitation is washed to conventional Soxhlet extractions 70%ethanol, dried at 50°C in a vacuum Cabinet at a residual pressure of 0.1 ATM. The output of gel-fraction 96.7%. The phosphorus content in the obtained sample is 7.0%, nitrogen is 2.7%. The degree of substitution for phosphate groups (soPequal 0,49; urethane groups (soN) at 0.42. The amount of absorbed water, 1 g of dextran phosphate - 174,6 g/g

Examples 2-14. Samples of phosphate dextran get analogously to example 1 at different process parameters. Conditions for the exercise of phosphorylation for all examples shown in table 1.

Samples of phosphate dextran obtained in accordance with examples 1 to 14, characterized by the content of phosphate and urethane groups, structural features, degree of swelling, acid-base properties methods of elemental analysis, IR spectroscopy, scanning electron microscopy, potentiometric titration [15].

Elemental analysis. The content of phosphate groups in samples of phosphate dextran determined by the spectrophotometric method [14], nitrogen - method celdas [15].

The compounds are characterized by the degree of substitution for phosphate (SzP) and urethane (soNgroups (number of phosphate or urethane groups per EN itroglycerin link (GTF) polysaccharide). The data obtained are shown in table 1.

IR-spectroscopy. The IR spectrum of the claimed compounds is visible absorption band near 790 cm-1(nelokalnye deformation of groups R-O-R), the shoulder near 950 cm-1the absorption band near 1020 cm-1(stretching vibrations of groups R-O-p and P-On-N), the shoulder near 1210 cm-1(stretching vibrations of the phosphoryl group (P=O), indicating the formation of phosphate groups. In the IR spectra of all samples dextran, esterified orthophosphoric acid in the melt of urea, there is intense absorption band near 1720 cm-1due to asymmetric stretching vibrations of the relations C=O urethane groups. With increasing degree of esterification these spectral changes are amplified.

Scanning electron microscopy. The result of phosphorylation (figure 1) granules of dextran dissolved in uniform in length and width pieces that have a loose, porous structure (the size of micropores in the range of 2 to 10 nm). Increasing the concentration of phosphoric acid in tarifitsiruemih mixture contributes to the gradual compaction of the structure of dextran, increase the size of the fragments and the disappearance of micropores.

Absorptivity. Absorptivity (Q, g/is) is determined by gravimetric method and calculated by the formula:

,

where Q is the absorptivity (Q, g/g);

m1is the mass of swollen in water sample, g;

m2- weight of the sample dried to constant weight,

Hydrogels dextran phosphate is separated from the excess water by centrifugation on a glass filter with a pore size of 160 μm when the centrifugal force 2400 g. Drying to constant weight is carried out in the presence of phosphorus oxide (V) at 50°C, the residual pressure of 0.1 ATM.

The absorptivity values of hydrogels based on phosphates dextran are shown in table 1 and figure 2.

The obtained hydrogels phosphate dextran are characterized by a high rate of water absorption: water absorption of hydrogels with different content of phosphate and urethane groups reaches its maximum value in less than 5 minutes and followed over time practically does not change (figure 2) - for example phosphate with Mm 60 kDa (soP=1,09; SzN=1,23).

Potentiometric titration. From table 2 it follows that

Table 2
The results of potentiometric titration of hydrogels based on dextran phosphate
SzPSzNData of potentiometric titration
OE1, mEq/gOYe, mEq/gpK1pK2
10,480,421,53,22,97,0
20,780,831,91,93,1-
31,091,231,31,33,0-

the resulting dextran phosphate have full exchange capacity in the range of 1.3 to 3.2 mEq/g According to the values of the apparent ionization constants (pK1and PK2in the composition of the phosphates dextran has one or two acidic functional groups, which dissociate mainly in the field of pH 1.8 to 5.4 and 5,0-9,0.

The study of the acute toxicity of hydrogels phosphate polysaccharides n vivo. Determination of acute toxicity of hydrogels FD was conducted on rats (each series of 4 rats weighing 200-250 g). The animals were introduced 10 g of 50% hydrogel intraperitoneally. Established (table 3), phosphates dextran belong to the class of low-toxic substances.

Table 3
Acute toxicity of hydrogels phosphate dextran
PolysaccharideSzPC3NLD50
Dextran (Mw=60 000)1,091,22~5000 mg/g
Dextran (Mw=500 000)0,851,16>5000 mg/g

Evaluation of antitumor activity of hydrogels phosphate dextran. Comparative study of the antitumor activity of the proposed phosphate dextran conducted in vitro and in vivo.

The study of antitumor activity of hydrogels dextran phosphate in vitro.

Evaluation of the antitumor effect of hydrogels based on phosphates dextran was performed on monolayer culture of tumor cleto is Hela (epithelioma carcinoma of the cervix person, clone M) by comparing the number of surviving cells from their original number before exposure phosphate dextran.

The decrease in the number of cells (N) after exposure to the claimed compounds below the reference level indicates the predominance of cytotoxic effect, while a higher source, but less control about the prevalence of the cytotoxic effect. The performance indicator of antitumor activity of hydrogels IR50(concentration causing inhibition of proliferation by 50%) was calculated by regression analysis of the obtained data. Statistical processing of the obtained results was performed using the program Origin 7.

The results are presented in table 4. It is seen that with increasing content of phosphate groups in the dextran ability of the inventive esters to inhibit the proliferation of tumor cells increases. Cytotoxic activity of the investigated compounds is dose-dependent.

The study of antitumor activity in vivo. The effectiveness of antitumor action of hydrogels based on phosphates of dextran in vivo was tested on white outbred rats of both sexes (16 animals), which subcutaneously in the area of the left thigh transplanted sarcoma M-1.

For 7-10 days after inoculation of the tumor rats intraperitoneally once (dose of 2000 mg/kg) was injected hydrogel phosphate dextran. Measuring the size of the tumors in the control and experimental groups was carried out 3 times per week, and tumor volume (V, cm3) was calculated by the formula Shrek:

V=(a×b×c)×π/6, where a, b, and C are the linear dimensions of the tumor (cm).

The inhibition of tumor growth was determined by the formula:

(Vcp.(Control)-Vav.(Experience))/Vav.(Control)

The results (figure 3) identify the antitumor activity of the claimed compounds. Two days after injection of dextran phosphate, the difference in the growth rate of tumor cells experienced party compared to the control becomes apparent; for 7 days - tumor volume compared with control reduced by approximately two times.

Thus, modification of dextran mixture of orthophosphoric acid and urea leads to the formation of toxic compounds with antitumor activity. The claimed connection provides compared with dextran and existing phosphate Dec the Tran the following benefits:

connection can be obtained in the form of hydrogels in a wide range of changes in the content of phosphate groups and the molecular weight of the dextran;

the hydrogels based on phosphates dextran have high rate of swelling;

- when getting used relatively non-toxic reagents that makes a stage of purification of the target product more simple and economical.

The proposed phosphate dextran can be obtained in terms of the companies producing chemicals and pharmaceuticals.

SOURCES of INFORMATION

1. WO Pat. 90/04970, MKI 5 AC 31/725, 1990.

2. Baba M., Pauwells R., Balzarini J., Arnout J., Desmyter J. at al. Mechanism of ingibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro. Proceeding of the National Academy of the United States of America. 1988. Vol.85. P.6132-6136.

3. US Pat. 20060154896, MKI AC 31/721, 2006.

4. US Pat. 6303148, MKI AC 9/16, A61K 9/14, 2001.

5. US Pat. 4847091, MKI AC 9/66, 1989.

6. Suzuki M., Mikami T., Malsumoto T., Suzuki S. Preparation and antitumor activity of o-palmitoyldextran phosphate, o-palmitoyldextrans and dextran phosphate. Carbohydrate Reseach. 1977. Vol.53. P.223-229.

7. US Pat. 2970141, MKI SR 19/08, C12P 19/00, 1961.

8. Kirci Century, Kaplan H., Rzaev Z.M., Guner A. Preparation conditions and swelling equilibria of dextran hydrogels prepared by some crosslinking agents. Polymer. 2004. Vol.45. P.6431-6435.

9. Whistler R.L., Towie G.A. Preparation and characterization of polysaccharide phosphates. Achives of biochemistry and biophysics. 1969. Vol.13. P.396-401.

10. European Pat. 1 184 032, MKI AC 9/16; SV 37/00; 2002.

11. Nakamae, K., Miyata T., Hoffman A.S. // Makromol. Chem. 1992. V.193. # 4. P.983-990.

12. Peters, U., D. Klemm, Under E., F. Piesher New starch Phosphate Carbamides of High Swelling Ability: Syntesis and Characterization // Starch/ blitz chess 2003. V.55. P.55-60.

13. US Pat. 6703496 B1, MKI C08B 31/00; C08B 31/06; C08B 33/00; C08B 33/02; C08B 35/00; 2004.

14. Colorimetric (photometric) methods for the determination of nonmetals: TRANS. from English. ed Aiyaa. M.: IL, 1963. 260 C.

15. Houben-Weyl. Methods of organic chemistry. - M.: Goskomizdat, 1963. 468 C.

1. Gelling mixed ethers of dextran containing phosphate and urethane groups, of General formula: {C6H7O2(OH)3-x-y{[(OP(O)ONa)mONa)]x1[(O2P(O)ONa)k]x2}x(OCONH2)y}nwhere x=x1+x2the degree of substitution for phosphate groups (mono - and diesters), x=0,47-1,09;
x1the degree of substitution on monoethers, x=0.01 to 0,48;
m is the number of phosphates in monoufia, m=1-2;
x2the degree of substitution on the diesters, x=0.01 to 1,09;
k is the number of phosphate diesters, k=1-2;
the y - degree of substitution by urethane groups, y=0,39-1,23;
n is the degree of polymerization, 20≤n≤1000, with antiproliferative activity toward tumor cells.

2. The method of producing dextran phosphate according to claim 1, including phosphorylation of dextran orthophosphoric acid in the melt of urea at 110-140°C. and residual pressure, adding water until pasty state of the reaction mixture followed by washing and drying of the final product, characterized in that Thu is the original dextran before the modification additionally dried, the phosphorylation is carried out at a higher residual pressure of 0,05-0,27 ATM with subsequent treatment of the reaction mixture to 0,75M solution of sodium chloride in 70%ethanol solution, bringing the pH of the solution to values of 11.0 to 12.0, obtained by washing the precipitate with 70%ethanol solution.



 

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67 cl, 106 ex, 2 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmacy and represents microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA), polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; copolymer or simple mixture of two or more polymers, selected from said group of polymers; copolymer of said polymer and polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound with said polymer or said copolymer, covering material is selected from group, consisting of essential amino acids, polypeptides and organic nitrogenous compounds, essential amino acid being one or more, selected from group, consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group, consisting of creatine, creatinine and urea, content of covering layer constitutes from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.

EFFECT: invention ensures increase of bioaccessability and reduction of initial peak of exendin for prevention of such side effects as vomiting, nausea, headache.

10 cl, 7 ex, 5 tbl, 7 dwg

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