N-substituted derivatives of (3r, 4r)-3-ethyl-4-[(1-methyl-1h - imidazol-5-yl)-methyl]-2-pyrrolidone or their pharmaceutically acceptable acid additive salts with antiglaucoma action

 

(57) Abstract:

Usage: in medicine. The inventive products - N-substituted derivatives of (3R, 4R-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone f-ly I listed in the description, where R-(C1-C20)-alkyl, possibly substituted on trimethylsilyloxy group, hydroxy, acetoxy or isopropoxycarbonyl group, norbornyl, (C1-C4) alkylbenzene or 3,4-dimethoxybenzyl group, or their pharmaceutically acceptable acid additive salts have antiglaucoma action. Reagent 1: (3R, 4R-3-methyl-4-[1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidone. Reagent 2: allerease agent: halogen - or cyanoformate f-crystals XCO2R, or the anhydride of the formula n1O2COCO2n, where R is described above; X is halogen or cyano; R1hydrocarbon group, or n-nitrophenylarsonic f-crystals of O2N=(C6-H4)-COOR, where R is described above. 6 Il., table 1.

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find PrimeTel-[(N-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidinone, known in this field and together with other 1-alkyl substituted derivatives of some basic structures are good antiglaucoma agents.

Structurally the original connection refers to the corresponding lactone, from which it can be obtained. The lactone is known antiglaucoma agent: (3S, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-3,4-dihydro-2(3H)-furanone (pilocarpine). Both compounds reduce intraocular pressure by reducing the ciliary muscle and causing instant muscles of the iris, resulting in reduction of the diameter of the pupil in the eye of the patient. Pilocarpine is an optically active compound (3R, 4R), i.e., stereoisomeric with isoproterenol, optically active TRANS-isomer (3R, 4R). Although pilocarpine is one of the most common medicines used for the treatment of glaucoma, it is limited because of the short time-steps.

The aim of the invention is the creation of pilocarpine analogs with increased activity and better permeability.

The purpose of the invention is achieved with new N-substituted carbonyl derivatives of (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidone General formula I:

where R is xikar - manilow group, norbornyl, (C1-C4)-alkylbenzene or 3,4-dimethoxybenzyl group, or their pharmaceutically acceptable acid additive salts with antiglaucoma action.

The proposed compound can be obtained by the reaction of racemic or optically active compounds of formula II:

or its salt with an appropriate N-allermuir agent. If desired, the compound obtained can be converted into its pharmacologically acceptable salt or obtained from the acid-attached salt. If the starting compound is used racemic compound, the compounds of formula I are obtained by racemates can be separated into the corresponding enantiomers by known in the field methods (Jaegue, J. , Collet A, Wilen S "Enantiomers Racemates and Resolutions", Wiley, NY. 1981).

The new compounds of formula I are potent ocular hypotensive, i.e. valuable antiglaucoma agents. They are also used for the treatment of so-called "dry eye" and show better activity compared with predshestvuyuschiy connections.

The original compound in the synthesis of compounds of formula I (R is described above) - (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidone of the formula II, moscioni conditions using known techniques. The preferred solvent is the ammonia. The reaction takes place in one stage, and it is conveniently carried out in an autoclave or at high pressure.

In accordance with the invention, racemic or optically active compound of the formula II or an acid additive salt of N-alleroed to obtain the desired N-substituted derivative corresponding to the formula I.

Preferably, the compound of formula II is reacted with halogen or cyanoformate derivatives of the formula III:

XCO2R , or with an anhydride of the formula IV:

R O2COCO2R , where R is previously defined;

X is halogen AI cyano;

R' is possibly substituted hydrocarbon group, i.e., identical to or different from R. the Above reaction is carried out in the presence of a base.

In contrast, the acylation of compounds of formula II can be carried out with suitable active esters or carbonates such as O-n-nitroaniline carbonates corresponding to formula V:

O2NO--OR where R has the same meaning as previously.

In the above formulas aliphatic hydrocarbon groups R may be a linear or branched alkyl group, typically containing up to 20 atomo, the AOR - and tert.-butyl, n - and isopentyl, n - and neohexyl, n - and isoheptyl, n - and isooctyl, and other groups. At the same time, the N-substituents in pyrrolidinium ring in the compounds of formula I preferably are lipophilic part, long, preferably branched R is an alkyl group.

Especially preferred compounds of formula I are, for example, (3R, 4R)-1-Carbo-(4-tert-butylbenzoic)-3-ethyl-4-[(1-methyl-1H-imidazol-5-or)methyl ] -2-PIR religon and (3R, 4R)-1-Carbo-(2-propyl-1-pentoxil)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidone.

If desired, the resulting compound of formula I, where R has the same significance as described above, is converted into pharmaceutically acceptable acid additive salt of this compound or obtained salt is converted into the corresponding free compound or into another pharmaceutically acceptable salt.

Such salts can be obtained with suitable organic or inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, citric acid, oxalic acid, lactic acid, maleic acid, etc. according to the methods previously known. The main requirement is that they must be pharmaceutically priemlemoj area.

The reaction of the starting compound of formula II with halogeno or cyanoformate formula III or anhydrides of the formula IV takes place in suitable solvents, preferably inert under the respective reaction conditions. Suitable solvents include tetrahydrofuran and dimethylformamide, but are not limited to.

The reaction takes place in the presence of a strong base, such as potassium hydride, sodium hydride, diisopropylamide lithium, which can be obtained by the reaction of Diisopropylamine AI n-utillity.

Although the reaction temperature is not critical, the reaction is preferably carried out at a temperature of about - 100-50aboutAnd more prepattern from about 78aboutWith 0aboutWith, depending on the reagents and solvent used.

Similarly, acylation with 0-n nitrophenylacetate formula V is carried out in an inert solvent, preferably in the presence of a strong base, such as potassium hydride illi sodium, preferably at a temperature between ambient temperature and 0aboutC.

The new compounds show valuable pharmacological properties: lowers intraocular pressure and increase local activity compared this mixture on the basis of the obtained compounds can be obtained by a combination of therapeutically active quantity of at least one of the compounds of formula I, where R is previously described, or its pharmaceutically acceptable salt as an active ingredient, with appropriate additives.

For ophthalmic applications, the preferred solutions prepared using saline as the main solvent, the pH of such oft - limnologische solution should be 6.5 to 7.2 with a suitable buffer system. The solution may also contain suitable either pharmacologically acceptable stabilizers and protective equipment.

Preferred protective equipment that may be used in pharmaceutical compositions include, benzylaniline, chlorobutanol, thimerosal, tatianatatiana and routinisation, but are not limited to.

Also, various preferred solvents may be used in ophthalmic compositions. These solvents include polyvinyl alcohol, hypromellose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water, but are not limited to.

Toning supplements can be used if necessary. They include (but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or the hypoxia buffers to maintain pH. Accordingly, the buffers include acetate buffer, phosphate buffer and borate buffer. If necessary to obtain a desired pH can be used acids and bases.

Such ophthalmologist acceptable antioxidants used in ophthalmic compositions include (but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, bottled hydroxyanisol and bottled hydroxytrol.

Other optional components that may be included in the ophthalmic compositions representing chelating agents. Preferred chelating agents include disodium salt of ethylenediaminetetraacetic acid, although other chelating agents may also be used instead of or together with this chelating agent.

The components included in the composition, are usually in the following ratio, wt.%:

Active modifications% of 0.1-5

The fuse is a great tool 0-0,10 Solvent 0-40

Toning agent 1-10 Buffer 0.01 to 10 pH additive of 4.5-7.5 Antioxidant In need

the necessity of Clean water If necessary-

the necessity of trust

Denia to 100%.

Typical offer pharmaceutical ophthalmological composition shown in note the administered compounds were applied in a volume of 25 µl (rabbits) or 10 µl (OWl monkeys). The solutions contained a concentration of active ingredient 0.5 to 4% . Pupil diameter was measured at the time 0, 0,5, 1, 2, 3, 4, 5 and 6 h after treatment. The number of control solvent used normal saline or pilocarpine (0.5 to 1%) as a positive control. Intraocular pressure was measured through the same intervals after processing the selected compounds. Since most of the compounds were oil they were first dissolved in 0.01 N. acetic kisame until the desired volume has been normal saline, the pH of all test solutions was approximately 6.

Results.

Penetration into the cornea of the eye was determined by measuring the diameter of the pupil. The effect of the compounds of formula I on pupil size in rabbits are shown in the table.

Subsequent typical purpose to reduce the diameter of the pupil due to the fact that most of the compounds showed better penetration through the cornea of the eye. The degree of reduction of the diameter of the pupil was changed in the range from about 3% to about 50%. The exposure time from 1 h to no more than 6 hours (the duration of the experiment). In General this time depends on the degree of reduction of the diameter of the pupil. However, sushestvitelnoe period. This suggests a prolonged effect.

Compounds in which R is 4-tert-butylbenzyl group (example 12) or 2-propyl-1-Pintilei group (example 13) were selected for further study, mainly because they showed the desired activity without side effects, usually corresponding to the type of connection, such as redness, swelling and bleeding.

(3R, 4R)-1-Carbo-(4-tert-butylbenzoyl)-3-ethyl-4-(1-methyl-1H-imidazol-5-yl-methyl) -2-pyrrolidone (example 12).

In Fig. 1-6 are given to illustrate the proposed research connections.

Impact on pupil size.

The investigated compound was generated in rabbits reduction of the diameter of the pupil, 1% solution reaches maximum activity within one hour (see Fig. 1), and its activity is similar to activity a 1% solution of pilocarpine (see Fig. 3). Because the connection of the lactam in accordance with the invention, is less effective than pilocarpine, these results suggest that the lactam has the permeability, more than two times better than pilocarpine. Activity 4-tert-butylbenzoic connection persists for more than 6 hours (see Fig. 2) that more time steps pilocarpine. The reason for this not to understand what littelest steps of lactam and slow its hydrolysis.

The effect on intraocular pressure (10P).

The analyzed connection has resulted in the reduction of 10P in rabbits 4.5 mm RT. Art. after 2 h after application. This decrease 10P remained evident within 6 h (see Fig. 2). This fact is unusual because pilocarpine does not cause reduction of 10P in normotensive rabbits.

The analyzed compound of example 12 also reduces 10P in monkeys. However, the response speed is lower reaches its maximum at 4 h after application (see Fig. 4). This implies a lower rate of hydrolysis of compounds in the tissues of monkey eyes.

3R, 4R-1-Carbo-2-propyl-1-pentoxil-3-ethyl-4-(1-methyl-1H-imidazol-4-yl-methyl)-2-p irreligion (example 13).

Impact on pupil diameter.

Mitotic activity of the compounds of example 12 in rabbits was greater than that of previously investigated compound of example 12. The maximum effect was achieved after 3 h and the diameter of the pupil immediately began to increase, but did not reach control levels by the end of the 6-hour period (see Fig. 5).

The effect on intraocular pressure (10P).

The compound of example 13 was depressed 10P in rabbits 6 mm RT.article (see Fig. 5). This effect was bilateral. This big snizhenie and m e R 1. (3R, 4R)-1-Carbomethoxy-3-ethyl-4-(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone (method A).

To a solution of Diisopropylamine (58 mg, or 0.57 mmol) in tetrahydrofuran (THF) (2 ml) at 0aboutTo add 251 μl of a 2.5 M solution of n-utility (0,63 mmol) in hexane. The solution was stirred at 0aboutC for 15 min, then cooled to -78aboutWith and (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone (118,2 mg, or 0.57 mmol) in THF (2.5 ml) is carefully added, then poured THF (0.5 ml). After 2 h at -78aboutWith add medicinepharmacy (50.9 mg, of 0.60 mmol) and keep the temperature of -78 reactionaboutC for 1.5 h, then warmed to room temperature for 15 h the Reaction is quenched with saturated aqueous NaHCO3, extracted 3 times with CHCl3, dried over Na2SO4, filtered, concentrated and the residue is purified chromatographically stagelevel column (5% Meon saturated NH3/CHCl3with getting them 44.3 mg (3R, 4R)-1-carbomethoxy-3-ethyl-4[(1-methyl-1H-imida-Zol-5-yl)methyl]-2-pyrrolidinone in the form of oil (28%).

1H NMR (300 MHz, CDCl3): 7,38 (s, 1H); 6,79 (s, 1H); a 3.87 (DD, I 7,4 Hz, I, is 1.1 Hz, 1H); of 3.80 (s, 3H); of 3.54 (s, 3H); to 3.34 (DD, j = 6,4 Hz, I = 11,1 Hz, 1H); 2,81-to 2.74 (m, 1H); 2,60 (DD, I 8,7 Hz, I = to 15.4 Hz, 1H); 2,37-2,22 (m, 2H), 1,73-of 1.64 (m, 2H); 0,97 (t, I, 7.5 Hz, 3H).

1313H19N3ABOUT3, 0,7 thousand atomic mass units.

P R I m m e R 2. (3R, 4R)-1-Carbomethoxy-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone.

This compound is synthesized according to method A, using a-butylchloroformate with getting to 43.4 mg (3R, 4R)-1-carbomethoxy-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidone in the form of oil (19%).

1H NMR (300 MHz, CDCl3); 7,46 (s, 1H), 6.87 in (C. 1H); 4.26 deaths (C, I, a 6.5 Hz, 2H); of 3.94 (DD, I 7,4 Hz, I and 11.0 Hz, 1H); 3,61 (s, 3H); 3.42 points (DD, j = 6,5 Hz and 11.0 Hz, 1H); of 2.86 (DD, j = 5,2 Hz, I = to 15.4 Hz, 1H); to 2.67 (DD, I = 9,00 Hz, 15,5 Hz, 1H); 2,44-of 2.28 (m, 2H); 1,81-164 (m, 4H); 1,51-to 1.38 (m, 2H); of 1.05 (t, j = 7.4 Hz, 3H); to 0.97 (t, j = 7.4 Hz, 3H).

13With NMR (75 MHz, CDCl3): 174,73, 151,50, 138,11, 128,37, 127,16, 66,53, 50,41, 49,68, 34,56, 31,28, 30,49, 27,90, 22,32, 18,93, 13,59, 10,95.

Mass spectroscopy high-resolution set 307,1900 for C16H25N3O3, 0,4 thousand atomic mass units.

P R I m e R 3. (3R, 4R)-1-Carboethoxy-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)me - Tyl]-2-pyrrole the down n ' utility (0,535 mmol) in hexane. The solution was stirred at 0aboutWith 15 minutes, then gently add (with 1.0 l of THF) to a solution of (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrole - don (105,8 mg, 0.51 mmol) at room temperature. The mixture is stirred at room temperature for one hour, then add isobutylparaben (73,7 mg, 0.54 mmol). The solution is stirred at room temperature for 16 h, quenched with saturated aqueous NaHCO3three times extracted with chloroform, dried over Na2SO4, filtered, concentrated and the residue is purified silikagelevye through column chromatography (5% Meon nasishenna NH3/CHCl3with the release of 18.6 mg (3R, 4R)-1-carboethoxy-3-ethyl-4[(1-methyl-1H-imida - Zol-5-yl)methyl]-2-pyrrolidone in the form of a Golden oil (12%).

1H NMR (300 MHz, CDCl3): was 7.45 (s, 1H); 6,86 (s, 1H); is 4.03 (d, j = 6,8 Hz, 2H); of 3.94 (DD, j = 7.5 Hz, I = 11,1 Hz, 1H); 3,61 (s, 3H); 3.42 points (DD, j = 6,6 Hz, I = 11,1 Hz, 1H); 2,85 (DD, j = 5.3 Hz, j = 15.3 Hz, 1H); to 2.67 (DD, j = 9,0 Hz, I = to 15.4 Hz, 1H); 2,44-of 2.28 (m, 2H); 2,11-of 1.94 (m, 1H); 1,81-17,00 (m, 2H); was 1.04 (t, j = 7.4 Hz, 3H); 0,99 (d, j = 6,7 Hz, 6).

13With NMR (75 MHz, CDCl3): 174,70, 151,55, 138,14, 128,40, 127,22, 76,62, 50,45, 49,68, 34,62, 31,32, 27,96, 27,65, 22,36, 18,94, 11,00.

Mass spectroscopy high-vacuum established 307,1902 for C16H25N3O3to 0.6 mils nuclear is").

To a suspension of potassium hydride (23,8 mg, 0.59 mmol) in THF (5 ml) at 0aboutWith added methanol (1.6 mg, 0.05 mmol). The mixture is stirred for approximately 10 min at 0aboutS, then add (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)-methyl] -2-pyrrolidone (99,4 mg, 0.48 mmol) in THF (1.5 l), then rinse THF (0.5 ml). Reaction at room temperature is carried out for 1 h, then cooled to 0aboutWith and added dropwise to propiolactone (73 mg, of 0.60 mmol). The mixture is heated to room temperature and stirred for 3.5 days. The reaction is quenched with saturated aqueous NaHCO3three times extracted with CHCl3, dried over Na2SO4, filtered, concentrated and the residue is purified silikagelevye chromatographic column (6% Meon saturated NH3/CHCl3with the release of 28.6 mg (3R, 4R)-1-turboprops-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)-methyl] -2-pyrrolidone in the form of oil (43%).

1H NMR (300 MHz, CDCl3): 7,44 (s, 1H); at 6.84 (s, 1H); 4,19 (t, j = 6.5 Hz, 2H); to 3.92 (DD, j = 7,4 Hz, j = 11.3 Hz, 1H); 3,59 (C, 23), 3,39 (DD, j = 7,6 Hz, I = 11,1 Hz, 1H); and 2.83 (DD, j = 5,1 Hz, j = 16.2 Hz, 1H); of 2.64 (DD, j = 9.6 Hz, j = 15.2 Hz, 1H); 2,55 is 2.43 (m, 2H); 1,79-to 1.67 (m, 4H); of 1.02 (t, j = 6.6 Hz, 3H); 0,99 (t, j = 6.8 Hz, 3H).

13With NMR (75 MHz, CDCl3): 175,01, 151,82, 138,36, 128,59, 127,42, 68,17, 50,39, 49,61, 34,58, 31,11, 27,76, 22,20, 21,70, 10,73, 9,95.

Mass-spectrace mass.

P R I m e R 5. (3R, 4R)-1-Carbo-(3,3-dimethyl)butoxy-3-ethyl-4[(1-methyl-1H-imida - Zol-5-yl)methyl]-2-pyrrolidone.

This compound was synthesized according To the method using 3,3-dimethyl-1-butylchloroformate with the release of 17.0 mg (3R, 4R)-1-Carbo-(3,3-dimethyl)-butoxy-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidone in the form of oil (10%).

1H NMR (300 MHz, CDCl3); 7,45 (s, 1H); 6,85 (s, 1H); 4,30 (t, j = 7.5 Hz, 2H); to 3.92 (DD, j = 7,4 Hz, j = 11.3 Hz, 1H); 3,60 (C. 3H); 3.40 in (DD, j = 6,5 Hz, j = 11.3 Hz, 1H); 2.82 from (DD, j = 6,6 Hz, j = 15.7 Hz, 1H); of 2.64 (DD, j = 9.1 Hz, j = 15.7 Hz, 1H); 2,41 was 2.25 (m, 2H); 1,78-169 (m, 2H); 1,65 (t, j = 7.5 Hz, 2H); of 1.03 (t, j = 7.4 Hz, 3H); to 0.96 (s, N);13With NMR (75 MHz, CDCl3): 174,98, 151,80, 138,35, 128,58, 127,45, 64,43, 50,51, 49,64, 41,51, 34,56: 31,10, 29,47, 29,30, 27,77, 22,22, 10,72.

Mass spectroscopy high-resolution set 335,2213 for C18H29N3O3, 0,4 thousand atomic mass units.

P R I m e R 6. (3R, 4R)-1-Carbobenzoxy-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidone (R = CH2Ph).

This compound was synthesized according To the method using 2-(tert. -butoxy-carbonyloxy-2-phenylacetamido - sludge outlet 135,7 mg (3R, 3R)-1-Carbo(2-methyl-2-propyl)-3-ethyl-4[(1-methyl-1H-imida - Zol-5-yl)methyl] -2-pyrrolidone in the form of oil (87%).

1H NMR (300 MHz, CDCl= 11.2 Hz, 1H); of 2.81 (DD, j = 4.9 Hz, j = 15.7 Hz, 1H); 2,62 (DD, j = 8,8 Hz, j = 15.2 Hz, 1H); 2,41 was 2.25 (m, 2H); 1,78 by 1.68 (m, 2H); of 1.01 (t, j = 7.5 Hz, 3H),13With NMR (75 MHz, CDCl3): 175,02, 151,59, 138,38, 135,38, 128,75, 128,59, 128,53, 128,45, 127,47, 68,04, 50,35, 49,64, 34,60, 31,10, 27,74, 22,18, 10,73.

Mass-spectoscopy high resolution established 341,1733, for C19H23N3O3to 0.6 mils atomic mass units.

P R I m e R 7. (3R, 4R)-1-Carbo-(2-methyl-2-propoxy)-3-ethyl-4-[(methyl-1H-imidazol-5-yl)methyl]-2 - pyrrolidone (R-tert.-butyl).

This compound was synthesized according To the method using 2-(tert. -butoxy-carbonyloxy)-2-phenylacetone - Rila with access 135,7 mg (3R, 4R)-1-Carbo-(2-methyl-2-propoxy)-3-ethyl-4-[(1-methyl-1H - imidazol-5-yl)methyl]-2-pyrrolidone in the form of oil (87%).

1H NMR (300 MHz, CDCl3): 7,46 (s, 1H); 6,85 (s, 1H); to 3.89 (DD, j = 7,4 Hz, I = to 11.0 Hz, 1H); 3,63 (s, 3H); to 3.36 (DD, j = 6,6 Hz, I = 11,1 Hz, 1H); 2,84 (DD, j = 5,1 Hz, j = 15.2 Hz, 1H); to 2.66 (DD, j = 8.6 Hz, j = 16.2 Hz, 1H); 2.40 a-2,24 (m, 2H); 1,77 by 1.68 (m, 2H); and 1.54 (s, N); of 1.03 (t, j = 7.4 Hz, 3H);13With NMR (75 MHz, CDCl3): 174,97, 149,48, 138,04, 128,48, 127,08, 82,62, 50,13, 49,45, 34,12, 30,84, 27,52, 27,43, 21,85, 10,49.

Mass spectroscopy high-resolution set 307,1900 for C16H25N3O3, 0,4 thousand atomic mass units.

P R I m e R 8. (3R, 4R)-1-Carbo-(2-propoxy)-3-EA method using 1 M isopropylcarbamate in toluene with access to 36.8 mg (3R, 4R)-1-Carbo-(2-propoxy)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrol - Dimona in the form of oil (33%).

1H NMR (300 MHz, CDCl3): 7,37 (s, 1H); is 6.78 (s, 1H); 5,03-4,96 (m, 1H); 3,83 (DD, j = 7,4 Hz, I = 11,1 Hz, 1H); to 3.52 (s, 3H); 3,30 (DD, j = 6,6 Hz, I = 11,1 Hz, 1H); 2,77 (DD, j = 5,1 Hz, I = to 15.4 Hz, 1H); to 2.57 (DD, j = 9,2 Hz, j = 15.6 Hz, 1H); 2,33-2,17 (m, 2H); 1,71-to 1.61 (m, 2H); 1,25 (d, j = 6.3 Hz, 6N);13With NMR (75 MHz, CDCl3): 151,15, 138,33, 128,62, 127,37, 70,67, 50,35, 49,59, 34,46, 31,11, 27,73, 22,12, 21,53, 10,74.

Mass spectroscopy high-resolution set 293,1741 for C15H23N3O3, 0,2-thousandths of an atomic unit of mass.

P R I m e R 9. (3R, 4R)-1-Carbo-(2-(trimethylsilyl)-1-ethoxy)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)m ethyl]-2-pyrrolidone (R-2-(trimethylsilyl)-1-ethyl).

This compound was synthesized according To the method (using 2-(trimethylsilyl)-1-ethylchloride) with the release of 21.3 mg (3R, 4R)-1-Carbo-(2-(trimethylsilyl)-1-ethoxy)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)me - Tyl]-2-pyrrolidone in the form of oil (14%).

1H NMR (300 MHz, CDCl3): 7,42 (s, 1H); 6,83 (s, 1H); 4,32 (t, j = 8.7 Hz, 2H); a 3.87 (DD, j = 8,1 Hz, j = 9.1 Hz, 1H); of 3.57 (s, 3H); 3,37 (DD, j = 7,1 Hz, I = 11,1 Hz, 1H); 2,78 (DD, j = 5.6 Hz, j = 15.2 Hz, 1H); 2,61 (DD, j = 10.1 Hz, j = 16.2 Hz, 1H); 2,36-of 2.23 (m, 2H); 1,75-of 1.66 (m, 2H); 1,09 (m, 2H); 1000 (t, j = 7.5 Hz, 3H); being 0.036 (C, N).

13With NMR (75 MHz, CDCl3): 175,08,decided 351,1980 for C17H26N3SiO3, 0,2 thousand atomic mass units.

P R I m e R 10. (3R, 4R)-1-Carboethoxy-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)-methyl] -2-pyrrolidone (R-n-octyl).

This compound was synthesized according To the method using n-octylglucoside with the release of 80.3 mg (3R, 4R)-1-carboethoxy-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone in the form of oil (46%).

1H NMR (300 MHz, CDCl3): 7,34 (s, 1H); 6.75 in (s, 1H); 4,12 (m, 2H); 3,82 (DD, j = 7,4 Hz, I = 11,1 Hz, 1H); 3,50 (s, 3H); 3,29 (DD, j = 6,7 Hz, I = 11,1 Hz, 1H); to 2.74 (DD, j = 5.6 Hz, j = 15.7 Hz, 1H); to 2.55 (DD, j = 9.1 Hz, j = 15.7 Hz, 1H); 2,32-of 2.16 (m, 2H); 1,69-of 1.55 (m, 4H); 1,33-of 1.13 (m, 10H); to 0.92 (t, j = 7.5 Hz, 3H); of 0.79 (t, j = 6.8 Hz, 3H).13With NMR (75 MHz, CDCl3): 174,98, 151,68, 138,25, 128,50, 127,29, 66,70, 50,23, 49,51, 34,37, 31,42, 31,03, 28,79, 28,76, 28,20, 27,63, 25,36, 22,24, 22,06, 13,68, 10,62.

Mass spectroscopy high-resolution set 363,2519 for C20H33N3O3, 0,2 thousand atomic mass units.

P R I m e R 11. (3R, 4R)-1-Carborexics-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)me - Tyl]-2-pyrrolidone (R = n-hexyl).

This compound was synthesized according To the method using vexillifera with access 51,4 mg (3R, 4R)-1-carborexics-3-ethyl-4[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidone in the form of oil (30%).

1MR. YAM IS, H); of 2.86 (DD, j = 5,1 Hz, I = to 15.4 Hz, 1H); to 2.67 (DD, I = a 8.9 Hz, j = 15.2 Hz, 1H); 2,45-of 2.27 (m, 2H); 1,83-to 1.67 (m, 4H); 1,47 of 1.28 (m, 6N); of 1.02 (t, j = 7.5 Hz, 3H); to 0.92 (t, j = 6.6 Hz, 3H).13With NMR (75 MHz, CDCl3): 174,69, 151,41, 138,04, 128,32, 127,09, 66,75, 50,34, 49,62, 34,48, 31,24, 31,19, 28,34, 27,83, 25,24, 22,32, 22,26, 13,85, 10,90.

Mass spectroscopy high-resolution set 335,2219 for C18H29N3O3, 1,0 thousand atomic mass units.

P R I m e R 12. (3R, 4R)-1-Carbo-(4-tert.-butylbenzoic)-3-ethyl-4-[(1-methyl-1H-them-Gasol-5-yl)meth yl]-2-pyrrolidone.

Method C.

A. To a mixture of p-tert-butylbenzyl alcohol (329 mg, 2.0 mmol) and pyridine (158 MMG, 2.0 Mall) in THF (10 ml) at room temperature was added 4-nitrophenylphosphate (402 mg, 2.0 mmol).

The solvent is evaporated under vacuum and the residue is purified silikagelevye through column chromatography (15% Me OAc/hexane) to yield 403,5 mg 0-(4-nitrophenyl)-0-(4-tert. -butylbenzyl)carbonate in the form of a white solid (61% ).1H NMR (300 MHz, CDCl3): of 8.27 (d, j = 9.1 Hz, 2H); of 7.48-7,38 (m, 6N); and 5.30 (s, 2H); of 1.36 (s, N).13With NMR (75 MHz, CDCl3): 155,4, 152,3, 152,1, 145,2, 131,1, 128,5, 125,6, 125,1, 121,6, 70,7, 34,5, 31,1.

Mass spectroscopy high-resolution set, 314,1027 for C17H16NO5(M+ -CH3), 0,1 thousand atomic mass units. is and 0aboutWith add (3R, 4R)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrole - don (98 mg, 0.47 mmol) in THF (1.5 ml), then washed with THF (0.5 ml). The reaction mixture was stirred at 0aboutC for 10 min, then at room temperature for 1.5 hours then the reaction mixture was cooled to 0aboutWith and add 0-(4-nitrophenyl)-0-(4-tert. -butylbenzyl)Carbo - NAT (207 mg, to 0.63 mmol) in THF (1.5 ml), then washed with THF (0.5 ml). The reaction SES stirred at 0aboutC for 10 min, then at room temperature for 18 hours the Reaction is quenched with a saturated solution of sodium bicarbonate. Then the solution is extracted three times methylenchloride, the organic layers dried over Na2SO4, filtered, concentrated and the residue is purified silikagelevye chromatographic column (3.5% of the Meon saturated NH3/CHCl3with the release of 78.8 mg (3R, 4R)-1-Carbo-(4-tert.-butylbenzoic)-3-ethyl-4[(1-meth-yl-1H-imidazol-5-yl)METI l] -2-pyrrolidone in the form of a foamed material (42%).

1H NMR (300 MHz, CDCl3): 7,42-7,30 (m, 5H); 6,83 (s, 1H); 5.25-inch (doctor, I = to 11.0 Hz, 1H); 5,20 (d, I = to 11.0 Hz, 1H); to 3.92 (DD, j = 8,1 Hz, 10.1 Hz, 1H); of 3.57 (s, 3H); to 3.38 (DD, j = 6,6 Hz, j = 10.1 Hz, 1H); 2,80 (DD, j = 4,6 Hz, j = 16.2 Hz, 1H); 2,63 (DD, j = 16.2 Hz, j = 8.6 Hz, 1H), 2,40-of 2.24 (m, 2H); at 1.73 (m, 2H); of 1.29 (s, N); 0,99 (t, j = 7,6 Hz, 3H);13With NMR (75 who ctroscopy high resolution established 397,2366 for C23H31N3O3, 0,1 thousand atomic mass units.

In Fig. 1 - the impact of a 1% solution of the compound from example 12 on pupil diameter in rabbits NZXDB, N = 6,25 μl; Fig. 2 - the same, but the effect on intraocular pressure (10P); Fig. 4 - 0.5% solution, the pressure in monkeys, N 6, 10 ál.

P R I m e p 13. (3R, 4R)-1-Carbo-(2-propyl-1-pentoxil)-3-ethyl-4[(1-methyl-1H-them-Gasol-5-yl)methyl] -2-pyrrolidone.

A. 0-(4-Nitrophenyl)-0-(2-propyl-1-pentyl)carbonate siteserver method With using 2-propyl-1-pentanol with access 397,5 mg Golden oil (66%).1H NMR (300 MHz, CDCl3): of 8.27 (d, j = 9.0 Hz, 2H); 7,39 (d, j = 9,3 Hz, 2H); is 4.21 (d, j = 5.7 Hz, 2H); 1,82-of 1.73 (m, 1H); 1,45-of 1.29 (m, 8H); of 0.93 (t, j = 5.7 Hz, 6N);13With NMR (75 MHz, Cl3): 155,49, 152,50, 145,12, 125,07, 121,65, 72,10, 36,78, 33,05, 19,66, 14,4.

Century (3R, 4R)-1-Carbo-(2-propyl-1-pentoxil)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)me - Tyl]-2-pyrrolidone was synthesized according to method D using 0-(4-nitrophenyl)-0-(2-propyl-1-pentyl)-carbonate with access 103,0 mg oil (60%).

1H NMR (300 MHz, CDCl3): 7,46 (s, 1H); 6,86 (s, 1H); 4,15 (d, j = 5.8 Hz, 2H); of 3.94 (DD, j = 7,4 Hz, I = 11,1 Hz, 1H); 3,62 (s, 3H); 3.42 points (DD, j = 6,4 Hz, I = 11,1 Hz, 2H); of 2.86 (DD, j = 5,2 Hz, I = to 15.4 Hz, 1H); of 2.68 (DD, I = a 8.9 Hz, j = 15.3 Hz, 1H); 2,43-of 2.28 (m, 2H); 1,82 was 1.69 (m, 3H); 1,43 of 1.28 (m, 8H); the 1.04 (t, j = 7.5 Hz, 3H); 0,95-of 0.90 (m, 6N);13With YAM who roscope high resolution established 363,2537 for C20H33N3O3of 1.5 thousandths of an atomic unit of mass.

In Fig. 5 - the impact of a 1% solution of the compound from example 13 on pupil diameter in NZXDB rabbits N = 6,25 μl; Fig. 6 - the same, on intraocular pressure, N = 3.

P R I m e R 14. (3R, 4R)-1-Carbo-(5-methyl-2-hexose)-3-ethyl-4-[(1-methyl-1H-them-Gasol-5-yl)methyl] -2-pyrrolidone.

Method E.

A. Method used for the synthesis of 0-(4-nitrophenyl)-0-(5-methyl-2-hexyl)Kar-Bo Nata with access 421,4 mg oil (75%).

1H NMR (300 MHz, CDCl3): of 8.25 (d, j = 9.4 Hz, 2H); 7,37 (d, j = 9.4 Hz, 2H); 4,89-rate 4.79 (m, 1H); 1,78 of 1.50 (m, 3H); to 1.35 (d, j = 7.2 Hz, 3H); 1,31-1,19 (m, 2H); 0,89 (d, j = 7,7 Hz, 6N).13With NMR (75 MHz, CDCl3): 151,59, 152,00, 145,12, 125,16, 121,72, 77,83, 34,14, 33,49, 27,81, 22,40, 19,66.

Mass spectroscopy high-resolution set 282,1334 for C14H20NO5, 0,7 thousand atomic mass units.

Century (3R, 4R)-1-Carbo-(5-methyl-2-hexose)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidon synthesized according to method D using 0-(4-nitrophenyl)-0-(5-methyl-2-hexyl)carbonate with access for 95.2 mg Golden oil (64%) as a mixture of diastereoisomers.

1H NMR (300 MHz, CDCl3): 7,44 (s, 1H); 6,86 (s, 1H); equal to 4.97-to 4.87 (m, 1H); 3.95 to of 3.85 (m, 1H); 3,62 (s, 3H); 3,41-to 3.33 (m, 1H); 2,92 (DD, j = 5.3 Hz, j = 15.6 Hz, 1H); 2.63 in (the 8 Hz, 6N).13With NMR (75 MHz, DCl3): 174,69, 150,81, 150,74, 137,92, 128,27, 126,96, 74,20, 74,15, 50,18, 49,50, 34,39, 34,34, 34,09, 33,32, 31,14, 27,67, 27,57, 22,25, 22,16, 22,06, 19,67, 10,81.

Mass spectroscopy high-resolution set 349,2359 for C19H31N3O3to 0.6 mils atomic mass units.

P R I m e R 15. (3R, 4R)-1-Carbo-(4-methyl-1-pentoxil)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrolidone.

A. 0-(4-Nitrophenyl)-0-(4-methyl-1)phenyl-carbonate synthesized using method C, except that 4-nitrophenylphosphate was added to a mixture of 4-methyl-1-pentanol, pyridine and THF at a temperature of 0aboutC and the mixture was stirred at room temperature throughout the night.

1H NMR (300 MHz, CDCl3): 9,31 (d, j = 9.4 Hz, 2H); the 7.43 (d, j = 9.4 Hz, 2H); 4,32 (d, j = 7.7 Hz, 2H); 1.85 to around 1.74 (m, 2H); 1,67-of 1.56 (m, 1H); 1,38-of 1.30 (m, 2H); to 0.96 (d, j = 7,7 Hz, 6N);13With NMR (75 MHz, CDCl3): 155,49, 152,44, 145,18, 125,62, 121,71, 69,82, 34,52, 27,59, 26,31, 22,33.

Mass spectroscopy high-resolution set 268,1168 Dublin core13H18NO5(MN+), 1,7 thousand atomic mass units.

Century (3R, 4R)-1-Carbo-(4-methyl-1-pentoxil)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)me - Tyl] -2-pyrrolidone was synthesized using 0-(4-nitrophenyl)-0'-(4-methyl-1-pentyl)carbonate with the release of 71.7 mg oil (57%).

Mass spectroscopy high resolution established 335 2198 for C18H29N3O3, 1,1 thousand atomic mass units.

P R I m e R 16. (3R, 4R)-1-Carbo-(4-methylbenzene)-3-methyl-4-(1-methyl-1H-imida - Zol-5-yl)methyl]-2-pyrrolidone.

A. 0-(4-Nitrophenyl)-0-(4-methylbenzyl)carbonate was synthesized using method E, with output 548 mg of a white solid (89%).

1H NMR (300 MHz, CDCl3): compared to 8.26 (d, j = 9,3 Hz, 2H); 7,38-7,31 (m, 4H); 7.23 percent (d, I = a 8.9 Hz, 2H); 5.25 in (s, 2H), 2,36 (s, 2H).

Century (3R, 4R)-1-Carbo-(4-methylbenzene)-3-methyl-4-(1-methyl-1-imidazol-5-yl)methyl] -2-PI religon synthesized according to method D using 0-(4-nitrophenyl)-0'-(4-methylbenzyl)carbonate with access from 71.3 mg oil (47%).

1H NMR (300 MHz, CDCl3): 7,41 (s, 1H); to 7.32 (d, j = 8.1 Hz, 2H); 7,17 (d, j = 8.0 Hz, 2H); PC 6.82 (s, 1H); 5.25-inch (D. I = 11.8 Hz, 1H); 5,20 (d, I = and 12.4 Hz, 1H); 3,90 (DD, j = 7,4 Hz, j = 11.3 Hz, 1H); of 3.56 (s, 3H); to 3.38 (DD, j = 6,5 Hz, I = to 11.1 Hz, 1H); 2,80 (DD, j = 5.4 Hz, I = to 15.4 Hz, 1H); 2,61 (DD, I = 8,9 Hz, I = to 15.4 Hz, 1H); to 2.35 (s, 3H); 2,32-of 2.24 (m, 2H); 1,75-of 1.66 (m, 2H); 1,01 (t, 21,02, 10,81.

Mass spectroscopy high-resolution set 355,1883 for C20H25N3ABOUT3, 1,3 thousand atomic mass units.

P R I m e R 17. (3R, 4R)-1-Carbo-(2,5-dimethoxyphenoxy)-3-ethyl-4-[(1-methyl-1H - imidazol-5-yl)methyl]-2-pyrrolidone.

A. Method E was used for the synthesis of 0-(4-nitrophenyl)-0-(2,5-dimethoxybenzyl)carbonate with the release of 518 mg of pale green solid compound (78%).

1H NMR (300 MHz, CDCl3): of 8.27 (d, j = 9,3 Hz, 2H); 7,41 (d, j = 9,3 Hz, 2H); 7,00 (d, j = 2.4 Hz, 1H); 6,93-6,85 (m, 2H); are 5.36 (s, 2H); 3,85 (s, 3H); of 3.80 (s, 3H).13With NMR (75 MHz, CDCl3): 155,49, 153,26, 152,32, 151,70, 145,13, 125,11, 123,22, 121,65, 161,07, 141,59, 11,51, 66,36, 55,86, 55,62.

Mass spectroscopy high-resolution set 333,0845 for C16H15NO7, 0,4 thousand atomic mass units.

Century (3R, 4R)-1-Carbo-(2,5-dimethoxyphenoxy)-3-ethyl-4-[(1-methyl-1H-imidazo-5-yl)methyl ] -2-pyrrolidone was synthesized according to method D using 0-(4-nitrophenyl)-0-(2,5-dimethoxybenzyl)carbonate with the release of 73.8 mg Golden oil (44%).

1H NMR (300 MHz, CDCl3): 7,41 (s, 1H); 7,06 (s, 1H); 6,92-for 6.81 (m, 3H); 5,32 (d, I = 13,0 Hz, 1H); at 5.27 (d, j = 13.1 Hz, 1H); 3,93 (DD, j = 7,4 Hz, I = 11,1 Hz, 1H); 3,79 (s, 3H); 3,78 (C. 3H); of 3.56 (s, 3H); to 3.41 (DD, j = 6.3 Hz, I = to 11.0 Hz, 1H); of 2.81 (DD, j = 10,9 Hz, I = 15,5 Hz, 1H); 2.63 in (DD, j = 9,0 Hz,40, 115,05, 113,77, 111,31, 63,40, 55,85, 55,58, 50,29, 49,61, 34,46, 31,19, 27,80, 22,25, 10,88.

Mass spectroscopy high-resolution set 40,1966 for C21H27N3O5of 1.5 thousandths of an atomic unit of mass.

P R I m e R 18. (3R, 4R)-1-Carbochemical-3-ethyl-4-[(1-methyl-1H-imidazol-6-yl) methyl]-2-pyrrolidone.

A. Method E was used for the synthesis of 0-(4-nitrophenyl)-0-(octadecyl) carbonate with the release of 483 mg of a white solid compound (55%).

1H NMR: (300 MHz, CDCl3): compared to 8.26 (d, j = 9.0 Hz); 7,38 (d, j = 9,3 Hz, 2H); to 4.28 (t, j = 6,7 Hz, 2H); of 1.75 (t, j = 6.6 Hz, 2H); 1,47-to 1.21 (m, 3H); from 0.88 (t, j = 6.3 Hz, 3H);13With NMR (75 MHz, CDCl3): 155,49, 152,38, 145,13, 125,08, 121,61, 69,49, 31,83, 29,62, 29,59, 29,47, 29,39, 29,29, 29,09, 28,39, 25,54, 22,50, 13,99.

Mass spectroscopy high resolution set to C25H42NO5(MN+) 436,3068, of 0.5 thousandths of an atomic unit of mass.

Century (3R, 4R)-1-Carbochemical-2-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2-pyrrole don synthesized according to method D using 0-(4-nitrophenyl)-0-(octadecyl)carbonate with access to 107.6 mg Golden solids (50%).

1H NMR (300 MHz, CDCl3): 7,42 (s, 1H); at 6.84 (s, 1H); is 4.21 (t, j = 6,7 Hz, 2H); 3,91 (DD, j = 8,2 Hz, j = 11.8 Hz, 1H); 3,62 (s, 3H); to 3.38 (DD, j = 6,6 Hz, I = 11,1 Hz, 1H); of 2.81 (DD, j = 5,1 Hz, j = 15.3 Hz, 1H); and 2.83 (DD, j = 8.7 Hz, I = to 15.4 Hz, 1H); 2,47128,27, 127,06, 66,70, 50,28, 49,57, 34,44, 31,73, 31,18, 29,50, 29,39, 29,28, 29,17, 29,01, 28,36, 27,77, 25,54, 22,50, 22,20, 13,95, 10,85.

Mass spectroscopy high-resolution set 503,4096 for C30H53N3O3, 0,8 thousand atomic mass units.

P R I m e R 19. (3R, 4R)-1-Carbo-Exo-norbornane-3-ethyl-4-[(1-methyl-1H-imida-Zol-5-yl)methyl]-2-p irreligion.

A. 0-(4-Nitrophenyl)-0-(AkzoNobel)carbonate was synthesized according to method E with access 425,9 mg of a white solid compound (75%).

N1NMR (300 MHz, CDCl3): of 8.28 (d, j = 9.4 Hz, 2H); 7,40 (d, j = 9.4 Hz, 2H); 4.72 in-of 4.67 (m, 1H); 2,52-2,48 (m, 1H); 2,52-2,48 (m, 1H); 2.40 a-2,34 (m, 1H); 1,89 and 1.80 (m, 1H); 1,67-of 1.09 (m, 7H),13With NMR (75 MHz, CDCl3): 155,46, 151,68, 144,97, 124,99, 121,57, 82,83, 41,25, 38,98, 35,17, 34,96, 27,72, 23,75.

Century (3R, 4R)-1-Carbo-Exo-norbornane-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl] -2-PI religon synthesized according to method D using 0-(4-nitrophenyl)-0-(Exo-norbornyl)-carbonate, with access to 98.1 mg oil (55%) as a mixture of diastereoisomers.

1H NMR (300 MHz, CDCl3): the 7.43 (s, 1H); at 6.84 (s, 1H); 4.72 in-of 4.66 (m, 1H); 3,88 (DD, j = 6,4 Hz, I = 11,1 Hz, 1H); of 3.56 (s, 3H); at 3.35 (DD, j = 6,4 Hz, I = 11,1 Hz, 1H); 2.82 from (DD, j = 5,1 Hz, I = to 15.4 Hz, 1H); 2,62 (DD, j = 8,8 Hz, j = 15.3 Hz, 1H); 2,42 is 2.33 (m, 3H); 1,80-to 1.67 (m, 3H); 1,63-147 (m, 4H); 1,22-of 1.09 (m, 4H); a 1.01 (t, j = 7.4 Hz, 3H);13With NMR (75 MHz, CDCl3): 174,61, 150,75, 137,95, 128,95, 126,87, 79,84, ustanovila 345,2043 for C19H27N3O3, 0,9 thousand atomic mass units.

P R I m e R 20. (3R, 4R)-1-Carbo-endo-norbornene-3-ethyl-4-[(1-methyl-1H-imida-Zol-5-yl)methyl]-2-p irreligion.

A. 0-(4-Nitrophenyl)-0-(endo-norbornyl)carbonate was sintezirovany according to method E with access 487,6 mg of a white solid (86%).

1H NMR (300 MHz, CDCl3): of 8.27 (d, j = 9,2 Hz, 2H); 7,40 (d, j = 9,2 Hz, 2H); 5,07-4,99 (m, 1H); 2,64-to 2.65 (m, 1H); 2,30-of 2.26 (m, 1H); 2,15-2,07 (m, 1H); 1,89-to 1.79 (m, 1H); 1,67 is 1.58 (m, 1H); 1,52-of 1.33 (m, 4H); 1,22-to 1.14 (m, 1H).13With NMR (75 MHz, CDCl3): 155,79, 152,42, 145,32, 125,24, 121,80, 80,90, 39,97, 37,00, 36,26, 36,15, 28,83, 20,47.

Century (3R, 4R)-1-Carbo-endo-norbornene-3-ethyl-4-[(1-methyl-1H-imidazol-yl)me - Tyl]-2-pyrrolidone was synthesized according to method D using 0-(4-Nitrophenyl)-0-(endo-norbornyl)carbonate, with access 81,8 mg oil (76%) as a mixture of diastereoisomers.

1H NMR (300 MHz, CDCl3): 7,46 (s, 1H); 6,86 (s, 1H); 5,07-free 5.01 (m, 1H); 3,97-3,86 (m, 1H); 3,61 (s, 3H); 3,45-3,37 (m, 1H); 2,85 (DD, j = 5.4 Hz, j = 15.6 Hz, 1H); 2,69 (DD, j = 9,3 Hz, j = 15.3 Hz, 1H); 2,56 (ush. C. 1H). 2,44-of 2.23 (m, 3H); 2,11-a 2.01 (m, 1H); 1,89-1,72 (m, 3H); 1,65-and 1.54 (m, 1H); 1,48 to 1.31 (m, 4H); 1,15 was 1.06 (m, 1H); was 1.04 (t, j = 7.8 Hz, 3H).13With NMR (75 MHz, CDCl3): 174,59, 151,26, 137,99, 128,30, 127,04, 78,03, 50,28, 49,49, 40,09, 37,03, 36,73, 36,66, 36,25, 34,44, 34,40, 31,20, 29,05, 27,79, 22,16, 20,96, 10,90, 10,86.

Mass spectroscopy high resolution R)-1-Carboxy-(5-carboethoxy)-1-pentyl-3-ethyl-4-[(1-methyl-1H-imidazol - 5-yl)methyl]-2-pyrrole - don.

A. To a solution of caprolactone (1,14 g 10.0 mol) in N2O (5 ml) at a temperature of 0aboutWith add 12.5 ml of 1M sodium hydroxide solution (12.5 mmol). The reaction mixture was stirred at 0aboutC for 1 h and then warmed to room temperature 18 hours To the mixture of 2.5 ml of 1M hydrochloric acid (2.5 mmol) then the reaction mixture was stirred at room temperature for 30 min, then concentrated under vacuum and dried over P2ABOUT5at 1 mm RT.article 4 days. Ethanol (35 ml) at 60aboutC) add to the mixture, filtered through celite and the residue washed with ethanol. The filtrate is concentrated under vacuum, to the precipitate add dimethylformamide (70 ml) and 2-bromopropane (1.20 g, 9,76 mmol), the mixture is stirred at room temperature for 24 hours Add ethyl acetate and the mixture is thoroughly washed with water, N2O and saturated solution of NaHCO3with a ratio of 10: 1. Then dried (Na2SO4), filtered and concentrated to yield 201 mg of oil. After this oil was dissolved in THF (5 ml) and pyridine (137 mg, at 1.73 mmol) at a temperature of 0aboutWith a 4-nitrophenylphosphate (237,5 mg, 1.18 mmol) is added in one portion. The reaction mixture was warmed to room temperature for 17 h, then concentrated under vacuum. The remainder of the clean n is pentyl)-carbonate in the form of an oil (4.6 per cent).

1H NMR (300 MHz, CDCl3): 8,30 compared to 8.26 (m, 2H). 7,41-7,38 (m, 2H). 5,08-of 4.95 (m, 1H); or 4.31 (t, j = 7,0 Hz, 2H); 2,32 (t, j = 8.0 Hz, 2H); 1.85 to of 1.65 (m, 4H); 1,54-of 1.45 (m, 2H); of 1.23 (d, j = 7,0 Hz, 6N).13With NMR (75 MHz, CDCl3): 173,08, 155,72, 152,61, 145,42, 125,26, 121,80, 69,06, 67,31, 34,04, 27,85, 24,81, 24,13, 21,45.

Century (3R, R)-1-Carboxy-(5-carboethoxy-1 pentyl)-3-ethyl-4[(1-methyl-1H-them-Gasol-5-yl)methyl] -2-pyrrolidone was synthesized using 0-(4-nitrophenyl)-0-(5-carboethoxy-1 pentyl)-carbonate with the release of 36.4 mg Golden oil (65%).

1H NMR (300 MHz, CDCl3): 7,42 (s, 1H); at 6.84 (s, 1H); 5,03-is 4.93 (m, 1H); 4.25 in-4,20 (m, 2H); 3,90 (DD, j = 7,4 Hz, j = 11.2 Hz, 1H); to 3.58 (s, 3H) 3,38 (DD, j = 6,5 Hz, I = 11,1 Hz, 1H); 2.82 from (DD, j = 5,1 Hz, I = 15,9 Hz, 1H); of 2.64 (DD, j = 9.0 Hz, I = 15.3 Hz, 1H); 2,41-of 2.28 (m, 2H); 2,28 (t, j = 7.5 Hz, 2H); 1,76 is 1.60 (m, 6N); 1,46 to 1.37 (m, 2H); 1,22 (d, j = 6.3 Hz, 6N); a 1.01 (t, j = 7.5 Hz, 3H); 13With NMR (75 MHz, DCl3): 174,59, 172,79, 151,29, 137,96, 128,26, 126,98, 67,25, 66,28, 50,22, 49,54, 34,40, 34,30, 31,17, 28,04, 27,71, 25,06, 24,32, 22,15, 21,62, 10,80.

Mass spectroscopy high-resolution set for C21H33N3O3407,2407, 1,3 thousand atomic mass units.

P R I m e R 22. (3R, 4R)-1-Carboxy(1-carbomethoxy-1 pentyl)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidone.

A. To a solution of DL-2-hydroxypropranolol acid (79,2 mg to 0.60 mmol) in dichloromethane (5 ml) while the temperature is asiania (approximately 4 ml). The mixture was stirred at 0aboutC for 45 min, then bubbled through the solution argon for 5 minutes the Mixture was concentrated in vacuo and the residue dissolved in THF (5 ml) and pyridine (71 m, 0.90 mmol). After the mixture is cooled to 0aboutTo add 4-nitrophenylphosphate (122,4 mg, 0.61 mmol) in one portion, the reaction mixture is heated to room temperature and stirred for 18 hours the Mixture is concentrated under vacuum and the residue is purified silikagelevye through column chromatography (10% EtOAc/hexane) to yield 140.0 g of 0-(4-nitrophenyl)-0'-(1-carbomethoxy-1 pentyl)carbonate in the form of oil (75%).

1H NMR (300 MHz, CDCl3): 8,31-of 8.28 (m, 2H); 7,45-7,42 (m, 2H); of 5.06 (t, j = 6.2 Hz, 1H); is 3.82 (s, 3H); 2,02-of 1.92 (m, 2H); 1,52-of 1.32 (m, 4H); to 0.94 (t, j = 7,1 Hz, 3H).13With NMR (75 MHz, CDCl3): 170,00, 155,56, 152,27, 145,62, 125,34, 121,77, 76,45, 52,37, 30,41, 26,68, 21,84, 13,38.

Century (3R, 4R)-1-Carboxy-(1-carbomethoxy-1 pentyl)-3-ethyl-4-[(1-methyl-1H-imida-evil-5-l)-methyl]-2-pyrrolidone was synthesized according to method D using 0-(4-nitrophenyl)-0-(carbomethoxy-1 pentyl)-carbonate, with the release of 46.2 mg Golden oil (40%) as mixture of diastereomers.

1H NMR (300 MHz, CDCl3): the 7.43 (s, 1H); 6,85 (s, 1H); of 5.05 (t, j = 6,4 Hz, 1H); 4,01-a 3.87 (m, 1H); of 3.75 (s, 3H); 3,59 (s, 3H); 3,51-to 3.36 (m, 1H); 2,90-of 2.81 (m, 1H); 2,72 2.63 in (m, 1H); 2,43-of 2.28 (m, 2H); 1.91 a-of 1.84 (m, 2H); 1,79-1,7,94, 52,29, 50,23, 50,16, 49,56, 34,67, 31,28, 30,54, 27,79, 27,07, 27,02, 22,27, 22,13, 22,03, 13,70, 10,96, 10,91.

Mass spectroscopy high-resolution set for C19H29N3O5379,2096, 1,1 thousand atomic mass units.

P R I m e R 23. (3R, hydroxy-(5-Carbo-2,5-dimethoxybenzene-1 pentyl)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl(2-PI

A. 0-(4-Nitrophenyl)-0'-(5-Carbo-2,5-dimethoxybenzene-1 pentyl)carbonate was synthesized using method E with access to 121.6 mg yellow oil (64%).

1H NMR (300 MHz, CDCl3): of 8.27 (d, j = 9,2 Hz, 2H); 7,38 (d, j = 9,2 Hz, 2H); 6,91 (s, 1H); PC 6.82 (s, 1H); 6.81 (s, 1H); 5,16 (s, 1H); to 4.28 (t, j = 6.6 Hz, 2H); of 3.80 (s, 3H); of 3.77 (s, 3H); to 2.42 (t, j = 7.4 Hz, 2H); 1,83 was 1.69 (m, 4H); 1,55 was 1.43 (m, 2H).13With NMR (75 MHz, CDCl3): 173,48, 155,71, 153,59, 152,62, 151,71, 14,742, 125,38, 125,28, 121,81, 115,64, 113,53, 111,52; 69,06, 61,33, 55,78, 55,47, 33,73, 27,86, 24,85, 24,13.

Mass spectroscopy high-resolution set for C22H25NO9447,1526 0,3 thousand atomic mass units.

Century (3R, C-(5-Carbo-2,5-dimethoxybenzene-1 pentyl)-3-ethyl-4[(1-me-til-1H-imidazol-5-yl)methyl] -2 - synthesized according to method D using 0-4-(nitrophenyl)-0-(5-Carbo-2,5-dietician-saxi-1 pentyl)carbonate with the release of 28.5 mg oil (28%).

1H NMR (300 MHz, CDCl3): the 7.43 (s, 1H). make 6.90 (s, 1H). at 6.84 (s, 1H). PC 6.82 (s, 1H), 5,13 (s, 2H), 4,22 (t, I =I 6 is); 2,63 (DD, j = 9,0 Hz, I = to 15.4 Hz, 1H); 2,45-of 2.24 (m, 4H); 1,77-of 1.65 (m, 6N); 1,48 to 1.37 (m, 2H); of 1.01 (t, j = 7.4 Hz, 3H); 13With NMR (75 MHz, CDCl3): 175,05, 173,61, 153,58, 151,83, 151,77, 138,35, 128,58, 127,42, 125,54, 115,70, 113,72, 111,64, 66,41, 61,37, 55,93, 55,63, 50,34, 49,61, 34,49, 33,89, 31,12, 28,01, 27,74, 25,07, 24,27, 22,18, 10,74.

Mass spectroscopy high-resolution set 516,2704 for C27H38N3O70,6 thousandths parts of the atomic unit of mass.

P R I m e R 24. (3R, 4R)-1-Carboxy-[2-(3,4,5,6-tetrahydro-2H-pyranyl-2-oxy)-1 - hexyl] -3-ethyl-4[(1-methyl-1H-imidazol-5 - yl)-methyl]-2-pyrrolidone.

A. 0-(4-Nitrophenyl)-0-[2-(3,4,5,6-tetrahydro-2H-pyranyl-2-oxy)-1-hexyl]Carbo - NAT synthesized according to method E with access 365,5 mg oil (83%).

1H NMR (300 MHz, CDCl3): 8,31 compared to 8.26 (m, 2H); 7,44-7,37 (m, 2H); a 4.83-rate 4.79 (m, 1H); 4,43 (DD, j = 3.0 Hz, j = 12.0 Hz, 1H); 4,20 (DD, j = 7,0 Hz, j = 12.0 Hz, 1H); 4,01-a 3.87 (m, 2H); 3,57 is-3.45 (m, 1H); 1,88-of 1.30 (m, N); of 0.95 (t, j = 8.0 Hz, 3H);13With NMR 3.75 MHz, CDCl3): 155,82, 152,83, 145,54, 125,46, 121,91, 97,84, 73,39, 70,35, 62,62, 31,75, 30,64, 27,36, 25,19, 22,46, 19,34, 13,69.

Century (3R,))-1-Carboxy-[2-(3,4,5,6-tetrahydro-2H-pyranyl-2-oxy)-1-hexyl] 3-ethyl-4[(1 - methyl-1H-imidazol-5-yl) methyl]-2-pyrrolidone synthesized according to method D using 0-(4-nitrophenyl)-O-[2-(3,4,5,6-tetrahed - ro-2H-pyranyl-2-oxy)-1-hexyl] carbonate, with the release of 144,2 mg oil (83%), as a mixture of diastereoisomer is-2-pyrrolidone (120,0 mg, 0.28 mmol) in dichloromethane (10 ml) at room temperature add methanol (1.98 g of 61.7 mmol) and o-toluensulfonate monohydrate (74,8 mg 0,39 mmol) and the mixture stirred at room temperature for 3 days. The mixture is concentrated and the residue is between CH2CL2and saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with CH2CL2, the organic fraction is dried (Na2SO4), filtered, concentrated and the residue separated on a chromatographic silikagelevye column (4% Meon saturated with NH3/CHCl3with access to 70.7 mg (3R, 4R)-1-carboxy(2-hydroxy-1-hexyl)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl ]-2-PIR rolidone in the form of oil (73%).

1H NMR (300 MHz, CDCl3): 7,42 (s, 1H); 6,79 (s, 1H); 4,29-4,20 (m, 1H); 4.09 to a 4.03 (m, 1H); 3,93-a-3.84 (m, 2H); to 3.58 (s, 3H); 3,39 (DD, j = 6,6 Hz, I = to 11.0 Hz, 1H); 2.82 from (DD, j = 5.3 Hz, j = 15.6 Hz, 1H); of 2.64 (DD, I = 8,9 Hz); I = 15.3 Hz, 1H); 2,41 was 2.25 (m, 2H); 1,78-to 1.67 (m, 2H); 1,51-of 1.30 (m, 7H); 0,99 (t, j = 7.4 Hz, 3H); to 0.89 (t, j = 7,1 Hz, 3H);13With NMR (75 MHz, CDCl3): 175,15, 151,83, 138,27, 128,46, 127,19, 70,78, 70,73, 68,94, 50,26, 49,46, 34,41, 32,49, 31,08, 27,55, 27,21, 22,26, 22,03, 13,61, 10,63.

Mass spectroscopy high-resolution set 351,2168 for C18H29N3O4, 1,0 thousand atomic mass units.

P R I m e R 25. (3R, 4R)-1-Carbo-(1-acetoxy-1-ethoxy)-3-ethyl-4-[(1-methyl-1H-them - Gasol-5-yl(methyl-2-pyrrolidinone and (3R, 4R)-1-acetyl-3-ethyl-4[(1-methyl-1H-imida - Zol-5-yl)methyl]-2-pyrrolidone.

To a solution of Diisopropylamine (76 mg, 0.75 mmol) in THF (2.0 ml) at UP>about
C for 12 min, then (3R, 4R)-3-ethyl-4[(1-methyl-1H-imidazol-5-yl)methyl] -2-pyrrolidinone (148,0 mg, 0.71 mmol) in THF (2.0 ml) is added, then washed with THF (1.0 ml) and the mixture is heated to room temperature. After 1.5 h 0-(4-nitrophenyl)-0-(1-acetoxy-1-ethyl)carbonate (202,3 mg, 0.75 mmol) is added to THF (1.5 ml), then added THF (0.5 ml) and the reaction mixture stirred at room temperature for 18 hours the Reaction is quenched (20:1) H2O and saturated aqueous NaHCO3thrice extracted with l3combined organic extract is dried (Na2SO4), filtered, concentrated and the residue separated on a chromatographic silikagelevye column (3% Meon saturated NH3/CHCl3with the release of 23.6 mg 3: 1 mixture of (3R, 4R)-1-Carbo-(1-acetoxy-1-ethoxy)3-ethyl-4[(1-methyl-1H-imida - Zol-5-yl)-methyl-2-pyrrolidone and (3R, 4R)-1-acetyl-3-ethyl-4[(1-methyl-1H-imidazol-15-yl)methyl]-2-pyrrolidone as a yellow oil (10% ).

1H NMR (300 MHz, CDCl3): 7,49 (s, 1H); 6,94 (C, 0.25 H); 6,93 (C, 0.25 H); 6.89 in (s, 1H); 4.04 the-3,90 (m, 1H); 3,63 (s, 3H); 3.46 in-3,37 (m, 1H); 2,93-2,82 (m, 1H); 2,74-of 2.64 (m, 1H); 2.57 m (s, 0.75); 2,45-to 2.29 (m, 2H); 2.13 and (s, 3H); 1,82-1,72 (m, 2H); to 1.59 (d, j = 7,0 Hz, 3H); 1.06 a (t, j = 7.5 Hz, 3H);13With NMR (75 MHz, CDCl3): 174,65, 174,59, 171,13, 168,89, 149,23, 138,18, 128,28, 127,31, 127,19, 126,97, 90,27, 50,90, 50,36, 50,29, 49,57, 48,58, 34,64, 34.27, 31,33,B>16H23N3O5337,1639, thousandths of 0.1 atomic mass units.

P R I m e R 26. Ophthalmic composition.

A mixture of typical ophthalmic composition in accordance with this invention contains, wt%:

Active Ingram - dient 0,15

Benzalkonija - Reid 0-0,10

Polyvinyl alcohol (brand 20-90) 0-40 sodium Chloride 1-10

Sodium citrate di - hydrate of 0.01-10

Citric acid, monohydrate of 0.01-2 Clean water To 100%

N-substituted derivatives of (3R, 4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)-methyl]-2-pyrrolidone General formula

< / BR>
where R1- C20-alkyl, possibly substituted on trimethylsilyloxy group, hydroxy, acetoxy or isopropoxycarbonyl group, norbornyl,1- C4-alkylbenzene or 3,4-dimethoxybenzyl group,

or their pharmaceutically acceptable acid additive salts with antiglaucoma action.

 

Same patents:

The invention relates to the chemistry of indole derivatives, specifically to the new derived isoindoline General formula I

NR3where both R1is hydrogen or together form a bond;

both R2is phenyl which may be substituted in position 2 or 3 halogen or stands;

R3is phenyl which may be substituted, if necessary, by one or more radicals such as halogen, hydroxyl, alkyl (which may be substituted with halogen, amine or alkylamine), alkoxy, alkylthio (which may be substituted by hydroxyl, dialkylamino or 4-methylpiperazine), Amin, alkylamino, dialkylamino, 1-pyrrolidinyl or morpholino; cyclohexadienyl; naphthyl; thienyl; dithienyl; pyridyl or indolyl,

X is an oxygen atom, a sulfur or a radical NR5where R5is a hydrogen atom, alkyl containing from 1 to 12 carbon atoms, optionally substituted by one or two radicals, such as carboxy radical, dialkylamino, acylamino, allyloxycarbonyl, allyloxycarbonyl, carbamyl, allylcarbamate, diallylbarbital (and the alkyl portions of these radicals can be dialkylamino is l, furyl, pyridinyl or imidazolyl, or dialkylamino, and alkyl and acyl radicals mentioned above, unless otherwise indicated, are straight or branched and contain from 1 to 4 carbon atoms, in the form of (3аR, 7aR) - or (3аRS, 7aRS)-forms or their mixtures or their hydrochloride, which are antagonists of substance P, which can find application in therapy

The invention relates to the chemistry of condensed heterocyclic systems and specifically relates to new compounds - 4-acetyl-3-benzyl-2-methylthiopyridine(4,5-b)indole of the formula I

< / BR>
Through the study of its biological activity is established that it has the property to protect the liver from carbon tetrachloride poisoning

The invention relates to new derivatives of 2-(21-cyano-31-dialkylamino-21- enylidene)indolinone-3 of the General formula I

(I) where R= R1= CH3(Ia),

R + R1= (CH2)5(IB) having antihypertensive activity

The invention relates to medicine, namely to obstetrics

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves intravitreously introducing two electrodes into intraocular neoplasm after carrying out vitrectomy and retinotomy to expose the intraocular neoplasm. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with current intensity of 100 mA during 1-10 min or 10 mA during 10 min in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2.The transformed retina and tumor destruction products are intravitreally removed. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. Another embodiment of the invention involves adjusting position and size of the intraocular neoplasm in trans-scleral diaphanoscopic way. Rectangular scleral pocket is built above the intraocular neoplasm to 2/3 of sclera thickness with its base turned away from limb. Several electrodes are introduced into intraocular neoplasm structure via the built bed. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with the same current intensity in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. Superficial scleral flat is returned to its place and fixed with interrupted sutures. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg after having carried out vitrectomy and retinotomy. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2. The transformed retina and tumor destruction products are intravitreally removed using vitreotome. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. The number of electrodes is equal to 4-8.

EFFECT: reduced risk of metastasizing.

4 cl, 13 dwg

FIELD: medicine.

SUBSTANCE: method involves building tunnel to posterior eyeball pole in inferoexterior and superexterior quadrants. The tunnel is used for implanting flexible polymer magnetolaser implant to the place, the subretinal neovascular membrane is localized. The implant has a permanent magnet shaped as a cut ring and is provided with drug delivery system and a short focus scattering lens of laser radiator connected to light guide. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 5-7 mTesla units intensity. It is arranged with its north pole turned towards sclera at the place of the subretinal neovascular membrane projection with extrascleral arrangement of laser radiator lens membrane being provided in the subretinal neovascular membrane projection area. The other implant end is sutured to sclera 5-6 mm far from the limb via holes made in advance. The implant is covered with conjunctiva and retention sutures are placed thereon. Light guide and drug supply system lead is attached to temple with any known method applied. Drugs are supplied via the implant drug supply system in retrobulbary way in any order. Triombrast is given in the amount of 0,4-0,6 ml and dexamethasone or dexone in the amount of 0,4-0,6 ml during 3-4 days every 12 h. 0.1-1% aqueous solution of khlorin is intravenously introduced at the third-fourth day after setting the implant as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, at a bolus dose of 0.8-1.1 mg/kg. Visual control of subretinal neovascular membrane cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the subretinal neovascular membrane with the photosensitizer to maximum saturation level, intravitreous, transretinal laser radiation of 661-666 nm large wavelength is applied at general dose of 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the subretinal neovascular membrane via laser light guide and implant lens, repeated laser irradiation of the subretinal neovascular membrane is carried out with radiation dose of 30-60 J/cm2.

EFFECT: accelerated subretinal edema and hemorrhages resorption; regression and obliteration of the subretinal neovascular membrane; prolonged vision function stabilization.

6 cl

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to analogs of prostaglandin of the formula (I): , wherein A means -CH2-CH2- or -CH=CH-; B is absent or means phenyl; Z means -C(O)OR' or tetrazole-5-yl wherein R' means hydrogen atom or (C1-C6)-alkyl; m = 1, 2, 3, 4, 5 or 6; R1 means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, halogen atom, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C3)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B means phenyl and R3, R4, R5 and R6 do not mean hydrogen atom simultaneously; or R1 means unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B is absent and R3, R4, R5 and R6 means hydrogen atom simultaneously; R2 means hydrogen atom; each among R3, R4, R5 and R6 means independently of one another hydrogen atom or (C1-C6)-alkyl, or its pharmaceutically acceptable salt or individual isomer. Compounds of the formula (1) possess a selective agonistic activity with respect to ER4-receptors and therefore they can be used in pharmaceutical composition.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 2 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

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