Inositolglicana with insulin-like action, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to new ansicompliant with insulin action formula I, where a denotes N-P(O)(OH)-, H-P(S)(OH)-, HO-P(S)(OH)-, S(O)2(OR1)-, or NH2-C(O)-, where R1denotes a hydrogen atom or (C1-C4)-alkyl, Z represents 2 to 6 sugar residues from the group of: mannose, glucose, gluconic acid, Galaktionova acid, mononova acid, glucosamine, fructose or galactose or 2 to 6 sugar residues of a group specified for Z replaced by one-six independently of each other stands, mannose, glucosamine, dumanoski or mannose-glucosamine, and glycosidic bond both sugars mannose and glucosamine is between C-atoms, 1-3, 1-2 or 1 to 6, both sugars, and R denotes Inositol, inositols, Invitational, insatallation or inositoltrifosfata. Also disclosed is a method of obtaining these compounds, farmacevticheskaja composition and a method of obtaining a pharmaceutical kompozizii. The invention can be used for the treatment of diabetes. 4 C. and 5 C. p. F.-ly, 2 PL.

A-Z-R (I)

The invention relates to ansicompliant having insulin-like action, which also shows the formation of low molecular weight compounds, with an insulin-like action (US 4446064). Already a number of connections insatalling expressing insulin-like action (WO 96/14075, JP 6/293790, JP 4/120089).

Diabetes of the 2nd type, non-insulin-dependent diabetes, is accompanied by insulin resistance of peripheral tissues, such as muscle or fat tissue. This caused the decreased use of glucose due to the missing insulin stimulation of glucose transport and subsequent metabolism.

When searching for other effective compounds having insulin-like action, it was found that the compounds according to the invention exhibit in vitro insulin action, have a nice stable serum, have on insulinorezistentne tissue insulin action and thus suitable for the treatment of diabetes.

The invention therefore relates to having insulin-like action of ansicompliant formula I

A-Z-R (I)

and/or physiologically acceptable salts of the compounds of formula I and/or stereoisomeric forms of the compounds of formula I, with

And indicates the balance

1) N-P(O) (OH)-,

2) H-P(S)(OH)-,

3) HO-P(S)(OH)-,

4) HS-P(S)(OH)-,

5) (C1-)-,

9) NH2-C(O)-,

10) R1R2N-,

11) R1R2N-C(O) -NH-,

12) R1O-SO2-NH-,

13) (C1-C4)-alkyl-SO2-,

14) (C1-C4)-alkyl-S(O)- or

15) R1-S-

where R1and R2independently from each other represent a hydrogen atom or (C1-C4)-alkyl,

Z denotes

1) 2 to 6 sugar residues,

2) 2 to 6 sugar residues from one - to six-times substituted independently of one another

2.1 the stands,

2.2 sugar balance,

2.3 descharnes balance,

2.4-SO2-OH,

2.5-C(O)-NR1R2,

2.6-C(O)-(C1-C4)-alkyl,

2.7-P(O)(H)HE,

2.8-P(O)(OH)2,

2.9-P(S) (H)OH,

2.10-P(S)(OH)2,

2.11-P(S)(SH)(OH),

2.12-P(O)(OH)-O-CH2-CH2-NR1R2or

2.13 glycosidic bond between 2-6-Tue sugar residues substituted one-six-CH2- or-S-, and where R1and R2independently from each other represent a hydrogen atom or (C1-C4)-alkyl,

R stands for

1) Inositol,

2) inositols,

3) Invitational,

4) inositoltrifosfata,

5) insatallation,

6) the rest of the group defined in the PP. R 2)-5), someseni uppy, defined in the PP. R 2)to (5), substituted once

7.1 cyclophosphate residue or

7.2 cyclotriphosphazene balance, or

8) Inositol, two neighboring Oh group substituted

8.1 group-CH2-SO2-NH-.

Preferred compounds of formula I, characterized in that

And does

1) N-P(O) (OH)-,

2) S(O)2(PR1), or

3) NH2-C(O)-,

Z denotes

1) 2 to 6 sugar residues from the group

1.1 mannose,

1.2 glucose,

1.3 gluconic acid,

1.4 Galaktionova acid,

1.5 mononova acid,

1.6 glucosamine

1.7 fructose or

1.8 galactose or

2) 2-6 sugar residue from a group defined in the PP. Z 1.1-1.8, replaced by one-six times independently from each other

2.1 the stands,

2.2 mannose,

2.3 glucosamine,

2.4 diminati or

2.5 mannose-glucosamine and glycosidic bond both sugars mannose and glucosamine lies between the C-atoms in position 1-3, 1-2, or 1 to 6, both sugars, and

R stands for

1) Inositol,

2) inositols,

3) Invitational,

4) insatallation or

5) inositoltrifosfata.

Especially preferred compounds of formula I differ is whether

1.2 glucosamine or

2) 2-4 sugar residue from a group

2.1 mannose or

2.2 glucosamine, once substituted mannose, and

R stands for

1) Inositol,

2) inositols or

3) inositoltrifosfata.

Under the remnants of sugars are understood to be compounds derived from aldos and ketosis with 3-7 carbon atoms, which may belong to D - or L-series; these include the amino sugar or uronic acid. As an example, should be called glucose, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, Galaktionova acid or mononofu acid.

Under descharme mean sugars, consisting of two sugar units. Tri-, Tetra-, Penta - or hexacore are formed as a result azathioprine communication 3-6 sugars. Communication may be established or form. Communication between the sugars are preferably formed through the C-atom 1 and atom 6 atom 1 and atom 2 and atom 1 and atom 4 of the respective sugars. Between sugars preferred form of communication.

The relationship between a and Z is, for example, through one of the oxygen attackof And 10)-12) preferably takes place via a carbon atom of Z, other relationships And is preferably via an oxygen atom z

The coupling between R and Z is analogous relations di-, tri-, Tetra-, Penta - or hexachrome. Next, the relationship between R and Z may be single - or multi-substituted with-CH2-or-S-.

If sugar is substituted, the substitution is preferably the hydrogen atom of the Oh-group of sugar.

The term "insulin resistant fabric" includes, for example, fat cells of rats, which do not have the insulin receptor.

Compounds according to the invention can contain one or more phosphate groups, which can be derivationally also posparotiditis group. Fosfataza.mestnye groups are, for example, phenyl, benzyl or hydroxypropionitrile (Houben Weyl, Methods der Organischen Chemie, Band 12/1 or Band 12/2; Teilheimer, Synthetic Methods of Organic Chemistry, Vol 45).

Under physiologically acceptable salts of the compounds of formula I it should be understood, in particular, pharmaceutically suitable or non-toxic salts. Such salts are formed, for example, the compounds of formula I containing an acid group, for example, phosphates or sulfates, alkali or alkaline earth metals such as Na, K, mg, and CA, and also with physiologically tolerated organic is s, for example, an amino group, form salts with inorganic acids such as hydrochloric, sulphuric or phosphoric acids, and with organic carboxylic or sulphonic acids such as acetic, citric, benzoic, maleic, fumaric, tartaric acid and p-toluensulfonate. Connections basic and acidic groups are present in equal numbers form inner salts and do not require third salt component.

The invention further relates to a method for obtaining compounds of formula I, characterized in that inositolglicana synthesize Paladino of protected sugar or inositols predecessors, then append the rest and from the resulting connection otscheplaut one or more protective groups temporarily introduced to protect other functions, and thus obtained the compound of the formula I, if necessary, transferred to its physiologically acceptable salt.

Synthesis of sugars from di - to polysaccharides is carried out by known methods (N. Paulsen, Angew. Chem. Int. Ed. 21 (1982) S. 155). For the synthesis of oligosaccharides preferably used trichloroacetimidate method (R. R. Schmidt, Angew. Chem. Int. Ed. 25 (1986) 212-235; T. Ogawa, Tetrahedron Lett. 31 (1990) 2439-2442).

Synthesis of phosphate Seiten 737-752).

As protective groups for hydroxyl groups in sugars consider mainly the following protective groups: benzyl, acetyl, benzoline, bialoleka, triticina, tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylidene.

The compounds of formula I and their physiologically acceptable salts are, first and foremost, as biologically active substances for farmacevticheskih drugs for the treatment of diabetes mellitus or non-insulin-dependent diabetes.

Therefore, the object of the invention is also a pharmaceutical composition which contains at least one compound of the formula I and/or at least one of its pharmaceutically acceptable salts in dissolved, amorphous and/or crystalline, preferably in amorphous and/or crystalline form.

The pharmaceutical composition is preferably a solution or suspension for injection with a pH of about 3.0 to 9.0, preferably approximately from 5.0 to 8.5, containing a suitable isotherwise tool, a suitable stabilizing agent and, if necessary, a suitable buffer, and, if necessary, an extended action, su is cally active substances, forms the carrier of the composition. Suitable isotherwise means are, for example, glycerol, glucose, mannitol, NaCl, calcium or magnesium, such as SAS2or MDS2. Suitable stabilizing means are, for example, phenol, m-cresol, benzyl alcohol and/or ether p-hydroxybenzoic acid.

As a buffer, in particular to bring the pH to a value of approximately from 5.0 to 8.5, you can apply sodium acetate, sodium citrate or sodium phosphate. In addition, for regulating the pH is also suitable physiologically acceptable diluted acid (usually model HC1) or alkali (usually NaOH).

To variations in the direction of action of the composition according to the invention can be modified mixed (compare EP-132769 and EP-132770) and/or unmodified insulin, as a rule, bovine, porcine or human insulin, in particular human insulin.

The pharmaceutical composition was prepared by placing at least one compound of the formula I and/or at least one of its physiologically acceptable salts, if necessary, together with modified and/or unmodified insulin (derived insulin), with physiologically, into a suitable dosage form.

Below the invention is explained in more detail by the following examples.

EXAMPLE 1

Receiving a connection

(The method of synthesis described in scheme at the end of the description).

Synthesis of compound 3

60 g (94 mmol) of 1 (T. G. Mayer, B. Kratzer, R. R. Schmidt, Angew. Chem. 106 (1994) 2289-93) and 21.2 g (42,4 mmol) 2 (A. Termin, R. R. Schmidt, Liebigs Ann. Chem. (1989) 789-795) dissolved in 200 ml of dry methylene chloride and 400 ml of dry n-heptane. After adding 70 g of dry molecular sieve (0.4 nm) is stirred for 15 min at room temperature. Then add 5 ml of 0.05 M trimethylsilyltrifluoroacetamide in methylene chloride (hereinafter designated as the solution of the catalyst). After 15 minutes add 300 ml of a mixture of n-heptane with ethyl acetate (1: 1) and filtered through silica gel. Washed with a mixture of n-heptane with ethyl acetate (1: 1) and then concentrated. After purification using flash chromatography receive 41,0 g (99%) of 3 as a colorless oil. Thin layer chromatography: n-heptane/ethyl acetate (1: 1), Rfor = 0.6, MS: (M+Li)+= 981,1 calculated C55H67N3O11Si, M= 974,21.

Synthesis of imidate 4

41 g (42.0 mmol) of 3 was dissolved in 400 ml of tetrahydrofuran (THF) and 9 ml of acetic acid. After adding 70 ml of 1 M solution of TBAF/THF in the UP>oC) and the filtrate after concentration purified by flash chromatography. Output: 34,1 g (94%) connection with the removed protection. The compound obtained is dissolved in 300 ml of dry methylene chloride. After adding 50 ml of trichloroacetonitrile and 20 g of potassium carbonate is stirred for 4 hours at room temperature. Filtered through silica gel, washed with a mixture of n-heptane with ethyl acetate (1: 1) and concentrate. Crude yield: 42,1, Thin-layer chromatography: n-heptane/ethyl acetate (2: 1): Rf= 0,5.1H-NMR (CDCl3): characteristic signals for imidate; == 8,78 for NH and 5.63 for anomers (-imidate).

Synthesis of trisaccharide 6

the 33.2 g (33.0 mmol) of 4 and 13.3 g (25,0 mmol) 5 (R. Aneja, S. G. Aneja, A. Parra, Tetrahedron, Asymmetry 6 (1995) 17-18; C. J. J. Elie, R. Verduyn, C. E. Dreef, D. M. Braunts, G. A. Van der Marel, J. H. Van Boom, Tetrahedron, 46 (1990) 8243-54) is dissolved in 120 ml of dry methylene chloride and 360 ml of dry n-heptane. After adding 100 g of molecular sieves was stirred for 15 min at room temperature. Cooled in an argon atmosphere at -20oC and then mixed with 20 ml of catalyst. After 30 min left to thaw to room temperature. To clean filtered through silica gel and washed with a mixture of n-heptane with ethyl acetate (1: 1). Concentrate and raw Prout 16 h at room temperature. The solution is mixed with 1 ml of water and concentrate. The oil obtained is dissolved in 50 ml of ethyl acetate, diluted with 200 ml of a mixture of n-heptane/ethyl acetate (1: 1) and filtered through silica gel. After concentrating purified by flash chromatography. Output: 32,5 g (97%) of a white foam as a mixture of anomers. Thin layer chromatography: n-heptane/ethyl acetate (2: 1), Rf= 0,5. MS: (M+Li)+= 1336,7; calculated C80H87N3O15M= 1330,59.

Synthesis of trisaccharide 7

A mixture of anomers 6 can be easily separated chromatographic only in the form of a derivative 7. 32,4 g (24.4 mmol) of 6 was dissolved in 200 ml of methylene chloride. After adding 500 ml of 0.5 M HCl/MeOH (from 17.5 ml As 500 ml Meon) and 20 ml of ethylene glycol leave for 17 h to stand at room temperature. After concentrating purified by flash chromatography. The resulting product (26,9 g, 88%) was dissolved in 300 ml of methylene chloride. Add 3.0 g of imidazole and 4.6 g TBDMSCI. After 16 hours at room temperature, diluted with 500 ml of a mixture of n-heptane with ethyl acetate (2: 1) and filtered through silica gel. Washed with a mixture of n-heptane with ethyl acetate (2: 1) and concentrate. The resulting crude product was then purified by flash chromatography. Output: 21.1 g (72%) 7 and 6.3 g (22%) alpha product.SUP>+= 1370,6; calculated: C80H93N3O15Si, M= 1364,71.

Synthesis of trisaccharide 8

of 21.2 g (of 15.5 mmol) 7 dissolved in 60 ml of methylene chloride and 180 ml of dimethoxypropane. Add 250 mg of TsOH and incubated for 1 hour at room temperature. After adding 2 ml of triethylamine concentrate and obtain 23.1 g of crude product. The latter is dissolved in 150 ml HF and mixed with 30 ml of 1 m solution of TBAF/THF. After 16 hours, concentrated and purified by flash chromatography. Output: 20,0 g (99%) of 8 as a white foam. Thin layer chromatography: n-heptane/ethyl acetate (2: 1), Rf= 0,4. MS: (M+Li)+= 1296,7; calculated C77H83N3O15M= 1290,51.

Synthesis of tetrasaccharide 10

20 g (15,4 mmol) of 8 and 15.0 g (23.5 mmol) of 9 (T. G. Mayer, B. Kratzer, R. R. Schmidt, Angew. Chem. 106 (1994) 2289-93) is subjected to interaction similar to that described for compounds 6 and get a 20.3 g (76%) tetrasaccharide 10 in the form of a white foam. Thin layer chromatography: n-heptane/ethyl acetate (2: 1), Rfor = 0.6, MS: (M+Li)+= 1770 calculated C107H115N3O20M= 1763,09.

Synthesis of pentasaccharide 12

of 20.3 g (to 11.8 mmol) of 10 and 12.0 g (20.3 mmol) 11 (T. G. Mayer, B. Kratzer, R. R. Schmidt, Angew. Chem. 106 (1994) 2289-93) is subjected to interaction similar to that described for compounds 6 and get to 19.4 g (ASALA. Add 6.0 g (40.0 mmol) and TBDMSCI stirred for 15 h at room temperature. After adding 5 ml of methanol stand 10 minutes, then diluted with 200 ml of a mixture of n-heptane with ethyl acetate (1: 1) and filtered through silica gel. Then washed with a mixture of n-heptane with ethyl acetate (1: 1), concentrated and purified by flash chromatography. Output: 19,4 g (95%) of 12 as a white foam. Thin layer chromatography: n-heptane/ethyl acetate (2: 1), Rf= 0,7, MS: (M+Li)+= 2226 calculated WITH133H151N3O25Si, M= 2219,75.

Synthesis of hexasaccharide 14

of 19.4 g (8.9 mmol) of 12 and 14.0 g (20.0 mmol) 13 (T. G. Mowag, C. Kratzer, R. R. Schmidt, Angew. Chem. 106 (1994) 2289-93) dissolved in 100 ml dry methylene chloride and 300 ml of dry n-heptane. After adding 40 g of molecular sieve (0.4 nm) is stirred for 15 min at room temperature. Add 10 ml of the catalyst solution and stirred for 15 minutes To clean filtered through silica gel and washed with a mixture of n-heptane with ethyl acetate (1: 1). Concentrate and obtain 33 g of crude product. The latter is dissolved in 200 ml of methylene chloride and mixed with 500 ml of 0.5 M solution of model HC1 in methanol. After 2 hours at room temperature, concentrated and re-concentrating the methylene chloride. Received PR is After 16 hour cleanse is similar to the connection 12. Yield: 20.2 g (85%) of 14 as a white foam. Thin layer chromatography: n-heptane/ethyl acetate (2: 1), Rf= 0,3, MS: (M+Li)+= 2669; calculated WITH161H177N3O30Si, M= 2662,26.

Synthesis of compound 15

30.0 g of triazole are dissolved in 800 ml of dry THF. At 10oWith added dropwise to 13.5 ml of phosphorus oxychloride. Then added dropwise 60 ml of triethylamine and stirred for 15 min at room temperature. The precipitate is filtered off and washed with a small amount of dry THF. The filtrate is added to 19.1 g (7.2 mmol) 14. The solution is concentrated to 100 ml After 15 min, diluted with ethyl acetate (500 ml) and washed twice with water (100 ml water). The organic phase is dried over magnesium sulfate, filtered and concentrated. After flash chromatography receive 19,0 g (97%) of the cyclic phosphate derivative as a white foam. Thin layer chromatography: methylene chloride/methanol/33% NH3(100/7/1), Rf= 0,3, MS: (M+2Li-H)+= 2737 calculated C161H174N3O32PSi, M= 2724,22. The cyclic phosphate is dissolved in 350 ml of THF and add 100 ml of TBAF (1 M in THF). After 20 hours, concentrated and the residue purified by flash chromatography. Output: 18,1 g (99%) of 15 as a white foam. Thin layer chromatography: methylene chloride/methanol/33% NH3(100/7/1,96.

Synthesis of compound 16

14 g of phosphorous acid four times concentrate pyridine and then absorb in 200 ml dry pyridine. At 10oWith added dropwise 16 ml of pivaloate. This reaction solution was incubated for 15 minutes at room temperature. In the above reaction solution is injected to 18.1 g (6,9 mmol) 15. After 1 hour, diluted with 200 ml of toluene and 150 ml of a mixture of methylene chloride/methanol/33% NH3(30/10/3). After concentration three times distilled with toluene residual pyridine. The residue is suspended in 200 ml of a mixture of methylene chloride/methanol (20: 1). Undissolved components are filtered off and washed twice with 50 ml of a mixture of methylene chloride and methanol (20: 1). The filtrate is concentrated and purified by flash chromatography. Output: 16,9 g (91%) protected the target product. Thin layer chromatography: methylene chloride/Metha-Nol/33% NH3(100/7/1), Rf= 0,25. MS: (M+3Li-2H)+= 2691 calculated WITH155H163N3O34P2M= 2673,94. To unprotect condense 600 ml of ammonia at -78oC. Dissolve them in 4.7 g (204 mmol) of sodium. This solution was diluted with dry THF (300 ml) and then at a temperature of -78 reactionoWith him slowly added dropwise to 16.9 g (6.3 mmol) of the protected target product melts with 10 g of ammonium chloride. If the blue color disappears, then carefully diluted with 100 ml of water and 300 ml of methanol. Thawed and then concentrated to approximately 150 ml of This solution was diluted with two liters (2 liters) a mixture of methylene chloride/methanol/33% NH3(3/3/1) and served on a flash chromatography column (700 ml silica gel). Then elute three liters (3 l) mixture of methylene chloride/methanol/33% NH3(3/3/2) 3 l (3/3,5/3). Product elute, then when chromatographic in the system n-butanol/ethanol/water/33% NH3(2/2/2/1). Yield: 5.5 g (78%) of 16 as a white solid. Thin layer chromatography: (2/2/2/1), Rf= 0,4. MS: (M+N)+= 1116,5; calculated C36H63NO34P2M= 1115,83.31P-NMR (D2O) == 16,3 PPM for cyclic phosphate and 7.9 for H-phosphate.

EXAMPLE 2

Compounds a, C, D, E, F, G, H and I get similar to the methods described in example 1. In table. 1 shows the structural formula, the total formula and mass spectra.

EXAMPLE 3

Pharmaceutical activity

Biological activity proposed according to the invention compounds of formula I determined on isolated fat cells of the rat.

Preparation of the fat cells of the rat produced as follows.

White iravul fat cells separated by filtration from undigested tissue and washed several times with buffer Krebs-ringer-Henseleit (KRH-buffer).

A) Lipogenesis

This test determines stimulated insulin conversion of glucose dissolved in toluene products (triglycerides, phospholipids, fatty acids), which requires transport of glucose and synthesis of triglyceride/phospholipid/fatty acid (synthesis of glycerol-3-P, etherification), including the insulin cascade of signal transmission. When glucose concentration of 2.5 mm during the test etherification (and not the synthesis of glycerol-3-P, including the transport of glucose) is the stage that determines the rate of stimulation of lipogenesis.

200 ál (3x105cells/ml) of the fat cells of the rat in KRH-buffer and incubated with 100 μl of D-[3-3H] glucose (25 mm, 0.4 MCs) in the presence or in the absence of insulin (10 ng/ml) or the invention the compounds of formula I for 90 min at 37o(Final volume 1 ml). Adding soluble in toluene scintillation mixture (10 ml), dissolve the cells and separate the lipids from water-soluble products and incubation medium. After separation of the phases induced in the lipid radioactivity determined directly scintillation measurement without removal of the aqueous phase ([CH] lipid[dpm*10-3] ). From this radioactivity subtract the reference value (incubation under identical conditions is acii - i.e., the ratio of the incubation with insulin result of incubation without insulin is taken for 100%. Percentage data "%Insmax" are parts of certain thus the maximum factor stimulation. The EC50determines the concentration of the compounds of formula I, in which there is 50% of maximum stimulation obtained the corresponding compound of formula I.

B) the Transport of glucose

The fat cells of the rat in 100 μl KRH buffer (titer 5x105cells/ml) incubated with insulin or with proposed according to the invention a compound of formula I for 15 min at 37oC. After adding 50 µl of 2-[3H] deoxyglucose (0.3 mm, 0,2 MX) incubation continued at room temperature. After a certain period of time (0-20 min) take 100 ál of the test sample and transferred to the reaction vessel (capacity 400 µl), in which there are 250 ál of dinonyl-phthalate. After centrifugation (15000g, 1 min) the cells on the oil layer is separated from the incubation medium under oil layer by cutting the tube at the height of the oil layer and transferred to scintillation vessel. After adding 5 ml of water-soluble scintillation fluid to determine the radioactivity. With the prisoners in the extracellular space [3H] deoxyglucose by subtracting the control values (incubation in the presence of an inhibitor of glucose transport of cytochalasin). The initial stimulated rate of glucose transport is up to 15 min linear. Maximum stimulation coefficient - i.e., the ratio of the incubation with insulin result of incubation without insulin is taken for 100%.

The concept of "%Insmaxand EU50" defined in section (A) "Lipogenic". The pharmaceutical composition according to the invention contains an effective amount of at least one compound of formula (1) and, if necessary, a physiologically acceptable carrier, conventional additives and auxiliary substances (see table. 2). So, for example, to obtain a solution for injection active substance of the formula (1) dissolved in double-distilled water, add if necessary isotonic agent and establish a pH in the range from 3.0 to 9.0, preferably from 5.0 to 8.5, the solution is filtered under sterile conditions, bottled in glass containers for preparations for injection, lyophilizer in sterile sterile conditions and closed. As isotonic funds can be used glycerol, glucose, mannitol, soie means, specified by the applicant above.

1. Inositolglicana formula I

A-Z-R (I)

and/or a physiologically acceptable salt of the compounds of formula I, And this means 1)N-P(O)(OH)-, 2) H-P(S)(OH)-, 3) HO-P(S)(OH)-, 4)S(O)2(OR1)-, 5) NH2-C(O)-,

where R1denotes a hydrogen atom or (C1-C4)-alkyl,

Z denotes 1) 2 to 6 sugar residues from the group: 1.1 mannose, 1.2 glucose, 1.3 gluconic acid, 1.4 Galaktionova acid, 1.5 mononova acid, 1.6 glucosamine, 1.7 fructose or 1.8 galactose or 2)2 to 6 sugar residues of a group specified for Z 1.1-1.8, replaced by one-six times independently from each other 2.1 stands, 2.2 mannose, 2.3 glucosamine, 2.4 diminati or 2.5 mannose-glucosamine, and glycosidic bond both sugars mannose and glucosamine is between C-atoms and 1-3, 1-6 1-2 or both sugars, and R denotes 1) Inositol, 2) inositols, 3) Invitational, 4) insatallation or 5) inositoltrifosfata.

2. The compound of formula I under item 1, characterized in that means 1)N-P(O)(OH)-, 2) S(O)2(OR1) or 3) NH2-C(O)-, Z represents 1) 2 to 6 sugar residues from the group: 1.1 mannose, 1.2 glucose, 1.3 gluconic acid, 1.4 Galaktionova acid, 1.5 mononova acid, 1.6 glucosamine, 1.7 fructose or from each other 2.1 stands, 2.2 mannose, 2.3 glucosamine, 2.4 diminati or 2.5 mannose-glucosamine, and glycosidic bond both sugars mannose and glucosamine is between C-atoms, 1-3, 1-2 or 1 to 6, both sugars, and R denotes 1) Inositol, 2) inositols, 3) Invitational, 4) insatallation or 5) inositoltrifosfata.

3. The compound of formula I under item 1, characterized in that a denotes N-P(O)(OH)-; Z represents 1) 2-4 sugar residue from the group: 1.1 mannose or 1.2 glucosamine or 2) 2-4 sugar residue from the group: 2.1 mannose or 2.2 glucosamine, once substituted mannose, and R denotes 1) Inositol, 2) inositols or 3) inositoltrifosfata.

4. The method of obtaining the compounds of formula I according to one or more paragraphs. 1-3, characterized in that inositolglicana synthesize Paladino from the original protected sugars and inositols connections, then attach the rest and from the resulting connection otscheplaut one or more protective groups temporarily introduced to protect other functions, and thus obtained the compound of the formula I, if necessary, transferred to its physiologically acceptable salt.

5. Farmacevticheskaja the composition having insulin-like action, characterized in that Armaceutical composition p. 5, characterized in that it contains at least one modified or unmodified insulin or derivative of insulin.

7. The method of obtaining pharmaceutical compositions under item 5 or 6, wherein preparing at least one of the compounds of formula I and a physiologically acceptable carrier and, if necessary, suitable additives and/or excipients suitable dosage form.

8. The method according to p. 7, characterized in that add at least one modified or unmodified insulin or derivative of insulin.

9. The compound of formula I according to one or more paragraphs. 1-3, characterized in that it is used for obtaining the pharmaceutical composition having insulin-like action.

 

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The invention relates to derivatives of 3-N-1,2,3-triazolo-[4,5-d]-pyrimidine of the General formula I, in which a represents O or CH2; X is selected from NR1R2, SR1and C1-C7-alkyl; Y is chosen from SR1, NR1R2and C1-C7-alkyl; R1and R2each independently represents N or C1-C7-alkyl, or R1represents C1-C7-alkyl, optionally substituted in the alkyl chain one atom of O or S or one or more halogen, and R2is hydrogen; R3and R4both represent hydrogen or together form a bond; a is COOH, C(O)NH(CH)pCOOH, C(O)N[(CH2)q-COOH]2WITH(ABOUT)NНСН(COOH)(CH2)rCOOH or 5-tetrazolyl, in which p, q and r each independently is 1, 2 or 3, as well as their pharmaceutically acceptable salts or esters

The invention relates to medicine and relates to compositions for the treatment of anorectal and colon-intestinal diseases

The invention relates to new ascomycin General formula I, where Y represents a phenylene; Z is selected from carboxyl and physiologically hydrolyzable of oxycarbonyl or alkyl, CNS, alkylamino or dialkylamino bearing from 1 to 4 carboxyl or physiologically hydrolyzable oxycarbonyl group; Q is O or S; R1Is H, alkyl or aryl; R2is hydrogen or hydroxyl; R3is methyl, ethyl, propyl or allyl; R4is hydroxyl or alkoxyl; R5-oxoprop or (H, OH), R6- oxoprop, H, HE H, alkoxyl); n is an integer 1 or 2, in free form or in the form of a pharmaceutically acceptable salt

The invention relates to the medical industry, namely the production of medicines, containing four, pathcomponent mixture of acetylsalicylic acid, paracetamol, ascorbic acid, organic salts of calcium, Dimedrol, and(or) routine used for relief of acute manifestations of influenza

The invention relates to medicine and veterinary medicine, in particular to medicines for external use, and can be used for the treatment of infected superficial and deep wounds, burns, and inflammatory diseases of the skin and mucous membranes

The invention relates to medicine and veterinary medicine and can be used for treatment and prophylaxis of viral diseases of different etiology

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

FIELD: medicine, obstetrics, gynecology.

SUBSTANCE: at the background of therapy conducted one should introduce derinate immunomodulator into the body of pregnant woman additionally nasally per 1-2 drops of 0.25%-solution into each nasal canal 5-8 times daily for 3-5 d and - parenterally per 5.0 ml of 1.5%-solution once daily for 3-8 d along with preparation that improves microcirculation and along with antioxidant at a certain sequence, moreover, derinate should be introduced 30-40 min after application of microcirculation-improving preparation, and antioxidant - 20-30 min after derinate's introduction. The present innovation favors decreased edemas, decreased body weight, stabilization of Macluer-Aldrich test that in its turn enables to avoid perinatal losses, decrease the risk for the development of fetoplacental insufficiency and intrauterine fetal infection.

EFFECT: higher efficiency of therapy.

1 ex, 2 tbl

FIELD: medicine, otolaryngology.

SUBSTANCE: the present innovation deals with introducing neomycin sulfate antibiotic in granules prepared by the following technique. Tablet of neomycin sulfate 1.0g should be put into a vial with 100 ml distilled water till tablet's decomposition. Then vial's content should be shaken and kept till suspension sedimentation. In a day one should take 1 ml of supernatant liquid to be put into another vial and diluted with distilled water at 1:100 ratio. This procedure should be repeated 4 times more, moreover, during the last procedure one should apply alcohol for dilution. Then one should transfer the drop of alcoholic solution into a vial with granules out of milk sugar to then shaken and kept open for 1 d till granules" drying up. The suggested preparation should be applied per 1 granule under the tongue, moreover, multiplicity and duration of the above-suggested intake should be matched individually by patient's sensitivity and obtaining the clinic effect. The method enables to improve the value of tonic threshold audiometry by about 30-50 dB, decrease perception threshold of vocal range frequencies and widen the range towards high frequencies.

EFFECT: higher efficiency of therapy.

1 dwg

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of chronic lympholeukosis. Method involves intravenous drop and jet administration of antitumor chemopreparations and carrying out the autochemotherapy. At the 1-st and 8-th day of treatment cyclophosphan in the dose 750 mg/m2, vincristine in the dose 1.4 mg/m2 and doxorubicin in the dose 30 mg/m2 incubated with 200 ml of autoblood are administrated to patients. From the 1-st to 14-th day of treatment prednisolone is used every day in the therapeutic dose. The treatment course is repeated in 30-35 days depending on blood indices and patient state. The total treatment of courses is 4-5. Method provides reducing cardiotoxicity of doxorubicin and cumulative toxicity of chemopreparations that allows carrying out administration of antitumor chemopreparations in the full volume to patients of elderly age groups.

EFFECT: improved method for treatment.

1 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, immunology, nucleic acids.

SUBSTANCE: invention relates to a method for stimulation of the immune response using nucleic acids-containing immunostimulating compositions, oligonucleotide-containing composition and to a method for treatment or prophylaxis of allergy or asthma. For stimulation of the immune response thymidine-enriched nucleic acid comprising poly-T sequences and/or comprising above 60% of thymidine-containing nucleotide residues is administrated. Invention provides the development of new method for stimulation of the immune response due to administration of the proposed immunostimulating nucleic acid.

EFFECT: valuable medicinal properties of nucleic acid.

27 cl, 12 dwg, 12 ex

FIELD: veterinary science.

SUBSTANCE: the suggested method should be performed under conditions of experimental modeling dystrophic process due to intraosseous introduction of glucosamine hydrochloride at the dosage of 15-25 mg/kg 1-2 times weekly during a month. The method provides high local concentrations of medicinal preparation, at its steady entering the circulation by leaving aside hepatic barrier and, as a result, optimization of chondroprotector action of glucosamine hydrochloride and better treatment of articular alterations induced in the course of an experiment in animals.

EFFECT: higher efficiency of correction.

8 dwg, 1 ex

FIELD: veterinary science.

SUBSTANCE: the suggested method should be implemented under conditions of experimental modeling dystrophic process due to intramuscular injection of glucosamine hydrochloride at the dosage of 15-25 mg/kg once or twice weekly for 1 mo. The method provides good effect in treating a lesion induced in the course of an experiment due to matching adequate dosages and a certain mode of injecting chondroprotector in animals.

EFFECT: higher efficiency of correction.

6 dwg

FIELD: medicine, neurology.

SUBSTANCE: method involves intravenous administration of autolymphocytes treated with an immunomodulating agent by extracorporal method using cycloferon (250 mg) as an immunomodulating agent. Simultaneously, the following medicinal mixture comprising lidocaine, 100 mg; lidazum, 32 U; dexamethasone, 4 mg; leukinferon, 10 000 U; 40% glucose solution, 4 ml is administrated into interspinal ligaments of spinal column at levels corresponding to thoracal and lumbar enlargements of the spinal cord. The procedure is repeated three times with interval for 48-72 h. Method provides enhancing the effectiveness of lymphostimulation and immunomodulation in cerebrospinal sclerosis. Invention can be used for lymphostimulation and immunomodulation in cerebrospinal sclerosis.

EFFECT: improved method for treatment.

1 tbl, 1 ex

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