1,3-dinitroglycerol esters of polyunsaturated fatty acids, hydroxy fatty acids and prostaglandins and methods of their production

 

(57) Abstract:

Usage: in experimental biology. The essence of the invention: 1,3-dinitroglycerol esters f-crystals RCOOCH(CHOHO), where R is the remainder of polyunsaturated fatty acids, hydroxypropylamino fatty acids or prostaglandin and 3 ways of obtaining them. 3 S. p. f-crystals, 6 PL.

The invention relates to organic chemistry, specifically to new biologically active compounds derived from polyunsaturated fatty acids, hydroxypregnenolone fatty acids and prostaglandins of General formula I:

< / BR>
where R the rest prostaglandin formula:

< / BR>
where one of the two groups at C-9 atom (R1or R2) a hydrogen atom, and the other hydroxyl (R2or R1or R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-11 of the atom (R3or R4) a hydrogen atom, and the other hydroxyl (R4or R3or R3and R4together form a keto or hydroxyisopropyl; provided that R3and R4do not form a keto or hydroxyisopropyl when R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-15 atom (R5or6) a hydrogen atom, the; or R is the residue of a prostaglandin of the formula:

< / BR>
where one group at C-9 atom (R7or R8) a hydrogen atom, or hydroxyl and the other is hydrogen, the symbol represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or provided that if7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond; and where one of the two groups at C-15 atom (R9or R10) a hydrogen atom, and the other (R10or R9) hydroxyl;

or R the rest of the prostaglandin type I formula:

< / BR>
where the group Q at C-5 of the atom the atom is iodine or bromine, the symbol represents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond;

or R residue of the unsaturated fatty acids of the formula:

< / BR>
where a 0 6, f 1 6, 1 7, provided that the total carbon chain length from 18 to 22 carbon atoms;

or R residue hydroxy acid of the formula:

< / BR>
where m 1 7 x 0 4, k 0 4, n is 0 to 3, provided that the total carbon chain length from 18 to 22 carbon atoms, and methods for their preparation.

The proposed compounds have changed compared to the natural range of compounds is The change in the spectrum of physiological activity is to strengthen some kinds of biological activity of compounds, or the emergence of new, previously not typical for this type of connection properties while maintaining or weakening of other types of biological activity. Polyunsaturated fatty acids, hydroxypregnenolone fatty acids and prostaglandins are polyfunctional compounds, which are characterized by the simultaneous expression of a wide spectrum of biological activity, for example, a combination dilatator (on smooth muscles of the bronchi), vasomotor (on smooth muscles of the gastrointestinal tract), antiaggregatory (platelets), Hypo - or hypertensive activities. A wide range of biological activity of compounds of this class prevents their use as medicines because of multiple side effects. The modification of such compounds to modify the spectrum of their biological activity towards reducing those types of activity that are responsible for the occurrence of unwanted side effects while strengthening the core types of biological activity allows you to bypass these restrictions.

The new compounds of General formula I have, in particular, antiaggregatory activity, the ability to relax the smooth muscles of the bronchi, aorta, as well as hypotensive effects in laboratory animals.

The proposed compounds belong to a new class that is and prostaglandins, combining in one molecule two pharmacophore. Pharmacophor chemical fragment with certain pharmacological properties. With the right combination of different pharmacophores within one molecule of the new substance is a considerable strengthening of the physiological effects inherent in both the original pharmacophore, and in some cases for new, binary, compounds characterized by the emergence of new types of biological activity. This new binary, the connection has generally increased pharmacological efficacy and is characterized by a decrease in side effects.

To obtain the proposed compounds used as a second, non-lipid, pharmacophore chemical compound that generates nitric oxide, namely, 1,3-glycerol dinitrate treatment.

Nitric oxide (NO) is a biological mediator, acting on many cells and tissues, as suggested, through a mechanism involving activation of cytosolic guanylate cyclase (S. Moncada, E. A. Higge, J. R. Berrazueta "Clinical Relevance of Nitric Oxide in the Cardiovascular System", 1991, Edicomplet, S. A. Spain).

Nitrovasodilator, such as itroglycerin, nitrosobis, etc. act as a means of delivery of NO in cells of organs and tissues in the related logicheskie effects of NO and some prostaglandins and hydroxypregnenolone fatty acids are often similar in their physiological orientation, what caused the choice dinitrate glycerol as the second component of the binary compounds of the above formulas.

1,3-Dinitroglycerol esters of General formula I can be obtained in several ways.

One of the proposed methods is that the carboxylic acid of General formula II:

R-COOH (II),

where R has the above values, the first turn in the offset anhydride with arylsulfatase treatment arylsulfonamides in an organic solvent in the presence of a tertiary amine. Mixed anhydride and then condensed with 1,3-dinitrate treatment of glycerol in the presence of dimethylaminopyridine.

Another way to obtain 1,3-dinitroglycerol esters of General formula I is that 1,3-dinitrate treatment of glycerin condense with imidazolium derived from a carboxylic acid of General formula II, processing carbonyl diimidazol in an organic solvent, in the presence of pyridine hydrochloride.

The third of the proposed methods for obtaining 1,3-dinitroglycerol esters of General formula I is that of the original carboxylic acid of General formula II is treated initially with a mixture consisting of hexamethyldisilazane and trimethylchlorosilane, pretorious reagent, prepared from equimolar mixtures of morpholinobutyrophenone and trimethylsilylpropyne, in the environment of an organic solvent at low temperature. Then to the mixture was added 1,3-dinitrate treatment of glycerin and tertiary amine.

In all three proposed methods the process of esterification takes place with a high output that enables you to get from a few milligrams to a few grams dinitroglycerol esters in the individual condition.

For some dinitroglycerol esters of prostaglandins have been used are described in the literature, the methods of transformation of prostaglandins some types in the other.

So, 1,3-dinitroglycerol esters of prostaglandins J2and J1were obtained from 1,3-dinitroglycerol esters of prostaglandins D2and D1accordingly, according to the described method (N. Fukushima, T. Kato, K. OTA, Y. Arai, S. Narumia, S. Narumiya, O. Hayaishi. Biochem.Biophys.Res.Commun. 1982, Vol. 109, No 3, p. 626-633) incubation at pH of 7.2 at 30 35oC for 1 to 3 days. Also 1,3-dinitroglycerol esters Delta-12 prostaglandins were obtained from 1,3-dinitroglycerol esters corresponding prostaglandins types D or J according to the described method (U. L. Bundy, D. R. Norton, D. C. Peterson, E. E. Nishizawa, W. L. Miller. J. Med. Chem. 1983, Vol. 26, Tableout a viscous colourless or slightly coloured oil (except for some Asimov prostaglandins, which is crystalline compounds). Their alcoholic solutions temporary dosage form, used when conducting biological experiments, stable when stored at a temperature not exceeding 5 7oWith at least 1 year.

The biological activity of the synthesized compounds was studied on isolated preparations of smooth muscles of laboratory animals (rat, Guinea pig), human platelets, and whole anesthetized animals (rabbit, rat).

Studies have shown that the proposed compounds are altered compared to the parent compounds spectrum of biological activity.

Thus, pharmacological tests revealed a number of significant differences in the properties of nitropaste (1,3-dinitroglycerol ester of prostaglandin E2) and prostaglandin E2nitropaste 5 times more active than prostaglandin E2as a hypotensive agent (in experiments on rats and rabbits) (table.1). When using nitropropene no marked changes in heart rate and tachyphylaxis in experimental animals. Another important difference of nitropaste is its high vasodilatory activity is no reduction in the aorta (table. 2,3). For nitropropene is characterized by a significant increase (20-fold) bronchodilatators activity (EC507,18 nm, isolated trachea of the Guinea pig) compared with prostaglandin E2(PL.3).

Change the pharmacological spectrum was also observed in 1,3-ad esters of prostaglandin E1, oxime prostaglandin E1and prostaglandin FAlpha. So, prostacet (1,3-dinitroglycerol ester of prostaglandin E1possesses a strong ability to inhibit the aggregation of human platelets induced by ADP (IC50to 0.19 μm). At the same time he, unlike natural prostaglandin E1effectively relaxes isolated rat aorta (EC50the 2.1 µm). Nitropress (1,3-dinitroglycerol ester 9-examinationin E1), was more active than prostacet as a vasodilator (EC50of 0.64 μm, the aorta of the rat), but less active as antiagregant (IC501.1 µm, human platelets) (table.4).

Pharmacological tests showed that necropost-F (1,3-dinitroglycerol ester of prostaglandin FAlphasubstantially exceeds the prostaglandin F2-alphathe ability to reduce the myometrium of the uterus of the rat (EC509 n ctor smooth muscle of the rat stomach, and not different from him in action on the smooth muscles of the intestine (PL.5).

Most of the proposed connections there is a strong antiaggregatory activity, and this effect was observed even for 1,3-dinitroglycerin ether aphidinae acid, which itself is known to be an inducer of platelet aggregation (table.6).

Starting materials for the synthesis of the proposed compounds have been obtained or pilot plant organic synthesis (Tallinn, Estonia) (prostaglandins) or the Pacific Institute of fisheries and Oceanography (TINRO, Russia) (fatty acids and hydroxyzine acid). Prostaglandins A1and A2were obtained from the corresponding prostaglandin E1and E2by well-known methods (Corey, E. J. et al. Total synthesis of pure dl-E1, -F1, -A1and B1Hormones, J. Am. Chem. Soc. V. 90, pp.3245 3247, 1968). 15-Fluoro-15-deoxyprostaglandin were synthesized according to previously described methods (centuries Bezuglov and L. D. Bergelson. Synthesis of procrastination. 11-Fluoro - 15-procrastinatin. Bioorgan. chemistry, I. 5, S. 1531-1536, 1979. Bezuglov et al. Synthesis of 15-targetexception A2and E2of prostaglandin A2Plexaura homomalla. Reports of the USSR Academy of Sciences, I. 379, S. 378-379; U. S. Patent 4, 665, 214).

The following 1,3-dinitroglycerol esters were obtained by the method described above from the appropriate starting compound:

1,3-dinitroglycerin ether CR is 10:1); PMR (CDCl3d,, M. D. of 5.6 (2H, m), are 5.36 (3H, m), 4,74, 4,56 (4H, DD), 4,11 (2H, m), of 2.72 (2H, DD), to 0.92 (3H, t), mass spectrum (FAB) m/z 515 (M + H). 1,3-dinitroglycerol ester of prostaglandin A1: colorless viscous oil, UVmax218 nm, mass spectrum (FAB) m/z 501 (M + N - N2O).

1,3-Dinitroglycerol ester of prostaglandin A2: viscous yellow oil, UVmax218 PM, mass spectrum (FAB) m/z 499 (M + H), 481 (M + N - N2O).

1,3-dinitroglycerol ester of prostaglandin D2: colorless viscous oil, mass spectrum (FAB) m/z 515 (M + H).

1,3-dinitroglycerol ester of prostaglandin D1: colorless viscous oil, mass spectrum (FAB) m/z 517 (M + H).

1,3-dinitroglycerin ether 15-fluoro-15-deoxyprostaglandin E2: colorless viscous oil, Rf0,7 (toluene-dioxane-acetic acid, 40:10:1) mass spectrum (EI), m/z 519, 498, 480, 472, 452, 371, 353, 316, 298.

1,3-dinitroglycerol ester of prostaglandin FAlpha(nitropress-F): colorless viscous oil, Rf0,25 (benzene-dioxane-acetic acid: 20:10:1); PMR (CDCl3) , M. D. 5,49 (2H, m), of 5.34 (3H, m), 4,78, 4,58 (4H, DD), 4,14 (1H, m), Android 4.04 (1H, q), a 3.9 (1H, m) to 0.89 (3H, t), mass spectrum (FAB) m/z 517 (m + H), 501 (M +- H H2O).

1,3-dinitroglycerol ester of 11-EPI-prostaglandin FAlpha: colorless viscous oil, Rff0,37 (benzene-hexane, 1:1).

1,3-dinitroglycerol ester of docosahexaenoic acid: a viscous colorless oil, Rf0,69 (benzene).

1,3-dinitroglycerol ester 9,12,15-octadecatrienoic acid: a viscous colorless oil, Rf0,61 (benzene), mass spectrum (FAB) m/z 442 (M).

1,3-dinitroglycerin ether 13-hydroxy-6,9,11-octadecatrienoic acid: a viscous colorless oil, Rf0.84 (benzene-acetone, 4:1), mass spectrum (FAB) m/z 441 (M H2O + N).

Example 2. Obtaining 1,3-dinitroglycerol ester 9-acetiminophen E1(nitropress).

1,3-Dinitroglycerol ester of prostaglandin E1(170 mg, 0.33 mm) was dissolved in 1.5 ml of methanol. To the resulting solution was added a solution of hydrochloric acid hydroxylamine (170 mg, 2.5 mm) and sodium acetate (215 mg, 3,26 mm) in 3 ml of 50 methanol. The solution is stirred for 30 min at 25oC. the Reaction mixture is diluted with 5 ml of water and evaporated methanol. Precipitated white crystalline precipitate is filtered off and dried. Obtain 172 mg of 1,3-dinitroglycerol ester 9-examinationin E1in the form of white crystalline powder, so pl. 81 82oC, Rfof 0.55 (chloroform-acetone, 1:1); PMR (CDCl3), d memorial plaques to 5.57 (2H, m), of 5.39 (1H, m), 1,77, of 4.67 (1H, DD), 4.09 to the yli obtained by the method described above from the appropriate starting compounds:

1,3-dinitroglycerol ester 9-acetiminophen E2in the form of white crystalline powder, Rfof 0.54 (chloroform-acetone, 1:1), mass spectrum (FAB) m/z 534 (M + H).

1,3-dinitroglycerol ester 9-acetiminophen A2in the form of white crystalline powder, Rfto 0.72 (chloroform-acetone, 1:1).

1,3-dinitroglycerol ester 9-acetiminophen A1in the form of white crystalline powder, Rfto 0.72 (chloroform-acetone, 1:1).

Example 3. Obtaining 1,3-dinitroglycerol ester of prostaglandin FBeta.

To a stirred solution of 24.8 mg of 1,3-dinitroglycerol ester of prostaglandin E1in 2 ml of methanol at 0oTo add one portion of 25 mg of sodium borohydride in an atmosphere of inert gas. The mixture is stirred 20 min at 0oC. Then the reaction mixture was diluted with 1 ml water and 1 ml of saturated solution of ammonium sulfate and extracted with ethyl acetate (2 x 5 ml). The combined organic extracts are washed with 2 ml of water, then a saturated solution of sodium chloride and dried with sodium sulfate. The dried organic extract was evaporated to dryness in a vacuum. The residue is dissolved in methanol and purified micropreparative HPLC (column: SEPARON SGX C18 4 is the atur 35,0oC). Received: 13,24 mg 1,3-dinitroglycerol ester of prostaglandin F1-alpha: viscous, colorless oil, Rf0,25 (benzene-dioxane-acetic acid, 20:10:1) and up 11,86 mg 1,3-dinitroglycerol ester of prostaglandin FBeta: viscous, colorless oil, Rf0,16 (benzene-dioxane-acetic acid, 20: 10: 1), mass spectrum (FAB) m/z 519 (M + H), 503 (M + N H2O).

1,3-Dinitroglycerol ester of prostaglandin FBetawas obtained by the same method from the corresponding ester of prostaglandin F2: viscous, colorless oil, Rf0,16 (benzene-dioxane-acetic acid, 20:10:1), mass spectrum (FAB) m/z 517 (M + H), 501 (M + N H2O).

Example 4. Obtaining 1,3-dinitroglycerin ether 15-fluoro-15-deoxyprostaglandin A2.

100 mg prostaglandin AND2dissolved in 2 ml of methylene chloride, cooled to -48oC and in an atmosphere of argon was added 200 μl of morpholinobutyrophenone. The reaction mixture was stirred for 1 h at -48oC. After completion of the fluorination reaction to mass add 3 ml of saturated ammonium chloride solution and leave the mixture to spontaneously warm to room temperature. After that, the mixture is diluted with 5 ml of water, separate the organic layer is 6.5 to 7 with a saturated solution of sodium chloride, dried by sodium sulfate. The dehydrator is filtered off, the filtrate is evaporated. The resulting oil is purified column chromatography on silica gel L (100 to 160 MMK) (20 g) in a gradient system of hexane-ether with a gradual increase in the polar phase (hexane, hexane ether 10:1, 7:1, 5:1, 3:1, 1: 1; the volume of each system 50 ml). Received 70 mg (70) forwareded 15-fluoro-15-deoxyprostaglandin A2(F-15-F-GAA2), a yellowish viscous oil, Rf0,62 (benzene, ethyl acetate 7:1); UV lmax217 nm, 6000, ethanol. Mass spectrum, m/z (1;): 338 (M; 38), 318 (M-HF; 45), 310 (M-CO; 10), 298 (M-2HF; 30), 190 (100).

The obtained F-15-F-GAA2dissolved in 2 ml of benzene and added sequentially 1,3-dinitrate treatment of glycerol (75 mg, 0.4 mm), triethylamine (75 mg, 0.75 mm) and a catalytic amount of 4-dimethylaminopyridine (1 mg) and stirred for 1 h at 25oC. the Reaction was poured on a column of silica gel L (100 to 160 MMK) (20 g) in a gradient system of hexane ether with a gradual increase with increase in the polar phase (hexane, hexane-ether 10:1, 7:1, 5:1, 3:1, 1:1; the volume of each system 50 ml). Received 89,6 mg (30) 1,3-dinitroglycerin ether 15-fluoro-15-deoxyprostaglandin AND2yellowish viscous oil, Rf0,7 (benzene, ethyl acetate 5:1); UV lmax218 nm, ethanol. Mass spectrum, m/z (1;): 500 (M; 3), 480 (M-HF; 2,8), ONO2)2SON; 13,4), 315 (M-(CH2ONO2)2SON-HF; 22,3), 190 (100).

Example 5. Obtaining 1,3-dinitroglycerol ester of prostaglandin E2(nitropaste).

100 mg prostaglandin E2dissolved in 2 ml of acetonitrile and under stirring was added 70 mg of carbonyldiimidazole (Fluka). The reaction mixture was stirred at room temperature for 1.5 h (21oC) until the gas evolution stops. Then to the reaction mixture was added 0.1 ml of 1,3-dinitrate glycerol and 70 mg of dry pyridine hydrochloride. The resulting mixture was stirred for 1.5 to 2 h at room temperature and diluted with 10 volumes of ethyl acetate and 2 volumes of water. The organic layer was washed with 2M solution NsHSO4, water (3 x 5 ml), saturated NaCl solution. The organic layer is separated and dried Na2SO4, filtered and evaporated in a water jet vacuum pump. The residue is dissolved in benzene and applied to a column of 20 ml of silica gel L (100 to 250 μm) and elute with a gradient system of benzene - acetone with a gradual increase in the polar phase (benzene, benzene, acetone 20:1, 7:1, 1:1; the volume of each system 30 ml). The eluate after the column is collected in a test tube and 10 ml Tubes containing the product (the control was carried out using TLC) are pooled and upar 6. Obtaining 1,3-dinitroglycerol esters of prostaglandins J2and J1.

1,3-dinitroglycerol esters of prostaglandins J2and J1from 1,3-dinitroglycerol esters of prostaglandins D2and D1accordingly, incubation in Tris-HCl buffer (0.05 m, pH of 7.2) at 30 -35oC for 1 to 3 days followed by extraction with organic solvents and purification by chromatography on silica gel.

1,3-dinitroglycerol ester of prostaglandin J2colorless oil, UVmax216 (ethanol);

1,3-dinitroglycerol ester of prostaglandin J1colorless oil, UVmax216 (ethanol).

Example 7. Obtaining 1,3-dinitroglycerol esters Delta-12 prostaglandins.

1,3-dinitroglycerol esters Delta-12 prostaglandins were obtained from 1,3-dinitroglycerin the corresponding esters of prostaglandins types D or J by reaction with 1,5-diazabicyclo[4.3.0]non-5-Yong in tetrahydrofuran (room temperature, 12 and 18 h), followed by purification by chromatography on silica gel.

1,3-dinitroglycerin ether Delta 12-prostaglandin J2yellowish oil, UVmax245 (ethanol);

1,3-dinitroglycerin ether Delta 12-prostaglandin J1yellowish oil, UV 244 (ethanol);

1,3-dinitroglycerin ether Delta 12-prostaglandin D1colorless oil, UVmax244 (ethanol).

Example 8. Obtaining 1,3-dinitroglycerol ester 5-iodoprotein I1.

To a solution of 70 mg of 1,3-dinitroglycerol ester of prostaglandin F2p2.5 ml of ether at 4oC was added a saturated aqueous solution of sodium bicarbonate (6 ml) and with constant stirring in an argon atmosphere is added dropwise a solution of iodine (45 mg) in ether (3.5 ml). The mixture is stirred in the dark overnight at 4oC. the Reaction mixture is diluted with 20 ml of ether, the organic layer is separated, washed with aqueous 10 solution of Na2S2O3, water, us.NaCl, dried with Na2SO4, filtered and evaporated in a water jet vacuum pump. The residue is dissolved in chloroform and applied on the column with 15 ml of silica gel L (40 to 100 μm) and elute with a gradient system of chloroform acetone with a gradual increase (2 per level) polar phase (i.e. 25 ml of chloroform, 25 ml of 2 acetone in chloroform, 25 ml of 4 acetone in chloroform, and so on). The eluate after the column is collected in a test tube and 10 ml Tubes containing the product (the control was carried out using TLC) are pooled and evaporated in vacuum. The output 55 is hloroform acetone, 1:2), mass spectrum (SIMS), m/z 667 (M++ Na), 627 (M+CH).

Example 9. Obtaining 1,3-dinitroglycerol ester of prostaglandin I2.

A solution of 10 mg of 1,3-dinitroglycerol ester 5-iodoprotein I1and 10 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml of benzene was heated at boiling solvent for 2 hours, the Reaction mixture was diluted with 6 ml of ether was quickly washed with cold water (4oC) water and us.NaCl solution. The organic layer was separated, filtered through 10 g of anhydrous Na2SO4and was evaporated to dryness in vacuum. Yield 8 mg of 1,3-dinitroglycerol ester of prostaglandin I2(prostacyclin): viscous, slightly yellow oil, Rfto 0.45 (chloroform-acetone, 1:2).

Example 10. Obtaining 1,3-dinitroglycerol ester of prostaglandin E2through floramite prostaglandin E2.

100 mg prostaglandin E2dissolve in 5 ml of THF, add 300 ál hexamethyldisilazane and 150 μl of trimethylchlorosilane and the reaction mixture is stirred 2 h at room temperature in an argon atmosphere and evaporated to dryness in a vacuum. The residue is dissolved in 5 ml of dry benzene and evaporated to dryness in a vacuum. The residue is dissolved in 0.5 ml of methylene chloride (solution A).

Lina under stirring in an argon atmosphere at 4oC. the Reaction mixture was stirred 1 h at this temperature (solution B).

To a cooled to -65oC solution B was added to the solution with vigorous stirring in an argon atmosphere and stirred for 30 min at this temperature. To the reaction mass is added 2 ml of a saturated solution of NaCl and extracted with 5 volumes of ethyl acetate. The combined organic extract was washed with water (3 x 5 ml), saturated NaCl (1 x 5 ml) and dried with anhydrous Na2SO4. The drying agent is filtered off, the filtrate is evaporated. The resulting floramite dissolved in 2 ml of dry benzene and added sequentially 150 mg of 1,3-dinitroglycerin, 150 mg of triethylamine and 0.01 to 0.1 equivalent of 4-dimethylaminopyridine under stirring. The reaction mixture was stirred at room temperature for 3 h and evaporated in vacuum. The residue is dissolved in 2 ml of methanol and add 100 ál of 1M aqueous HCl. After 30 min the reaction mixture was diluted with 15 ml of ethyl acetate. The organic layer was separated, washed with water (3 x 5 ml), saturated NaCl (1 × 5 ml) and dried with anhydrous Na2SO4. The dehydrator is filtered off, the filtrate evaporated in vacuum. The residue is dissolved in benzene and applied to a column (15 x 100 mm) with 20 ml of silica gel L (40 to 100 μm) and elute the gradient of the phase (i.e., 20 ml of benzene, 20 ml of 10 to 20 ml of 20 etc. ethyl acetate in benzene) to pure ethyl acetate. The eluate after the column is collected in a test tube, 10 ml test Tubes containing the product (the control was performed using TLC) are combined and evaporated in vacuum. Yield 50 mg of pure 1,3-dinitroglycerol ester of prostaglandin E2.

Example 11. The hypotensive effect of synthesized compounds. Hypotensive effect dinitroglycerol esters of prostaglandins studied in anesthetized rabbits and rats (males) without artificial respiration. Rabbits were narcoticyou intravenous injection of Barbara (50 to 60 mg/kg), rats by intraperitoneal injection of urethane (1.3 g/kg). Blood pressure was measured in the femoral artery (rabbits) or in the right carotid artery (rats).

It is shown that in experiments with rats, nitropaste power hypotensive actions more than 3 times higher than prostaglandin E2and Dibazol. In experiments on rabbits maximum pressure drop for prostaglandin E2amounted to 427 and nitropaste 355 however, the effect of the latter in the first seconds was softer, and the duration and the total effect is greater than the prostaglandin E2(see tab.1).

Example 12. Myotropic aktivnosti and Guinea pigs of both sexes, weight 23030 and 35050 g, respectively. The preparation of smooth muscles were placed in a thermostatted bath of 10 ml as a physiological saline solution was used Krebs (aorta, trachea, the fundus of the stomach, intestine) or De-Galena (uterus), the temperature of the medium 302oC, pH of 7.8, aeration with Carbogen. All the experiments were carried out in the presence in the environment of indomethacin at a concentration of 3 μm to suppress endogenous biosynthesis of prostaglandins. As standard agonist used prostaglandin E1E2FAlphaor histamine. The results of the tests are presented in table.2 5.

Example 13. Antiaggregatory activity of synthesized compounds.

In our experiments we used platelet-rich plasma of human blood. Record of platelet aggregation was performed on aggregometry firms "Chrono-Log Corp. (USA) and Payton (USA). The degree of aggregation was evaluated by the percentage drop in the optical density of the platelet-rich plasma after the reaction compared with the initial level.

It is shown that most of the tested compounds possessed marked ability to inhibit the aggregation of human platelets induced by ADP. So, dinitroglycerol ester of arachidonic who itov. At doses of 0.1 and 1 mg/ml plasma dinitroglycerol esters octadecatrienoic, docosahexaenoic and 5-hydroxyeicosapentaenoic acids inhibited platelet aggregation 30 50 High activity of the platelet aggregation inhibitors showed also some dinitroglycerol esters of prostaglandins (see tab. 6).

Thus it is shown that the proposed compounds are modified compared to the original polyunsaturated fatty acids, hydroxy or prostaglandins spectrum of biological activity, in particular in the direction of strengthening mechanism, vasodilatory and antiaggregatory activities.

Proposed substances have a new, previously undescribed structure, which leads to their new noted above useful properties.

1. 1,3-Dinitroglycerol esters of polyunsaturated fatty acids, hydroxy fatty acids and prostaglandins of General formula I

< / BR>
where R is the residue of a prostaglandin of the formula

< / BR>
in which one of the two groups at C-9 atom R1or R2the hydrogen atom and the other is hydroxyl or R1and R2together form a keto or hydroxyimino, one of the two groups at C-is whether hydroxyisopropyl, provided that R3and R4form a keto or hydroxyimino, when R1and R2together form a keto or hydroxyimino, one of the two groups at C-15 atom R5or R6the hydrogen atom and the other is hydroxyl or fluorine atom, the symbol represents a single or dis-double bond, or R residue prostaglandin of the formula

< / BR>
where one group at C-9 atom R7or R8a hydrogen atom or hydroxyl, and the other is hydrogen, the symbol represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or when the condition that if R7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond, and where one of the two groups at C-15 atom R9or R10the hydrogen atom and the other R10or R9hydroxyl, or R residue prostaglandin type I formula

< / BR>
where the group Q at C-5 of the atom the atom is iodine or bromine, the symbol represents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond, or R is the residue of the unsaturated fatty acid formula

< / BR>
where a 0 6, f 1 6, 1 7, provided that the total carbon chain length of 18 to 22 carbon atoms, and the Noah circuit 18 to 22 carbon atoms.

2. The method of obtaining compounds of General formula 1 p. 1, characterized in that the carboxylic acid of General formula II

R COOH,

where R takes values that are subjected to interaction with arylsulfonamides in an organic solvent in the presence of a tertiary amine, and then 1,3-dinitrate treatment of glycerol in the presence of dimethylaminopyridine.

3. The method of obtaining compounds of General formula I on p. 1, characterized in that the carboxylic acid of General formula II

R COOH,

where R takes values that are subjected to interaction with the carbonyl diimidazol in an organic solvent, and then 1,3-dinitrate treatment of glycerol in the presence of pyridine hydrochloride.

4. The method of obtaining compounds of General formula I on p. 1, characterized in that the carboxylic acid of General formula II

R COOH,

where R takes the specified values, is treated with excess (2-5 EQ) similitude mixture consisting of hexamethyldisilazane and trimethylchlorosilane when a volume ratio of 2:1, in an organic solvent, followed by the interaction of the obtained silyl derivative with a fluorinating reagent, prepared from equimolar mixtures of morpholinobutyrophenone and trimethylsilylpropyne, cf and tertiary amine.

 

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FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: animals science.

SUBSTANCE: the present innovation deals with intramuscular injection of sodium salt preparation cloprostenol 30-45 min before placing at the dosage of 750 mcg/animal. The method provides increased reproductive function, enhances sexual reflex, increases the volume of ejaculate, concentration, activity and quality of spermatozoa.

EFFECT: higher efficiency of breeding.

2 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 1-ethanolamide PGF of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.

EFFECT: new effective compound for relaxation of mammalian intraocular pressure.

4 cl, 1 ex, 16 dwg, 16 tbl

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.

EFFECT: valuable medicinal properties of pharmaceutical composition.

16 cl, 3 tbl, 5 ex

FIELD: medicine, obstetrics.

SUBSTANCE: invention relates to a method for treatment of delivery activity weakness. Method involves simultaneous administration of prostaglandin F in the concentration 12.5 mcg/ml at the rate 8 mcg/min and adenosine triphosphate sodium in the concentration 0.25 mcg/ml at the rate 0.25 mcg/min. Infusion continues up to end of the second stage of delivery. Method provides enhancing the delivery activity, increasing rate of uterine orifice opening on the background of the reduced dose of prostaglandin.

EFFECT: improved treatment method.

3 ex

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the suggested composition contains prostaglandin-like compound as an active component and it , also, deals with the method to treat disorders of external secretion that includes application of efficient quantity of prostaglandin-like compound for a person who needs such a treatment. The composition is of high efficiency at treating disorders inactivity of lacrimal and sudoriferous glands being of high bioavailability and nontoxic.

EFFECT: higher efficiency of therapy.

33 cl, 5 ex, 7 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a purgative agent composition comprising bicyclic compound of the formula (1) and a method providing the purgative effect and using compounds of the formula (1). He composition possesses the enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

42 cl, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.

EFFECT: enhanced effectiveness of treatment.

18 cl, 3 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves administration of the preparation "Ginkor-Fort" in the dose 1 tablet, 2 times per a day for 2 weeks and after one month break the preparation "Diovenor" is administrated in the dose 1 tablet, once per a day for 2 weeks at the constant instillation of the preparation "Ksalatan" in the dose 1 drop, once time before night. Such schedule of the method provides the stable normalization of intraocular pressure based on improvement of venous orbital and cerebral circulation. Invention is designated for medicinal treatment of glaucoma discirculatory variant.

EFFECT: improved method of treatment.

2 tbl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the diagnostics of primary open-angle glaucoma (POAG) should be carried out at fulfilling unloading diagnostic sample based upon evaluation of the dynamics of the data of computed static perimetry. At detecting alterations in the parts of vision field being characteristic for glaucomatous process it is necessary to conduct unloading sample: after preliminary control of intra-ocular pressure it is important to apply per 1 drop of ophthalmological preparation "Travatan" retroblepharally and in 24 h one should carry out control measurement of intra-ocular pressure and repeat computed static perimetry. In case of improved retinal sensitivity at the background of decreased intra-ocular pressure the sample should be considered to be positive and POAG diagnosis should be established. The innovation enables to prescribe selective hypotensive therapy in due time.

EFFECT: higher accuracy and efficiency of diagnostics.

3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 1-ethanolamide PGF of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.

EFFECT: new effective compound for relaxation of mammalian intraocular pressure.

4 cl, 1 ex, 16 dwg, 16 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a novel intermediate compound of the formula (VI)

and its salts wherein R3 means hydrogen atom (-H); R4 means -H, and means a simple or double bond, and its pharmaceutically acceptable salts.

EFFECT: improved preparing method.

4 cl, 12 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to novel compounds possessing properties of EP4 agonist and their using as EP4 agonist for preparing a pharmaceutical composition used in treatment of disorders associated with reducing the osseous mass. Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of pharmaceutical compositions.

13 cl, 125 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of prostaglandin of the general formula (I): wherein X means halogen atom in α- or β-position; Y means ethynylene group; R1 means (C3-C10)-cycloalkyl group; R2 means hydrogen atom (H) or -CO2R; R3 means H, (C1-C4)-alkyl group; n = 1-3; p = 0, or to its pharmaceutically acceptable salt or hydrate. Compounds of the formula (I) possess the sleep-inducing effect.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

8 cl, 2 tbl, 2 sch, 5 ex

FIELD: medicine.

SUBSTANCE: algae Gracilaria verrucoza are incubated in distilled water in order to transform unsaturated fatty acids under influence of present in alga enzymes into prostaglandins. Prostaglandins are transferred into distilled water. Extraction of prostaglandins from water solution by sorption with further eluting with water-organic solvents is carried out. Freshly collected alga is used, incubation is carried out during 1-3 hours with light illumination with intensity 100-300 mcE/m2s and temperature not higher than 4°C, before extraction of prostaglandins by sorption obtained water solution is acidified to pH 2.5-3.0, as sorbent non-polar modified silicagel with graft hydrocarbons with grain size to 100 mcm.

EFFECT: increase of product yield and process simplification.

3 ex

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