Glucocorticoids connected by means of aromatic linker in position 21 to nitrate esters, and their application in opthalmology

FIELD: biotechnologies.

SUBSTANCE: in general formula (I), R1 and R2 that have been taken jointly are a group of formula (II), R3 represents atom of hydrogen or F and R4 represents F; R1, R2, R3 and R4 are connected to 17, 16, 6 and 9 carbon atoms of steroid structure in position α or β; R represents (III) or (IV), and the rest values of radicals are given in the description.

EFFECT: improving use efficiency of compositions for curing of eye diseases, such as diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other macular and retina diseases.

11 cl, 4 dwg, 5 tbl, 11 ex

 

The invention relates to microexplosion steroids, methods for their preparation, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions for the treatment of eye diseases, especially diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other retinal diseases and yellow spots. The retina is the area of the eye that are sensitive to light. The macula is the area of the retina that allows us to read and recognize faces. Disease yellow spots, such as age-related macular degeneration and diabetic edema yellow spots, are a major cause of blindness.

For the treatment of these diseases has been investigated many drugs in their effects on disorders that cause blindness. Currently, these drugs are delivered to the macula and the retina surgical methods, such as intravitreal (into the vitreous body) or periorbital injections or systemic routes of administration.

Surgical methods often require repeated injections can lead to serious eye complications, including endophthalmitis, retinal detachment and hemorrhage into the vitreous body. Similarly, the system entered the e is associated with many potential systemic side effects and difficulty in achieving therapeutic levels of drugs in the retina.

Lately there were a lot of messages about the effectiveness of intravitreal triamcinolone acetonide for the treatment of diffuse macular edema unresponsive to laser therapy. However, intravitreal injection of triamcinolone associated with many ocular complications. Complications of intravitreal therapy include triamcinolone caused by steroid increased intraocular pressure, cataractogenesis, postoperative infection, non-infectious andoftalmit and pseudo-andoftalmit.

Currently in the symptomatic treatment as the main effective medicines used for chemotherapy, steroids and inhibitors of carbonic anhydrase, but their efficacy is unproven and their application in a long time leads to side effects such as cataract, caused by steroids increased intraocular pressure, glaucoma, and infection, and the continuous use of these medicines for chronic diseases such as diabetes mellitus, is difficult.

In EP 0929565 described compounds of General formula B-X1-NO2where contains the remainder of the steroid, in particular hydrocortisone, and X1is a bivalent connecting bridge, which is a benzyl ring, the alkyl chain or ether. Connections can ispolzovatsya the treatment of eye disorders.

EP 1475386 describes compounds of the formula A-B-C-NO2where a contains the remainder of the steroid and-represents a bivalent connecting bridge, which contains the rest of the antioxidant. Connections may be used for the treatment of oxidative stress and/or endothelial dysfunction. In the described compounds antioxidant linker connected with a group of 21-HE of the steroid through the carboxyl group forming the ester linkage.

In WO 03/64443 described compounds of General formula B-X1-NO2where contains the remainder of the steroid and X1represents a bivalent connecting bridge, which is a benzyl ring or heterocyclic linker. Connections may be used for the treatment of eye diseases.

WO 07/025632 discloses compounds of the formula R-Z-X-ONO2where R-X contains the remainder of triamcinolone acetonide, valerianate of betamethasone or ethylcarbonate prednisolone, and X1is a bivalent connecting bridge, which is an aromatic ring, alkyl chain, ether, Frolovo acid, vanillic acid or a heterocyclic ring. Connections may be used for the treatment of skin diseases or diseases of the mucosa membranes, in particular for the treatment of atopic dermatitis, contact dermatitis and psoriasis.

F. Galassi et al., Br J Ophtalmolory 2006, 90, 1414-1419 opisyvayuschie dexamethasone 21-[(4-nitroxymethyl)] benzoate in the model of experimental glaucoma in rabbit, caused by corticosteroid. Releasing NO dexamethasone was administered topically twice a day; the results show that the connection can prevent the increase of intraocular pressure, reduce retro bulbar circulation and morphological changes in the ciliary bodies, possibly caused by local treatment with corticosteroids.

The object of the present invention is to develop microexplosion steroids for the treatment of inflammatory diseases. Another object of the present invention is to develop microexplosion steroids for the prevention or treatment of eye diseases, especially diabetic macular degeneration, diabetic retinopathy, age-related macular degeneration and other retinal diseases and yellow spots. In one aspect of the present invention one or more of these compounds reduce side effects associated with standard steroid therapy. In another embodiment of the invention one or more of these compounds have superior pharmacological activity compared with standard therapy.

The object of this invention is a compound of formula (I)or its salt, or a stereoisomer

,

where

R1and R2taken together are a group of the formula (II)

,

R3represents a hydrogen atom or F and R4is F,

R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroidal structure in position α or β;

R represents:

or

where Y is selected from:

1) -R5-CH(ONO2R6

2) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9

or

3) - [(CH2)o-X]p-(CH2)q-CH(ONO2R9

where R5- straight or branched C1-C1Balkylen;

R6, R7, R8and R9each represents H;

n is an integer from 0 to 6;

o is an integer from 1 to 6;

p is an integer from 1 to 6;

q is an integer from 0 to 6;

X represents O, S or NR10where R10- N or C1-C4alkyl; preferably X is O;

with the exception of the compounds of formula (I), where R1and R2taken together, represent a group of formula (II)

,

R4is F and R3is a hydrogen atom, and R is a compound of formula (III), where Y is - R5-CH(ONO2R6and R6- N.

In another embodiment of the invention describes compounds of formula (I)

,

where

R4- F, R3- F, and

R1 and R2taken together, represent a group of formula (II)

R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroidal structure in position α;

R represents:

or

,

where

where Y represents

1) -R5-CH(ONO2R6

where R5direct1-C5alkylene and R6N;

or

2) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9where

R5- direct C1-C6alkylene, R9, R7and R8are N and n=0 or 1;

or

3) - [(CH2)o-X]p-(CH2)q-CH(ONO2R9where

R9represents H,

o is an integer from 2 to 4;

p is an integer from 1 to 4;

q is an integer from 0 to 4;

X is O. In another embodiment of the invention describes compounds of formula (I)

,

where

R1and R2taken together, represent a group of formula (II)

where R4is F and R3represents a hydrogen atom;

R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroidal structure in position α;

R represents:

or

,

where

where Y represents

1) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9where

R5- direct1-C6alkylene, R9, R7and R8represent H; n=0 or 1; or

2) -[(CH2)o-X]p-(CH2)q-CH(ONO2R9where

R9represents H,

o is an integer from 2 to 4;

p is an integer from 1 to 4;

q is an integer from 0 to 4 and X represents O.

In another embodiment of the invention describes compounds selected from the following groups:

o is an integer from 1 to 6; preferably o is an integer from 2 to 4, more preferably about equal to 2;

p is an integer from 1 to 6; preferably p is an integer from 1 to 4; more preferably p is 1 or 2;

q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably O or 1;

X represents O, S or NR10where R10- N or C1-C4alkyl; preferably X is O.

Preferred R are:

,

,

,

,

,

In another embodiment of the invention describes compounds selected from the following groups:

In another embodiment of the invention describes compounds of formula (I) for the treatment of inflammatory diseases.

In another embodiment of the invention describes compounds of formula (I) for the treatment of eye diseases, especially diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other retinal diseases and yellow spots. The preferred compound is the above compound of formula (I).

In another embodiment of the invention are described with the unity of formula (I), including the compounds of formula (I), where R1and R2taken together, represent a group of formula (II)

,

where R4is F and R3is a hydrogen atom, and R is a compound of formula (III), where Y is - R5-CH(ONO2R6and R6represents H, for use in the treatment or prevention of diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other retinal diseases and yellow spots, especially diabetic macular edema. The preferred compound is a compound of formula (18).

In yet another embodiment of the invention describes a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of formula (I) and/or its salt or stereoisomer and ophthalmologically acceptable excipient suitable for intravitreal or periorbital injection form.

The term "excipient" is used here to denote any component other than the compound(s) of the present invention. The choice of excipient largely depends on factors such as route of administration, the effect of excipients on the stability and type of dosage forms.

In one another embodiment of the invention described is tsya pharmaceutical composition, where the compound of the present invention is administered in the form of a suspension or emulsion in an ophthalmologist acceptable carrier.

Compounds of the present invention, intended for pharmaceutical use, you can enter as crystalline or amorphous products. Compounds of the present invention, intended for pharmaceutical use may be administered by one or in combination with one or more other connection of the present invention.

The usefulness of the compounds of the present invention as medicines for the treatment or prevention of diabetic macular edema, diabetic retinopathy, macular degeneration, age-related macular degeneration and other retinal diseases and yellow spots demonstrated by determining the activity of these compounds by conventional methods of testing.

The method of synthesis

1) Compound of General formula (I), where R1, R2, R3and R4as mentioned above, the radical R as defined in formula III and IV, where Y, as described above, can be obtained:

1.1) the Reaction of compounds of formula (V),

where R1, R2, R3, R4as mentioned above, W represents N or C(O)Cl, with a compound of formula (VII) or (VIII)

,

where Y to the to above and

W1is N, when W represents-C(O)Cl, or

W1represents-C(O)Cl or-CO-O-Rawhen W is N, where Rais pentafluorophenyl or 4-nitrophenyl, P1protection for diol groups such as acetal, p-methoxybenzylidene, butylidene, and groups are described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, 2ndedition.

1.1.a) the Reaction of compounds of formula (V), where W represents H, with a compound of formula (VII) or (VIII), where W1represents - C(O)Cl, or a reaction of the compound of formula (V), where W represents - C(O)Cl, with a compound of formula (VII) or (VIII), where W1- N, can be carried out in the presence of organic bases such as N,N-dimethylaminopyridine (DMAP), Treillis, pyridine. The reaction is carried out in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, polygalacturonic aliphatic hydrocarbon, at temperatures between -20°C and 40°C. the Reaction ends in the range from 30 minutes to 36 hours.

1.1.b) the Reaction of compounds of formula (V), where W is H with a compound of formula (VII) or (VIII), where W1represents-C(O)-Rawhere Raas described above, can be carried out in the presence of a catalyst, such as DMAP, or in the presence of DMAP and a Lewis acid such as Sc(OTf)3or Bi(OTf)3. The reaction is carried out in an inert organic is kOhm solvent, such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, polygalacturonic aliphatic hydrocarbon, at temperatures between -20°C and 40°C. the Reaction ends in the range from 30 minutes to 36 hours;

1.2) with optional removal obtained at the stage 1.1.a) or 1.1.b) compounds protective groups according to the methods described in .W.Greene "Protective groups in organic synthesis". Harvard University Press, 1980, 2ndedition. To remove the protective acetamino group preferably using hydrochloric acid in tetrahydrofuran.

Obtaining compounds of formula (V)

2) the compounds of formula (V), where:

W represents N and R1is HE, R2is CH3, R3is a hydrogen atom, R4Is F or Cl;

or W H, R3is a hydrogen atom or F, R4F and R1and R2taken together, represent a group of the formula (11)

,

are commercially available.

2.1) the compounds of formula (V), where W represents-C(O)Cl or -- CORaand R1, R2, R3and R4as mentioned above, can be obtained from the corresponding commercially available compounds of formula (V), where W represents N, using known literature methods.

Obtaining compounds of formula (VII) or (UPG)

3) the compounds of formula (VII) or (VIII), where W1-N, P1as indicated above, and Y represents:

-R5 -CH(ONO2R6

-[(CH2)o-X]p-(CH2)q-CH(ONO2R9,

where R5, R6, R9, o, p and q are as defined above, can be obtained in the following way:

A) Reaction of compounds of formula (IX) or (X),

,,

where P is a protecting hydroxyl group, such as a silyl ether group, for example trimethylsilyl, tertbutyl-dimethylallyl, or trityl, and which are described in .W. Greene "Protective groups in organic synthesis". Harvard University Press, 1980, 2ndedition, P1as mentioned above,

with the compound of the formula (XI) or (XII)

or

,

where R5, R6, R9, o, p and q as above, and Q represents ONO2or Q1where Q1represents a chlorine atom, a bromine atom, an iodine atom, a mesyl group or tonilou group,

in the presence of a condensing agent, such as dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC), N,N'-carbonyldiimidazole (CDI), optionally in the presence of a base, such as DMAP.

The reaction is carried out in a dry inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, polygalacturonic aliphatic hydrocarbon, at a temperature from -20°C to 50°C. the Reaction Zakan is foreseen within from 30 minutes to 36 hours;

3.1.b) by reacting the above compound of formula (IX) or (X) with the compound of the formula (XIII) or (XIV)

or

,

where R5, R6, R9, o, p, q, and Q as above, and W3Is Cl, Br, I,

in the presence of organic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine, Diisopropylamine, or inorganic bases such as carbonate or hydroxide of alkaline earth metal, potassium carbonate, cesium carbonate, in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, polygalacturonic aliphatic hydrocarbon, at a temperature from -20°C to 40°C, mainly from 5°C to 25°C. the Reaction ends within the range time from 1 to 8 hours. When W3selected from chlorine or bromine, the reaction is carried out in the presence of an iodide salt such as KI;

C) Reaction of compounds of formula (IXa) or (Ha)

,,

where P and P1as indicated above, and Rb- pentafluorophenyl, 4-nitrophenyl or N-succimidyl),

with the compound of the formula (XI) or (XII)

or

,

where R5, R6, R9, o, p, q, and Q as above,

in the presence of a catalyst, such the AK DMAP or in the presence of DMAP and a Lewis acid such as Sc(OTf)3or Bi(OTf)3. The reaction of lead in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, polygalacturonic aliphatic hydrocarbon, at a temperature from -20°C to 40°C. the Reaction ends within from 30 minutes to 36 hours;

3.1.d) Reaction of compounds of formula (IXb) or (Xb)

,?

with the compound of the formula (XI) or (XII)

or

,

where R5, R6, R9, o, p, q, and Q as above, in the presence of organic bases such as N,N-dimethylaminopyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, polygalacturonic aliphatic hydrocarbon, at a temperature from -20°C to 40°C. the Reaction ends within a time range from 30 minutes to 36 hours;

3.2) the Reaction of the compound obtained in stage a) - 3.1.d), where Q is Q1source and nitro, such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or nitrate of tetraalkylammonium (where alkyl is C1-C10alkyl) in a suitable organic dissolve the barely, such as acetonitrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, DFA, in the dark at a temperature of from room temperature to the boiling temperature of the solvent.

Alternative reaction with ArNO3may be under the influence of microwave radiation in a solvent such as acetonitrile or THF, at a temperature of about 100-180°C. for about 1-60 minutes. A preferred source of the nitrogroup is silver nitrate;

3.3) optionally removing protecting the hydroxyl protective group R according to the methods described in .W.Greene "Protective Groups in organic synthesis", Harvard University Press, 1980, 2ndedition. To remove the silyl ester group is preferred fluoride ion.

4) the compounds of formula (VII) or (VIII), where W1- N, P1as indicated above, and Y represents

- R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9

-[(CH2)o-X]p-(CH2)q-CH(ONO2)-(CR7R8)n-CH(ONO2R9,

where R5, R9, R7, R8, o, p and q as above, and n is 0, can be obtained in the following way:

A) by reacting the above compound of formula (IX) or (X) with the compound of the formula (XV) or (XVI)

,

where R5, o, p, q, X and R9as described above, according to etodo, described in a);

4.1.b) by reacting the above compound of formula (IX) or (X) with the compound of the formula (XVII) or (XVII)

,

where R5, o, p, q, X and R9as described above, and W3Is Cl, Br, I,

according to the method described in 3.1. b);

C) Reaction of the above compounds of formula (IXa) or (Ha) with the compound of the formula (XV) or (XVI)

,

where R5, o, p, q, X and R9as described above, according to the method described in s);

4.1.d) Reaction of the above compounds of formula (IXb) or (the XB) with the compound of the formula (XV) or (XVI)

,

where R5, o, p, q, X and R9as described above, according to the method described in 3.1. d):

A) Reaction of compounds of formula (VIIA) or (VIIIA)

,

where P and P1as indicated above,

and Y' represents:

-R5-CH=CH-R9

-[(CH2)O-X]p-(CH2)q-CH=CH-R9,

where R5, o, p, q and R9specified as above, the source of the nitro group, such as silver nitrate, in the presence of iodine in a suitable organic solvent, such as acetonitrile, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, DFA, in the dark when the temperature is t -20°C to the boiling point of the solvent. Alternative reaction can be performed under the influence of microwave irradiation in solvents such as acetonitrile or THF, at a temperature in the range of about 100-180°C. for about 1-60 minutes; or

4.2.b) Dihydroxypropane double bond of the above compounds of formula (VIIA) or (VIIIA) to obtain the compound (VIIB) or (VIIIB)

,

where P and P1as indicated above,

and Y represents:

-R5-CH(OH)-CH(OH)-R9

-[(CH2)O-X]p-(CH2)q-CH(OH)-CH(OH)-R9,

where R5, o, p, q and R9as indicated above,

reagent for asymmetric dihydroxypropane on he sang sharpless, such as AD-mix alpha or AD-mix-beta, in a mixture of water/tert-butanol at temperatures from -20°C to 30°C., preferably from -5°C to 5°C. the Reaction ends after 1-24 hours.

4.3) the Reaction of the compound obtained in stage 4.2.b), with nitric acid and acetic anhydride in a suitable organic solvent such as methylene chloride, in a temperature range from -50°C to 0°C according to known literature methods.

4.4) With optional unprotect obtained at the stage 4.2. (a) or (4.3) compounds as described in .W.Greene "Protective groups in organic synthesis", Harvard University Press, 1980, 2 ^edition. To remove the protective silyl ether groups are preferred t is aetsa fluoride ion.

5) the compounds of formula (VII) or (VIII), where W1- N, P1as indicated above, and Y represents

-R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9

-[(CH2)o-X]p-(CH2)q-CH(ONO2)-(CR7R8)n-CH(ONO2R9where R5, R9, R7, R8, o, p and q as above, and n is an integer from 1 to 6,

can be obtained in the following way:

5.1) by reacting the above compound of formula (IX) or (X) with the compound of the formula (XIX) or (XX)

or

where R5, R9, R7, R8, n, o, p and q as above, Q2is ONO2or HE W3Is Cl, Br, I, according to the method described in 3.1b);

5.2) the Reaction of the compound obtained in stage 5.1)where Q is HE, the source of the nitro group according to the method described in 4.3).

5.3) optionally removing protecting the hydroxyl group R according to the method described in 3.3).

Obtaining the compounds (IX), (IXa), (IXb), (X), (XA) and (Xb)

5) the compounds of formula (IX), (IXa), (IXb), (X), (XA) and (Xb), where P, P1and Pbas described above, can be produced from commercially available vanillic acid or gallium acid according to known literature method.

Obtaining the compounds (XI)-(XX)

6.1) the compounds of formula (XI)to(XIV), g is e R 5, R6, R9, o, p, q and W3as described above, and Q represents the Q1where Q1as described above, are commercially available or can be obtained according to known literature methods.

6.2) the compounds of formula (XI)to(XIV), where R5, R6, R9, o, p, q and W3as described above, and Q represents a group ONO2can be obtained from the corresponding compounds where Q is Q1the reaction with the source of the nitro group as described above.

6.3) the compounds of formula (XV)to(XX), where W3, R5, R9, R7, R8, n, o, p and q are as defined above, are commercially available or can be obtained according to known literature methods.

Example 1 (Compound (1))

Synthesis of 4-(nitroxy) butyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-daftar-11-hydroxy-16,17-16,17-(1-methylethylidene(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate.

A) 4-(Nitroxy)butyl 4-hydroxy-3-methoxybenzoate.

To a solution of vanillic acid (5.0 g, 29,73 mmol) in N,N-dimethylformamide (50 ml) is added cesium carbonate (9,68 g, 29,73 mmol). The reaction mixture was cooled to 0°C and add 20% solution of 1-bromo-4-(nitroxy)butane in dichloromethane (29,45 g). The reaction mass is stirred PR the room temperature for 69 hours. The mixture is poured into 5% aqueous solution of NaH2PO4and extracted with diethyl ether (3×70 ml). The organic layers washed with water (70 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge FLASH column 65+MTMKP-Sil, eluent: gradient of n-hexane/ethyl acetate 95/5 (500 ml) to n-hexane/ethyl acetate 1/1 at 4000 ml, n-hexane/ethyl acetate 1/1 (500 ml)). Get 5,88 g of the product.

B) 4-(Nitroxy)butyl-3-methoxy-4-((4-nitrophenoxy)carbonyloxy) benzoate.

To a cooled to 0°C solution of compound A (2,94 g, 10,30 mmol) in dichloromethane (50 ml) is added pyridine (1,01 ml, 10,30 mmol) and p-nitrophenyl chloroformiate (2,07 ml, 10,30 mmol). The reaction mass was stirred at room temperature for 16 hours. The mixture was washed with 1M aqueous HCl solution (2×50 ml), the organic layer dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge FLASH column 65+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 93/7 (500 ml) to n-hexane/ethyl acetate 1/1 at 4000 ml, n-hexane/ethyl acetate 1/1 (500 ml)). Obtain 3.50 g of product.

C) 4-(Nitroxy)butyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-16,17-(1-methylethylidene(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-meth is sibental.

To a solution of the compound In (a 1.00 g, 2.28 mmol) in chloroform (30 ml) add triplet scandium (0.10 g, 0.22 mmol) and DMAP (0.54 g, 4,56 mmol). The reaction mixture was cooled to 0°C and add fluotsinolon acetonide (0,99 g, 2.28 mmol). The reaction mass was stirred at room temperature for 28 hours. The mixture is diluted with dichloromethane, washed with 5%NaH2PO4and then saturated aqueous sodium carbonate. The organic layer is dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (500 ml) to n-hexane/ethyl acetate 3/7 at 2000 ml, n-hexane/ethyl acetate 3/7 (500 ml)). Get to 0.29 g of the product.

The product is crystallized from a mixture of n-hexane/ethyl acetate.

MP.=199-200°C

1H-NMR: (DMSO), δ: 7.65 (2H, d); 7.38 (1H, d); 7.27 (1H, d); 5.60 (1H, dm); 5.50 (1H, s); 5.35 (2H, m); 4.60 (2H, t); 4.35 (2H, t); 4.20 (1H, m); 3.89 (3H, s); 2.75-2.50 (2H, m); 2.25 (1H, m); 2.00 (2H, m); 1.90-1.30 (13H, m); 1.15 (3H, s); 0.83 (3H, s).

Example 2 (Compound (3))

Synthesis of 5, 6-bis(nitroxy)hexyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-Dior-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate.

D) Gex-5-enyl 4-hydroxy-3-methoxybenzoate

To a solution of vanillic the acid (0.6 g, of 3.56 mmol) in N,N-dimethylformamide (7 ml) add diisopropylethylamine (0,93 g to 5.35 mmol) and 6-bromex-1-ene (of 0.71 ml, to 5.35 mmol). The reaction mixture was stirred at 50°C for 8 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 95/5 (200 ml) to n-hexane/ethyl acetate 7/3 at 2000 ml, n-hexane/ethyl acetate 3/7 (400 ml)). Get a 0.59 g of the product.

E) Gex-5-enyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzoate

To a solution of compound D (1,16 g, with 4.64 mmol) in N,N-dimethylformamide (30 ml) was added imidazole (1.18 g, 17,40 mmol) and tributyltinchloride (1.31 g, 8,7 mmol). The reaction mass was stirred at room temperature for 12 hours. The mixture is poured into an aqueous solution (50 ml) and extracted with diethyl ether (3×50 ml). The organic layers dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: n-hexane/ethyl acetate 95/5. Obtain 1.56 g of the product.

F) 5,6 Bis(nitroxy)hexyl-4-(tertBUTYLPEROXY)-3-methoxybenzoate

To a solution of compound E (1.4 g of 3.97 mmol) in acetonitrile (30 ml) is added silver nitrate (0.8 g, 4.77 mmol). The reaction mixture is cooled to -15°C and add iodine (1,21 g, 4.77 mmol). P is a promotional mass is stirred at -15°C for 20 minutes. Increase the temperature to 25°C and add iodine (2.7 g, 15.9 mmol). The reaction mixture is heated to 100°C for 60 minutes under the influence of microwave radiation. The resulting mixture is cooled, filtered and removed solvent under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (400 ml) to n-hexane/ethyl acetate 7/3 at 2000 ml, n-hexane/ethyl acetate 7/3 (400 ml)). Obtain 1.19 g of the product.

G) 5,6 Bis(nitroxy)hexyl 4-hydroxy-3-methoxybenzoate

To a cooled to About To a solution of compound F (1.19 g, 2,43 mmol) in tetrahydrofuran (40 ml) is added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (2/43 ml, 2,43 mmol). The reaction mass is stirred at 0°C for 20 minutes. The mixture is poured into 5% aqueous solution of NaH2PO4and extracted with ethyl acetate (3×50 ml). The organic layers washed with water (50 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (200 ml) to n-hexane/ethyl acetate 1/1 at 1000 ml, n-hexane/ethyl acetate 1/1 (200 ml)), and n-hexane/ethyl acetate 4/6 with 200 ml n-hexane/ethyl acetate 4/6 (400 ml)). Obtain 0.9 g of product.

H) 2-((6S,9R,10S,11S,13S,16R,17S)-6,9-Debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oxoethyl carbonochloridic.

To a cooled to 0°C solution fluotsinolon acetonide (1.2 g, to 2.65 mmol) in tetrahydrofuran (24 ml) is added in an atmosphere of N2a 20% solution of phosgene in toluene (5,58 ml, 10.6 mmol). The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 12 hours. The excess phosgene is removed by heating at 40°C for 45 minutes. The solvent is evaporated under vacuum. The crude product is used in the following stage without purification.

I) 5,6 Bis(nitroxy)hexyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate.

To a solution of compound H (0.56 g of 1.09 mmol) in dichloromethane (24 ml) add diisopropylethylamine (of 0.21 ml, 1.2 mmol). The reaction mixture was cooled to 0°C. and add a solution of compound G (0.45 g, 1.2 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 12 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 8/2 (200 ml) to n-hexane/ethyl acetate 2/8 at 2400 ml, n-hexane/ethyl acetate 2/8 (400 ml)). Get to 0.67 g of the product.

1H-NMR: (CDCl3), δ: 7.70 (2H, d); 7.30 (1H, d); 7.07 (1H, d); 6.45 (1H, s); 6.38 (1H, dd); 5.52-5.28 (2H, m); 5.16-4.91 (2H, dd);5.04 (1H, d); 4.74 (1H, dd); 4.50 (1H, m); 4.43-4.35 (3H, m); 3.95 (3H, s); 2.60-2.10 (4H, m); 1.90-1.47 (16H, m); 1.25 (3H, s); 0.95 (3H, s).

Example 3 (Compound (5))

Synthesis of 2-(2-(2-(nitroxy)ethoxy)ethoxy)ethyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-MN-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate

J) 4-(Tert-butyldimethylsilyloxy)-3-methoxybenzoic acid

To a solution of vanillic acid (2.0 g, 11,89 mmol) in N,N-dimethylformamide (50 ml) was added imidazole (Android 4.04 g, 59,45 mmol) and tert-butyldimethylchlorosilane (4,48 g, 29,72 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture is poured into an aqueous solution (70 ml) and extracted with diethyl ether (3×70 ml). The organic layers dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of acetonitrile/water 65/35 (600 ml) to acetonitrile/water 80/20 at 1200 ml). Get 0,70 g of the product.

K) 2-(2-(2-Chloroethoxy)ethoxy)ethyl-4-(tert-butyldimethylsilyloxy)-3-methoxybenzoate

To a solution of compound J (1.25 g, was 4.42 mmol) in dichloromethane (60 ml) is added 2-(chloroethoxy)-ethoxy ethanol (0,83 g of 5.75 mmol) and DMAP (catalytic amount). React the mixture was cooled to 0°C and added EDAC (1.10 g, of 5.75 mmol). The reaction mass was stirred at room temperature for 12 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (40 ml) to n-hexane/ethyl acetate 6/4 at 2000 ml, n-hexane/ethyl acetate 6/4 (400 ml)). Earn 1.25 g of the product.

L) 2-(2-(2-Nitroacetate)ethoxy)ethyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzoate

To a solution of compound K (1,53 g, 3.54 mmol) in acetonitrile (45 ml) is added sodium iodide (3,18 g, 21,24 mmol). The reaction mixture is heated to 120°C for 20 minutes under microwave irradiation.. The resulting mixture is cooled, filtered and removed solvent under reduced pressure. To a solution of the residue in acetonitrile (45 ml) is added silver nitrate (2,04 g, 14,16 mmol). The reaction mixture is heated to 120°C for 5 minutes under the influence of microwave radiation. The resulting mixture is cooled, filtered and removed solvent under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (600 ml) to n-hexane/ethyl acetate 6/4 at 2000 ml, n-hexane/ethyl acetate 6/4 (400 ml). Get to 1.37 g of product.

M) 2-(2-(2-Nitroacetate) ethoxy) ethyl 4-hydroxy-3-methoxybenzoate

To a cooled to 0°C solution of compound L (1.10 g, 2.4 mmol) in tetrahydrofuran (40 ml) is added 1M solution of tetrabutylammonium in tetrahydrofuran (2.4 ml, 2.4 mmol). The reaction mixture was stirred at 0°C for 20 minutes. The mixture is then poured into 5% aqueous solution of NaH2PO4(100 ml) and extracted with ethyl acetate (3×50 ml), the organic layers washed with water (100 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, Cartridge column FLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/ethyl acetate 9/1 (600 ml) to n-hexane/ethyl acetate 1/1 at 2000 ml, n-hexane/ethyl acetate 1/1 (400 ml). Get 0,76 g of the product.

N) 2-(2-(2-(nitroxy)ethoxy)ethoxy)ethyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate.

To a solution of compound H (0,508 g, 0/98 mmol) in dichloromethane (15 ml) add diisopropylethylamine (of 0.18 ml, 1.06 mmol). The reaction mixture is cooled at 0°C. and add a solution of compound M (0,37 g at 1.08 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 12 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, Cartridge column PLASH 40+M™ KP-Sil, eluent: gradient of n-hexane/etilize is at 8/2 (200 ml) to ethyl acetate 100% at 2400 ml, the ethyl acetate 100% (400 ml). Get 0,70 g of the product.

1H-NMR: (CDCl3), δ: 7.70 (2H, d); 7.30 (1H, d); 7.07 (1H, d); 6.45 (1H, s); 6.38 (1H, dd); 5.52-5.32 (1H, m); 5.15-4.91 (2H, dd); 5.04 (1H, d); 4.57-4.49 (4H, m): 4.41 (1H, m); 3.95 (3H, s); 3.84 (2H, dd); 3.78 (2H, dd); 3.68 (4H, m); 2.60-2.10 (4H, m); 1.90-1.47 (YOON, m); 1.25 (3H, s); 0.95 (3H, s).

Example 4 (Compound (6))

Synthesis of 4-(nitroxy)butyl 3-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-4,5-dihydroxybenzoate.

A) Methyl 7-hydroxy-2-(4-methoxyphenyl)benzo[d][1,3]dioxol-5-carboxylate.

To a suspension of Mergellina (10 g, to 54.3 mmol) in toluene (25 ml) is added p-toluensulfonate (29 mg) and dimethylacetal-p-anisaldehyde (to 11.56 ml, 67,88 mmol). The reaction mixture is refluxed for 1.5 hours with continuous removal of water. The mixture is diluted with dichloromethane (70 ml), washed with saturated aqueous solution of Mancos (100 ml) and extracted with ethyl acetate (CH ml). The organic layer was washed with water (100 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is crystallized with n-hexane. Obtain 8.6 g of product.

R) 7-Hydroxy-2-(4-methoxyphenyl)benzo[d][1,3]dioxol-5-carboxylic acid

To a suspension of compound (8.6 g, 28,41 mmol) in MESI water/ethanol 5/95 (260 ml) is added sodium hydroxide (2.5 ml, 62.5 mmol). The reaction mixture is heated under reflux for 15 hours, the solvent evaporated under vacuum. The residue is dissolved in water (150 ml) and extracted with ethyl acetate (100 ml). The aqueous layer was acidified with 1N aqueous HCl to pH 4 and extracted with ethyl acetate (6×50 ml). The organic layers dried over sodium sulfate and concentrate under reduced pressure. The crude product (5,78 g) used in the next stage without any treatment.

Q) 4-(Nitroxy)butyl-7-hydroxy-2-(4-methoxyphenyl)benzo[d][1,3]dioxol-5-carboxylate.

To a solution of compound R (5,78 g, 20,05 mmol) in N,N-dimethylformamide (50 ml) is added cesium carbonate (6,52 g, 20,05 mmol). The reaction mixture was cooled to 0°C and add 20% solution of 1-bromo-4-(nitroxy)butane in dichloromethane (19,85 g). The reaction mixture was stirred at room temperature for 40 hours. The mixture is poured into 5% aqueous solution of NaH2PO4and extracted with diethyl ether (2×70 ml). The organic layers washed with water (50 ml), dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient of n-hexane/ethyl acetate 9/1 (200 ml) to n-hexane/ethyl acetate 1/1 at 1200 ml, n-hexane/ethyl acetate 1/1 (400 ml)). Get 4,36 g of the product.

R) 4-(Nitroxy)butyl 7-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-who etilefrine)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro)-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-2-(4-methoxyphenyl)benzo[d][1,3]dioxol-5-carboxylate.

To a solution of compound Q (0,519 g, 1.28 mmol) in dichloromethane (13 ml) add diisopropylethylamine (0,179 ml, 1.28 mmol). The reaction mixture was cooled to 0°C. and add a solution of compound H (0.6 g, of 1.16 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient of n-hexane/ethyl acetate 9/1 (200 ml) to n-hexane/ethyl acetate 3/7 at 1200 ml, n-hexane/ethyl acetate 3/7 (400 ml)). Get 0,979 g of the product.

4-(Nitroxy)butyl 3-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-4,5-dihydroxybenzoate.

To a solution of compound R (0.97 g, of 1.09 mmol) in tetrahydrofuran (22,4 ml) add IN water model HC1 (22,4 ml). The reaction mixture was stirred at room temperature for 17 hours. The solvent is evaporated under vacuum. The residue is extracted with ethyl acetate (2×30 ml), the organic layers dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient of acetone/dichloromethane 5/95 (200 ml) to the acetone/dichloromethane 2/8 at 900 ml, to the acetone/dichloromethane 3/7 at 600 ml). P what do 0,344 g of the product.

1H-NMR: (CDCl3), δ: 7.51 (2H, dd); 7.14 (1H, d); 6.47 (1H, s); 6.40 (1H, dd); 5.52-5.32 (1H, m); 5.24-4.93 (2H, dd); 5.03 (1H, d); 4.53 (2H, t), 4.43-4.33 (3H, m); 2.54-2.17 (4H, m); 2.00-1.65 (8H, m); 1.53 (3H, s); 1.47 (3H, s); 1.25 (ZN, s); 0.94 (3H, s).

Example 5 (Compound (10))

Synthesis of 4-(nitroxy)butyl 3-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-4,5-dihydroxybenzoate.

S) 2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oxoethyl carbonochloridic.

To a cooled to 0°C solution of triamcinolone acetonide (3 g, 6,9 mmol) in tetrahydrofuran (33 ml) in an atmosphere of N2add 20% toluene solution of phosgene (21,8 ml, up 41.4 mmol). The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 17 hours. The excess phosgene is removed by heating at 40°C for 30 minutes. The solvent is evaporated under vacuum. The crude product used in the next stage without any treatment.

T) 4-(Nitroxy)butyl 7-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-2-(4-methoxyphenyl)benzo is[d][1,3]dioxol-5-carboxylate.

To a solution of compound Q (0,583 g of 1.32 mmol) in dichloromethane (14 ml) add diisopropylethylamine (0,231 ml of 1.32 mmol). The reaction mixture was cooled to 0°C. and add a solution of compound S (0.6 g, 1.2 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent is evaporated under vacuum. The residue is purified using flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient of n-hexane/ethyl acetate 9/1 (200 ml) to n-hexane/ethyl acetate 3/7 at 1200 ml, n-hexane/ethyl acetate 3/7 (400 ml)). Get 0,819 g of the product.

U) 4-(Nitroxy)butyl 3-((2-((9R,10S,11S,13S,16R,17S)-9-fluorescent-11-hydroxy-16,17-((1-methylethylidene)bis(oxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-4,5-dihydroxybenzoate.

To a solution of compound T (0,81 g of 0.93 mmol) in tetrahydrofuran (19,5 ml) is added 1N aqueous HCl (19,5 ml). The reaction mixture was stirred at room temperature for 18 hours. The solvent privault vacuum. The residue is extracted with ethyl acetate (2×30 ml), the organic layers dried over sodium sulfate and concentrate under reduced pressure. The residue is purified using flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient of acetone/dichloromethane 5/95 (200 ml) to the acetone/dichloromethane 3/7 at 900 ml acetone/dichloromethane 3/7 (200 ml)).

Get the 0,245 g of the product.

1H-NMR: (CDCl3), δ: 7.51 (2H, dd); 7.23 (1H, d); 6.38 (1H, s); 6.18 (1H, dd); 5.21-4.90 (2H, dd); 5.03 (1H, d); 4.53 (2H, t), 4.41-4.32 (3H, m); 2.69-2.35 (4H, m); 2.00-1.65 (10H, m); 1.53 (3H, s); 1.45 (3H, s); 1.24 (3H, s); 0.94 (3H, s).

Example 6 (Compound (17))

2-(2-(2-(Nitroxy)ethoxy)ethoxy) ethyl 4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1 methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate

The compound was synthesized using the procedure described in example 3, on the basis of connection S and the connection M.

1H-NMR: (CDCl3), δ: 7.71 (2H, d); 7.26 (1H, d); 7.15 (1H, d); 6.31 (1H, dd); 6.12 (1H, s); 5.12 (1H, d); 4.91 (1H, d); 5.01 (2H, d); 4.56 (2H, m); 4. 49 (2H, t), 4.40 (1H, m); 3.95 (3H, s); 3.79 (2H, t); 3.76 (2H, m); 3.67 (4H, m); 2.65-2.35 (4H, m); 2.15-2.00 (1H, m); 1.92-1.84 (1H, m); 1.72-1.55 (2H, m); 1.51 (3H, s); 1.45 (3H, s); 1.25 (5H, m); 0.93 (3H, s).

Example 7 (Compound (18))

4-(Nitroxy)butyl 4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-(1-methylethylidene bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate

The compound was synthesized using the procedure described in example 1, on the basis of triamcinolone acetonide and connections C.

1H-NMR: (CDCl3), δ: 7.65 (2H, m); 7.26 (1H, d); 7.17 (1H, d); 6.40 (1H, dd); 6.10 (1H, s); 5.11-4.84 (2H, dd); 4.99 (1H, d); 4.53 (2H, t); 4.37 (2H, t); 3.93 (3H, s); 2.71-2.30 (5H, m); 2.00-1.50 (6N, m); 1.87 (4H, m); 150 (3H, s); 1.41 (3H, s); 1.22 (3H, s); 0.92 (3H, s).

Example F1: a Study of vascular tone Test connections:

Connection (1)described in the other 1;

Connection (3)described in the other 2:

Connection (5)described in the other 3;

Connection (6)described in the other 4;

Connection (10)described in the other 5;

Connection (18), described in the other 7.

Control connection:

Fluotsinolon acetonide (FC)

Triamcinolone acetonide (TAAS)

The ability of the compounds of the present invention to induce vasorelaxation compared with compounds precursors was investigated in vitro on isolated preparations of the thoracic aorta of a rabbit (Wastall J.C. at al., Br. J. FharmacoL, 134:463-472, 2001). Male new Zealand rabbits (1,8-2 kg) were anestesiologi by thiopental sodium (50 mg/kg, iv)was scarificial by bleeding, then opened the chest and dissect the aorta. The aorta was immediately placed in Krebs buffer-HEPS (pH 7.4; composition in mm: NaCl 130.0, KCl 3/7, NaHCO314.9 KN2RHO41.2, MgSO4·7H2O 1.2, glucose 11.0, HEPES 10.0, CaCl2·2H2About 1.6) and cut into ring segments (length 4-5 mm). For measurement of isometric tension2each ring was placed in the incubator for tissue cultures of 5 ml, filled with Krebs buffer-HEPS (37°C) and the winding 95% O2with 5% CO2and then combined with the force measuring transducer (Grass FT03), wired the m measuring system BIOPAC MP150. The drugs were given an opportunity to be balanced within 1 hour when the passive tension of 2 g, changing the buffer every 15 minutes and then stimulated by the action of 90 mm KCl (3 times) with intermediate washing. Upon reaching trim caused their prior submaximal contraction with methoxamine (3 μm) and after attaining a stable pre-reduction built a cumulative curve of the concentration-response to test compounds. The time intervals between doses was determined on the basis of the time required to achieve complete response steady state. Responses to the test compounds was expressed as the percentage of residual reduction and constructed a chart depending on the concentration of the tested compounds. Values EU50(where EU50represents the concentration providing 50% of the maximum relaxation to test the connection) interpolable of these charts. As shown in Table 1, the test compounds are able to induce relaxation, depending on the concentration.

no effect
Table 1:
The study of vascular tone.
Test connectionECso (µm)
FC
Connection (1)2,2
Connection (3)0,21±0,07
The compound (5)0,83±0,25
Connection (6)1,44±0,41
TAASno effect
The compound (18)1,56
The compound (10)2,3 5±0,98

Example F2

Evaluation of the effectiveness of the compounds of the present invention in vivo in the VEGF-induced model of transudation of fluid through the vessels of the rat.

Growth factor vascular endothelial (FRES) activates a common way of transudation through the vessels, which is associated with various pathological processes, including diabetic edema yellow spots (DME). Test the connection:

Connection (1)described in Example 1

- Fluotsinolon acetonide (FC): control connection for connection (1),

Connection (18)described in Example 7,

- Triamcinolone acetonide (TAAS): control connection for the connection (18).

Male rats Sprague, doli (~250 g; Charles River laboratory) were anestesiologi inhalation izoflurana and topically applied to the eye drop 0.5% tetracaine on g is Aza. Pupils expanded local application of 1% cyclopentolate hydrochloride in order to see the needle for the implementation of intravitreal (into the vitreous body) injection. Recombinant growth factor vascular endothelial (FRES; 100 ng/eye) or FRES 100 ng/eye plus test compounds were prepared in 0.5% carboxymethylcellulose (CMC) in sterile saline and was injected into the vitreous body of the needle 30-caliber (Xu, Q., et al. Invest. Ophthalmol. Vis. Sci, 42:789-794, 2001). Compounds of the present invention was compared with the corresponding steroids in equimolar doses. For example, for comparison with fluotsinolon the acetonide as at 25 and 50 μg/eye, the compound (1) was administered at a dose 42,4 and 84.7 µg/eye, respectively. Control animals received media. For comparison next to triamcinolone-acetonide similar doses were administered the compound (18).

The transudation through the retinal vessels were measured previously described method (Xu, Q., et al. Invest. Ophthalmol. Vis. Sci, 42:789-794, 2001). After approximately 18 hours after injection of the test compounds rats intraperitoneally was anestesiologi ketamine (80 mg/kg) and xylazine (4 mg/kg). Then was injected into the jugular vein of 45 mg/kg Evans blue (ES). The paint was given the opportunity to circulate for 2 hours. Opened the chest cavity and rats were perfesional 1%formalin in 0.5 M citrate buffer (pH 3.5 and 37°C) through the left ventricle. From enyl the new eye was carefully taken away millimetre of the retina, put them in a pre-weighed Eppendorf tubes, dried in speed vacuum during the night and record the dry weight. Was extracted with Evans blue, incubare each retina in 120 μl of formamide for 18 hours at 70°C, and centrifuged for 2 hours at 6000 rpm. Measured the absorbance 60 µl of the extract at 620 nm and determined the background absorbance at 740 nm. The final absorbance was calculated by subtracting the background absorbance at 740 nm from the absorbance at 620 nm. Was measured by a standard curve of Evans blue in formamide and expected to Transudation of Evans blue in formamide, expressed as μl/g/h, as shown below:

[EB (ng/ml) × 120 (mm) × 1000] / [dry weight of the retina (mg) × time circulation (h) × ES in plasma (ng/ml) × 100].

As shown in figure 1 and, intravitreal injection of 100 ng of VEGF leads to a 3.5-fold increase (n=17, P 0.05) vascular permeability later, 18 hours after injection. Processing 25 μg/eye fluotsinolon acetonide and 42.4 g/eye connection (1) inhibits the VEGF-induced the transudation of 86.1% and 77.1 percent respectively (Figures 1A and 1b, n=9, P<0.05). Similarly triamcinolone acetonide at a dose of 10 μg/eye and an equivalent dose of a compound (18) caused a reduction of 67.5% to 54.3%, respectively (Figures 2A and 2b). In all cases, the inhibition of transudation of similar magnitude as for connections this is the first invention (compounds (1) and (18)), and the corresponding steroid.

Example F3

Evaluation of the improvement of steroid-induced intraocular pressure (IOP) in vivo in rats with compounds of the present invention. Test the connection:

Connection (1)described in Example 1

- Fluotsinolon acetonide (FC): control connection

- Des-nitroazoles the compound (I): butyl 4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-debtor-11-hydroxy-16,17-16,17-(1-methylethylidene bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent[a]phenanthrene-17-yl)-2-oksidoksi)carbonyloxy)-3-methoxybenzoate.

Male grey rats (250-275 g; Charles River laboratory) before measurement of intraocular pressure (IOP) acclimatized during the week. Before intravitreal injection of the test compounds in awake rats was measured initial (basic) IOP using the Tonolab tonometer (Tinolat Inc) (Pease, M.E., et al j Glaucoma, 15:512-519, 2006). Then rats were anestesiologi inhalation izoflurana and topically applied to the eye drop 0.5% tetracaine. Pupils expanded local application of 1% cyclopentolate hydrochloride and 2.5% phenylephrine hydrochloride, in order to see the needle for the implementation of intravitreal injection of test compounds. The compound (1) was compared with the corresponding steroid and des - nitro analogue in equimolar doses. For example, for comparison with fluotsinolon Antonida as at 25, that is, and at 50 μg/eye, the compound (1) was administered at a dose 42,4 and 84.7 µg/eye, respectively. Des necroanal compound (1) was administered at a dose 39,1 μg/eye (equivalent to 25 μg FC). Control animals received the media.

For each point in time of the five dimensions were chosen medium. The IOP measurement was performed in the first and second weeks after intravitreal injection of test compounds.

The base pressure in the gray rats was 18 mm Hg. As shown in figure 3, one week after injection fluotsinolon acetonide YUR increased by 4 mm Hg at 25 μg/eye and 3 mm Hg at 50 μm/g, respectively. These results were confirmed after two weeks (p<0.05). However, injection of the compound (1) in doses of 25 or 50 μg/eye, equivalent 42,4 and 84.7 µg/eye, respectively, did not cause changes in IOP in the first and second week after injection (figure 3). In another experiment, as shown in figure 4, dinitroanisole connection (1) at a dose of 25 μg/eye, equivalent to 39, 1 μg/eye, fluotsinolon acetonide (FC) at a dose of 25 μg/eye caused an increase in IOP compared to compound (1) at a dose of 25 μg/eye, equivalent 42,4 μg/eye.

Example F4

Evaluation of the effectiveness of the compounds on intraocular pressure, ocular hemodynamics and protection of the retina and the assessment of the content of inflammatory cytokines in the aqueous humor fluid in vivo of induzirovanny the th endothelin-1 ischemia in new Zealand white rabbits. Test connection

Connection (1) Example 1

- Fluotsinolon acetonide (FC): control connection

Test system and methods

For the experiment used twenty adult new Zealand albino rabbits male weighing 2-2 .5 kg Animals were divided into two groups for the selected specific processing. Methods experiment corresponded to the methods permitted by the Association for research of vision and ophthalmology for the use of animals in accordance with good laboratory practice on the use of animals. Rule Italy for the protection of animals used for experimental and other scientific purposes (DM 116/1992), and in accordance with the Rules of the European Union (OJ ofECL 358/1, 12/12/1986). Rabbits were kept in individual cages and had free access to food and water. The animals were housed in a room with controlled room temperature (22°-23°C) with a regime of 12/12 hours light/dark.

Model of ocular ischemia was obtained by injection twice a week for 6 weeks endothelin-1 (ET-1) 250 nm and 500 μl of sterile saline solution into the vitreous of both eyes, using the cannula to the lachrymal canal, under General anaesthesia (tiletamine plus zolazepam (zoletil 100, 0.05 mg/kg) plus xylazine (xelor 2%, 0.05 ml/kg) intramuscularly.

Fluotsinolon acetonide (FC) (0.5 mg/eye in 100 μl of napolnitel is) or the Compound (1) (equivalent to 0.5 mg / eye in 100 μl of filler) was dropwise introduced into the vitreous body (IVT) two weeks after the start of injection of ET-1 (T2) in one eye, the same amount of filler was injected into the other eye.

- Intraocular pressure

Intraocular pressure (IOP) was measured twice using a Tono-Pen XL (Medtronic Solan. USA) as described Maren''s group (Exp. Eye Res. (1992) 55:73-79; Exp.Eye Res. (1993) 57: 67-78), with a measurement standard pressure at two points. The IOP measurement was carried out by two independent researchers (.U. and R..), using the same tonometer.

The data in Table 2 show that treatment of ET-1 did not modify the IOP in new Zealand white rabbits. Fluotsinolon acetonide increased intraocular pressure after induced ET-1 ischemia, connection (1), in contrast, did not change in intraocular pressure after induced ET-1 ischemia.

Table 2:
Impact fluotsinolon acetonide (FC) or compound (1) against the media on IOP. IOP was measured daily before the introduction of medicines
IOP (mm Hg)
MediaFC*MediaConnection (1)
basal13,00±2,8313,50±0,17 12,60±2,0112,70±1,89
ET-113,50±0,7113,00±2,8312,80±1,5513,30±1,49
I week14,00±2,8315,50±0,7113,30±1,4915,30±0,95
II week14,40±0,7119,00±0,0013,60±1,9615,00±1,33
III week15,00±1,4113,00±2,8313,00±2,8313,00±2,83
IV week13,50±1,2713,00±2,8313,00±2,8313,00±2,83
V week13,30±1,7713,00±2,8313,00±2,8313,00±2,83
VI week13,00±1,5613,00±2,8313,00±2,8313,00±2,83
* p<0,001 against whom osites (N=10)

The electroretinogram (ERG)

The electroretinogram (ERG) was shot in basal conditions (THAT), before drug treatment (T2) and at the end of drug treatment (T6). Prior studies have been conducted biomicroscopy using a slit lamp and indirect ophthalmoscopy all eyes. Animals showing clouding of the cornea or lens, or retinal lesions, were excluded. Used local anesthesia, using a drop of 0.2% oxybuprocaine hydrochloride (Novesine, Sandoz). Eye pupils expanded local application of Tropicamide (1%), adaptation to darkness has carried out for at least 2 hours, and took the standard electroretinogram (ERG) both eyes using corneal electrodes. The ears were inserted reference electrode and a grounding electrode made of surgical needles made of stainless steel. The ERG signals were recorded using Retimax (CSO, Florence, Italy). Register adapted to the darkness scotophase answer (answer rod system of the retina) and scotophase response to flashes of light (photopic or cone ERG). The intensity of the outbreaks ranged from -2,50 to +0,4 log scot CD sec/m2. For each eye was determined by the average of three separate ERG. For each stage was calculated amplitude of a - and b - waves. Baseline values were compared with the response obtained at the 2 and at the end of treatment (T6). Treatment with ET-1 significantly reduced the amplitude of the photopic or cone ERG (T2, p<0.05 vs and T6 p<0.05 against IT). The results presented in Table 3, show that eyes treated fluotsinolon the acetonide (FC) or a Compound (1), exhibit a significant (p<0.05 vs. vehicle) to a smaller decrease of the wave amplitude of the ERG than those who were treated filler. In addition. The compound (1) was slightly more effective than fluotsinolon acetonide.

Table 3:
Effect of compound (1) or fluotsinolon acetonide (FC) for photopic ERG after processing of ET-1.
Photopic ERG (amplitude (µv))
BasalMediaFCConnection (1)
147,41±7,4368,85±6.41136,34±11,98140,94±6,22
* p<0,001 against the media (N=8)

Ocular hemodynamics

Assessment of hemodynamics was performed using color Doppler mapping (DDC) DynaView TM II SSD-1700 (Aloka Holding Europe AG Milan, Italy). All animals were examined with color Doppler imaging before injection of ET-1 (IT), before instillation of medicines (T2) and at the end of drug treatment (T6). Special attention was paid to the assessment of blood flow in the ophthalmic and ciliary arteries. For each vessel measured blood flow velocity, and calculated the resistance index (IR) (F. Galassi et al., Acta Opht. Scand Suppl. (2000) 37-38).

The data presented in Table 4 show that fluotsinolon acetonide significantly increases (p<0.001 vs. filler) the resistance index in the ophthalmic artery, which indicates a decrease in blood perfusion; this effect is not observed in the processing of Compound (1).

Table 4:
Effect of Compound (1) or fluotsinolon acetonide (FC) against the media on ocular hemodynamics assessed using the index of resistance.
The index of resistance
BasalAfter 2 weeksAfter 6 weeks
Media0,46±0,07 0,48±0,05
FC0,45±0,060,45±0,060,60±0,04
Connection (1)0,43±0,060,43±0,080,41±0,03
* p<0,001 against the media (N=10)

- Concentration of inflammatory cytokines in the aqueous humor

The intraocular fluid samples were taken from both the front camera and rear camera each eye before the introduction of ET-1 (IT), before introducing the Compound (1) or fluotsinolon acetonide (T2) and at the end of the treatment (T6). Each time re-entered the same amount of saline. The intraocular fluid samples were immediately frozen at -80°C until use.

In the intraocular fluid was determined by the tumor necrosis factor (TNFa) and interleukin 6 (IL-6) using a commercial kit using ELISA method (Amersham Pharmacia Biotech). For IL-6 and TNFa minimum detectable concentration amounted to 0.10 PG/ml and the Coefficient of variation for a series of experiments was 0.7% for all analyses. The data presented in table 5, show that the treatment of ET-1 significantly increases the amount of TNFa, IL-6 and VEGF in the samples of intraocular fluid, while for the Connection to (1) counteracts these effects more effectively, than fluotsinolon acetonide (FC).

Table 5:
The influence of Compounds (1) and fluotsinolon acetonide (FC) on the content of TNFα, IL-6 and VEGF in the aqueous humor
TNFα (PG/ml)Of VEGF (PG/ml)IL-6 (PG/ml)
Basal0,55±0,44-0,67±0,43
Media27,00±4,30166,76±4,5420,47±2,97
FC20,76±1,74114,58±5,6116,82±0,98
Connection (1)18,93±0,98105,79±1,9815,70±1,73
* p<0,001 against the media (N=6).

- Protection of the retina: Morphological analysis

The eye of each animal was nucleosomal, removed the cornea and the vitreous body and fixed eyes with paraformaldehyde. Then the samples dehydrational increasing alcohol concentration(50°-75°-95°-100°. After treatment at 95° alcohol eyes were divided in the longitudinal plane from the cornea to attachment of the optic nerve. Thus obtained samples were embedded in paraffin. Section 8 mm thick were stained with hematoxylin-eosin. Microscopic fields were recorded using a digital camera using an optical microscope with lens 20x and 40x. On digitized images was carried out by morphological analysis of the tissues of the retina. Analysis of tissues of the retina showed that long-term treatment of ET-1 induces profound morphological changes, confirming thus the functional impairment observed in ERG. These morphological changes were absent in animals treated with Compound (1), whereas fluocinolone acetonide was not effective.

Detailed description of drawings

Figure 1A: Measurement of the transudation of the retina in the VEGF-induced rats: control, treatment with compound (1) and the corresponding steroid, fluotsinolon the acetonide (FC).

Figure 1b: Percentage inhibition of transudation FC and connection (1)calculated on the basis of Figures 1 and.

Figure 2A: Measurement of the transudation of the retina in the VEGF-induced rats: control, treatment of compound (18) and the corresponding steroid, triamcinolone-acetonide (TAAS).

Figure 2b: Percentage of inhibition of the transudation of the compound (18) and with the criterion him a steroid, triamcinolone-acetonide (TAAS), calculated on the basis of Figure 2A.

Figure 3: the Effect on IOP of intravitreal injection in vivo fluotsinolon acetonide against compounds (1) gray of rats.

Figure 4: the Effect on IOP of intravitreal injection in vivo fluotsinolon acetonide (FC), compounds (1) and des-nitroanisole connection (1) gray of rats.

1. The compound of formula (I)or its salt, or a stereoisomer

where R1and R2taken together, represent a group of formula (II)

R3represents a hydrogen atom or F and R4is F;
R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroidal structure in position α or β;
R is
or
where Y is selected from:
1) -R5-CH(ONO2R6,
2) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9or
3) -[(CH2)o-X]p-(CH2)q-CH(ONO2R9,
where R5straight or branched C1-C10alkylen;
R6, R7, R8, R9each represents H;
n is an integer from 0 to 6;
o is an integer from 1 to 6;
p is an integer from 1 to 6;
q is an integer from 0 to 6;
X represents O, S or NR10where R10- N or C1-C4alkyl; pre is respectfully X represents O;
with the exception of the compounds of formula (I), where R1and R2taken together, represent a group of formula (II)

R4is F and R3is a hydrogen atom, and R is a compound of formula (III), where Y is - R5-CH(ONO2R6and R6- N.

2. The compound according to claim 1, where R4is F, R3is F, R1and R2taken together, represent a group of formula (II), R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroidal structure in position α.

3. The compound according to claim 2, where Y is:
1) -R5-CH(ONO2R6,
where R5- direct1-C5alkylene and R6Is h; or
2) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9,
where R5- direct1-C2alkylene, R9, R7and R8are H and n is 0 or 1; or
3) - [(CH2)o-X]p-(CH2)q-CH(ONO2R9,
where R9represents H,
o is an integer from 2 to 4,
p is an integer from 1 to 4
q is an integer from 0 to 4 and X represents O.

4. The compound according to claim 1, where R1and R2taken together, represent a group of the formula
(II)
R1is F and R3is a hydrogen atom, and
R1, R2, R3and R4joined 17, 16, 6 and 9 carbon atoms steroids the th structure in position α.

5. The compound according to claim 4, where Y is:
1) -R5-CH(ONO2)-(CR7R8)n-CH(ONO2R9,
where R5- direct C1-C6alkylen,
R9, R7and R8represent H;
n is 0 or 1; or
2) -[(CH2)o-X]p-(CH2)q-CH(ONO2R9,
where R9represents H,
o is an integer from 2 to 4,
p is an integer from 1 to 4
q is 0 to 4 and X represents O.

6. The compound according to claim 1, selected from






7. The compound according to any one of claims 1 to 6 for use in the treatment of eye diseases.

8. The connection according to claim 7, where the eye disease is diabetic edema yellow spots, diabetic retinopathy, macular degeneration, age-related macular degeneration and other diseases of the retina and yellow spots.

9. The use of the compounds of formula (I)or its salt, or stereoisomer

in the treatment of eye diseases,
where in the formula (I)
R1and R2taken together, represent a group of formula (II)
,
R3represents a hydrogen atom, R4is F,
R1, R2and R4joined 17, 16 and 9 carbon atoms steroidal structure in position α;
R is

Y is-R5-CH(ONO2R6and R6is N.

10. The use of compounds according to claim 9, where eye diseases include diabetic edema yellow spots, diabetic retinopathy, macular degeneration, age-related macular degeneration and other diseases of the retina and yellow spots.

11. The use of compounds according to claim 9 or 10 of the formula (18)

in the treatment of eye diseases.



 

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35 cl, 164 ex, 19 tbl

FIELD: chemistry.

SUBSTANCE: 17β-oxoestratrienes of the general formula III and 17β-oxyestratrienes of the general formula II are used as intermediary products in obtaining 17α-alkyl-17β-oxyestra-1,3,5(10)-trienes of the general formula I with antiestrogenic effect, where Hal, R3, SK, R17', R17" represent elements listed in the invention claims.

EFFECT: improved method of obtaining the product.

19 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicine, oncology.

SUBSTANCE: invention describes four groups of dialkyltriazenyl-carrying estrogens and anti-estrogens that can be used for using as chemotherapeutic drugs in treatment of human and animal gonad carcinomas.

EFFECT: valuable medicinal properties of drugs.

8 cl, 11 dwg, 38 ex

Chemical compounds // 2462472

FIELD: chemistry.

SUBSTANCE: invention relates to certain glucocorticoids derived by unsaturated fatty acids having anticancer therapeutic action and pharmaceutical compositions containing said compounds.

EFFECT: improved properties of the compound.

26 cl, 7 ex, 3 tbl

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