Nitroethene corticoids connections

 

(57) Abstract:

The invention relates to new corticoides connections to nitroform corticoid compounds of the formula B-X1-NO2where is the rest of the formula I, where Z is H or F; R" is OH or 16, 17 provisions group is

< / BR>
the dashed line in position 1, 2 means possible double bond. The compounds possess anti-inflammatory, immunosuppressive and angiostatic activities, while having no side effects. 7 C.p. f-crystals, 10 PL.

The invention relates to the production of new corticoids connections.

In particular, it relates to compounds with steroid structure having anti-inflammatory, immunosuppressive and angiostatic activity (the so-called steroid anti-inflammatory drugs).

These compounds according to the present invention a therapeutically suitable for the treatment of pathological States, for which mainly applied corticosteroids (corticoid), and with greater benefit.

These representatives have the unexpected advantage over known corticoide products. In fact, given the attention to detail is second invention, it is possible to find the best combination of results compared with the known corticoide. In contrast to some expectations, the products of the present invention are characterized by the fact that they show superior therapeutic profile: high activity combined with low side effects.

Corticoide well known as the first selected measures for the treatment of inflammatory diseases. Drugs of this category, which include, for example, hydrocortisone, cortisone, prednisolone, prednisone, targetrotation, hypertension, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetamide", she fluocinolone acetonide, beclomethasone, acetoxyphenyl and others, have pharmacotoxicological effects on various organs. For this reason, their clinical use and interrupted use cause a series of side effects, some of them very serious. As an example, see Goodman & Gilman. "The Pharmaceutical Basis of Therapeutics", 9thEd., pp.1459-1456.

These toxic effects include:

- the effects on the bone, which leads to changes in cellular metabolism and the high incidence of osteoporosis;

- effects on the cardiovascular system, which vyzyvaemoi.

As an example, see Martindale "The Extrapharmacopoeia", 30thEd., pp.712-723, 1993.

In accordance with the above-mentioned prior art, seems almost impossible case in which therapeutic activity was separated from side effects, see the aforementioned Goodman et al., page 1474.

For prior art in this area known non-steroidal anti-inflammatory drugs with or without acid end, see patent WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641 for drugs with non-acidic ends and patents mentioned therein, for drugs with acid ends.

DE-A-2222491 (1) describes derivatives Pregnana having in position 21 group

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They say that the aforementioned compounds are endowed with anti-inflammatory, antiallergic and cardioprotective activities. Individual compounds are vasodilators.

US-A-3494941 (2) describes the steroid derivative estran-3-ol or variety-4-EN-3-one used as vasodilators in the treatment of heart conditions such as coronary insufficiency and angina. The above compounds are in position 17 ether linker associated with the nitrate radical. Nitrate groups may also be in positions 3 and dostana, 3,17-dinitropropane of androstene, 17-nitroethene testosterone derivatives and 21-nitroethene derived desoxycortisol, cortisone and prednisone. This article argues that the nitrate hypertension promotes protein anabolism in various organs.

WO-A-97/34871 (4) describes (i) compounds containing the steroid agonist, an anticholinergic agent, a stabilizer of mast cells or inhibitor of PDE (phosphodiesterase) that directly or not directly attached to at least one NO or NR2group or a group which stimulates endogenous production of NO or EDRF (endotheliopathy relaxing factor) in vivo, the above-mentioned group linked through sites such as oxygen, sulfur, carbon, and nitrogen; (ii) a composition containing a therapeutically effective amount of steroid agonists, anticholinergic agents, stabilizers fat cells or PDE inhibitor, optionally substituted by at least one NO or NO2a part or a group which stimulates endogenous production of NO or EDRF in vivo, in combination with the compound that gives, transfers, or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF of soedinenii chemically, pharmacologically and biochemically, as pharmaco-Toxicological mechanism of action of nonsteroidal products based on the inhibition of one or more cyclooxygenase (SOH), whereas steroid products do not contain anything to influence SOKH and have more complex pharmaco-Toxicological mechanisms of action are still not completely understood.

It is well known that these two groups of compounds are given in completely separate categories in the international Pharmacopoeia.

The applicant has surprisingly and unexpectedly discovered corticosteroids (corticoid), which are very effective, even more effective than known from the prior art and at the same time have a higher tolerance than a known corticoide, because, surprisingly, they do not cause the above side effects, and if called in a lower degree.

The object of the present invention are corticosteroids and their use as anti-inflammatory, immunodepressive and angiostatic agents having the General formula

B-X1-N02,

or their esters or salts, where

In has the following structure:

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the, what may be the following placeholders:

in position 1-2 may be a double bond;

in position 2-3 may be the next Deputy:

< / BR>
in position 2 may be C1, Br;

in position 3 can be CO-0-CH2-CH2-C1, IT;

in position 4-5 may be a double bond;

in position 5-6 may be a double bond;

in position 6 can be Cl, F, CH3, -SNO;

in position 7 may be Cl;

in position 9 can be Cl, F;

in position 11 may be HE, CO, Cl;

in position 16 may be of CH3HE, =CH2;

in position 17 may be HE, CH3, CCA(OH)ia(CH2)VACH3or

< / BR>
where ia denotes an integer from 0 to 1, va denotes an integer from 0 to 4;

in the 16-17 position may be the following groups:

< / BR>
R and R' are the same or different from each other and may be hydrogen or linear or branched alkilani having from 1 to 4 carbon atoms, preferably R=R'=CH3;

when in position 9 is F, at position 11 is, in positions 1-2 and 4-5 provisions are two double bonds in positions 3 and 20 two groups WITH, in lock position-(X)t1-

where t and t1 are integers equal to 1;

bivalent bridging group L is selected from:

< / BR>
where PA, n 'and n"and equal to or different from each other and are integers from 0 to 6, preferably from 1 to 3; nb, n b, n b, and n'"b is equal to or different from each other and are integers from 0 to 1; R4and R5equal to or different from each other and selected from hydrogen, linear or branched alkyl having from 1 to 5 carbon atoms, preferably from 1 to 3;

X is equal to X0= 0, NH, NR1cwhere R1cis a linear or branched alkyl having from 1 to 10 carbon atoms;

X1is a bivalent connecting bridge, chosen from:

-YO,

where Y denotes a linear or branched C1-C20alkylene, preferably having from 2 to 5 carbon atoms, or optionally substituted cycloalkyl having from 5 to 7 carbon atoms;

Y1selected from

< / BR>
where n3is an integer from 0 to 3;

< / BR>
< / BR>
where nf' is an integer from 1 to 6, preferably from 2 to 4;

< / BR>
where R1f=H, CH3and nf denotes an integer from 1 to 6, preferably from 2 to 4.

The following is the connect the Yong in accordance with the methods known from the prior art.

For example, as precursors and related methods can be mentioned predecessors and related methods described in The Merck Index, 12thEd. , 1996, cited here as reference. Among these predecessors (in accordance with item Merck) are compounds in which N2N, R, R', R" have the meanings provided in the compounds below: budesonide, hydrocortisone, alclometasone, algestone, beclomethasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, flashcart, fluchloralin, flumetazon, flunisolide, acetonide fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, acetate flaperon, acetate of fluprednidene, fluprednisolone, flurandrenolide, farmacita, halcinonide, propionate halobetasol, halometasone, acetate of halopedia, hydrocortamate, etabonate loteprednol, Madison, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetate prednisolone sodium phosphate prednisolone, prednisone, prednesol, prednison, tixocortol, hexacetonide triamcinolone.

As mentioned above, the connecting bridges X1receive, using known prior art methods, as described above, or by modification of known methods for the introduction of bridges X1that differ from the connecting bridges described in these patents, using techniques known in the prior art in this field. Mainly the relationship between V and1is the concatenation of the ester or amide type (NH or NR1cas defined in X). Can be used any well-known synthetic way, the formation of such connections to receive this communication.

In the case of esters, the most direct synthetic path includes:

the reaction acylchlorides IN-CO-C1 with halogenosilanes type HO-Ya-Cl, HO-Ya-Br, HO-Ya-I, in which Yaequal to Y or Y1without the oxygen atom in the experimental conditions, known from the prior art.

The reaction products of the formula B-CO-0-Y-C1 (Br, I) can be obtained by the reaction of potassium or sodium salts of the acids of formula-CO-HE dehalogenase derivatives of General formula aCl2, YaBr2or YaI2, ClYaBr, ClYaI, BrYaI.

Childbirth known from the literature.

The General scheme is the following:

In-CO-C1+HO-Ya-Br-->B-CO-O-Ya-Br+AgNO3-->B-X1NO2where X1=YaO.

The General scheme can also be the following:

B-CO-ONa+Br2Ya-->B-CO-O-Ya-Br+AgNO3-->B-X1NO2,

where X1=YaO.

In the case of the amide bond of the synthetic sequence involves the reaction of such acylchlorides WAS with aminoalcohols of General formula NH2-YaHE, WITH OTHER1c-OH to obtain amides of General formula

B-CO-NH-Ya-OH and B-CO-NR1c-Ya-OH,

carried out by known methods.

The reaction of such amides with halogenation agents such as, for example, PC15, Rvh3, SOC12and so on, gives one the General formula

B-CO-NH-Ya-Br(Cl) and B-CO-NR1c-Ya-Br(Cl).

The latter reacting with AgNO3in acetonitrile, in accordance with known methods from the literature give the final products BX1NO2.

This sequence can be represented as follows:

PC15< / BR>
In-CO-CL+other1c-Ya-OH-->B-CO-NR1c-Ya-OH-->B-CO-NR1c-Ya-Br+AgNO3-->B-CO-NR1c-Ya< is a reaction of the sodium or potassium salts of acids with nitropyrene of halogenation General formula

NO2-O-Ya-Cl(Br, I)

for direct receipt of the products of the invention.

The reaction scheme is the following:

B-CO-ONa+Br-Ya-ONO2-->B-CO-O-Ya-ONO2,

where YandO means X1.

Other synthetic routes, similar to above, dehalogenase derived Br2Yareacts with enolate. The reaction products then react with AgNO3in acetonitrile, in accordance with the above-mentioned reaction. The General scheme shown for IT in the group type-CH2HE, =CH-HE is the next:

AgNO3< / BR>
-ONa+Br2-Ya-->0-Ya-Br-->O-Ya-ONO2.

Methods of obtaining these linking groups X1described in the patent application W095/30641, shown here as a reference.

As mentioned above, the compounds of the present invention with the formula-X1-NO2or their pharmaceutical compositions are used to treat diseases for which treatment relies on the well-known corticoide products.

In particular, may be mentioned the use of respiratory disorders, such as protiwastmaticescoe, use as anti-arthritis, anti-itching the ve angiostatin means, the use of immunological disorders, such as immunosuppressive tools.

The compounds or compositions of the present invention can be introduced, for example, oral, rectal (intestinal disorders), parenteral or local application (dermal, local, transdermal, ocular, inhalation methods).

The following examples are presented for illustrative purposes to explain, but they are not limiting for the present invention.

EXAMPLE 1.

Chemical synthesis: obtain the nitro-derivatives of hydrocortisone (GKN)

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EXAMPLE 1A.

Receive (4-chloro)butanoate hydrocortisone

< / BR>
4 servings 4-chlorobutyronitrile (0,32 ml x 4) and triethylamine (0.3 g x 4) add 24 hours to a solution of hydrocortisone (1 g) in l3dried over P2ABOUT5and stirred for 3 days. The solution is treated with water, the organic phase is separated, dried (Na2SO4) and remove the solvent under reduced pressure. The crude residue is treated with hexane and CH2Cl2getting white solid in 53% yield by weight, which has a melting point (so square) 155oC.

, THE CH3), a 1.45 (3H, s, CH3), 2,12 (2H, t, CH22), and 2.6 (2H, t, CH2Soo), the 3.65 (2H, t, CH2Cl), 4,45 4,35 and of 5.05 (2H, 2D, PINES2O) 5,70 (1H, s, H of olefin).

Receive (4 nitroxy)butanoate hydrocortisone.

AgNO3(0.2 g) are added to a solution of 4-chlorobutanol hydrocortisone (0,23 g), obtained as described above, in acetonitrile (70 ml) and heated under reflux for 16 hours. From the solution to remove the solvent under reduced pressure and chromatographic on silica gel using ethyl acetate solution and CH2C12(3:7) as eluent.

4-Nitrosobutane cortisone is obtained from the head fractions.

The product is characterized1H-NMR (300 MHz, CDCl3):

of 0.95 (3H, s, CH3), a 1.45 (3H, s, CH3), 2,12 (2H, t, CH22), and 2.6 (2H, t, CH2Soo), 4,45 4,45 (2H, t, CH2O-NO2), 4,35 and of 5.05 (2H, 2D, PINES2O) of 5.68 (1H, s, H of olefin).

EXAMPLE 1B.

The product from Example 1A receives the same way, using a different synthetic route.

Getting 4-bromobutyrate hydrocortisone

< / BR>
Five servings 4-bromobutyronitrile (0,35 ml x 5) and potassium carbonate (0.4 g x 5) add 24 hours to a solution of hydrocortisone (1 g) in l3dried is dried (Na2SO4) and remove the solvent under reduced pressure.

Getting 4-nitrosobutane hydrocortisone (SIPC).

AgNO3(0.2 g) are added to a solution of 4-bromobutyrate hydrocortisone (0,23 g), obtained as described above, in acetonitrile (70 ml) and stirred for 48 hours at room temperature.

From the solution to remove the solvent under reduced pressure and chromatographic on silica gel using ethyl acetate solution and CH2CL2(3:7) as eluent.

4-Nitrosobutane cortisone is obtained from the head fractions and characterized by mass spectrometry: M+493. The spectrum obtained is the same as described in Example 1A.

EXAMPLE 2.

Assessment of safety and activity.

The products were introduced into a 2% by weight karboksimetilcelljulozojj suspension tests in vivo, whereas in vitro experiments were used 0.1% by weight dimethylsulfoxide suspension.

The experimental group always consisted of 8 samples (excluding cases where examples of other value is specified) for adequate statistical evaluation, which, if necessary, was performed in accordance with well-known statistical procedures.

Deaths and manifestation of toxic symptoms were investigated within 14 days after administration of the compound.

The animals showed no visible signs of toxicity even after a dose of 50 mg/kg

EXAMPLE 2B.

The study of anti-arthritis activity.

Adjuvant arthritis was induced in male rats Lewis, weighing 17015 g, by ventriculostomy injection of 0.6 mg of Mycobacterium butyricum (Difco), suspended in 0.1 ml mineral oil. Animals were treated intraperitoneally (i. p. ) solvent, representing 2% by weight carboximetilzellulozu suspension in water, also intraperitoneally hydrocortisone or GKN (in suspension above) at doses of 5 mg/kg doses of 10 mg/kg, starting from the first day after inoculation of bacilli.

Development of arthritis was assessed after 21 days. Conventional units for assessment of arthritic lesions were selected in accordance with the following scale:

- hindquarters: from 0 to 7 for each (0 in the absence of lesions, and 7 for the most severe lesions);

- forequarters: from 0 to 4.5 for each (0 in the absence of lesions and 4.5 for the most severe lesions);

- tail: 0 to 5 (0 in the absence of lesions and 5 for most of the forces of the

the nose and eyes: from 0 to 1 for each (0 in the absence of lesions, and 1 for the most severe lesions).

The results were expressed as percent inhibition when compared with the values obtained in the control group (animals treated only with the solvent).

The results are presented in Table 1.

As can be seen from the results of Table 1, the tested products may similarly inhibit arthritic process caused by mycobacteria. However, since tolerability GKN higher than that of hydrocortisone (see Example 2 below), the results from the point of view activity more positive in the case of GKN (cf 40% anti-arthritis activity obtained with 5 mg/kg of hydrocortisone, with 62% obtained for the 10 mg/kg SIPC).

EXAMPLE 2C.

The study of gastric tolerability (security).

Male rats Sprague-Dawley, starving for 24 hours, were treated intraperitoneally with doses of 5 and 10 mg/kg of hydrocortisone or SIPC.

Twenty-four hours later the animals omerville, removed the stomach and tissue approximately evaluated for the presence of lesions, as described by Del Soldato et al. "The influence of starvation and cimetidine on the relationship of molvania was evaluated in accordance with known methods and expressed in arbitrary units. The results are presented in Table 2.

As shown in Table 2, in rats treated with hydrocortisone, visibly manifested in the gastrointestinal tract, varying in severity from erosion of the mucosa to ulcers, including muscle layer, adhesion of the walls, ascites, peritonitis. In the other groups treated with a single solvent or SIPC, the damage was much less or even absent.

EXAMPLE 2D.

The study nitroxylenes activity.

Inhibition nitroxylenes activity induced by lipopolysaccharide (LPS) was determined in neutrophils and stomach of rats after administration of one of the test compounds and compared with the activity obtained after processing only suspendium solvent. Wistar rats, starving for 24 hours before treatment, received one of the test compounds intraperitoneally (10 mg/kg) and LPS intravenously (tail vein) (5 mg/kg). Four hours later the animals omerville. They took blood for isolation of neutrophils and stomach.

Enzyme activity was determined in accordance with the method described Assreuy et al. Negative control with feedback nitric oxide synthetase activity of nitric oxide". B is the product, as it turns out, are very effective in the inhibition of nitroxylenes when compared with the group treated only with solvent.

EXAMPLE 2A.

The study of bone toxicity.

Used bone parietal bone from fetal rat) grown in vitro according to the method described by Doherty et al. "The impact of glucocorticoids on the function of osteoblasts. The effect of corticosterone on osteoblasts, the expression of beta-integrins I". Journal of Bone and Joint Surgery, A77 Series/3, 396-404,1995. They were incubated with hydrocortisone or SIPC, or a solvent with a concentration of 100 nmol.

After 90 hours was measured calcium content and dry weight of bone.

The results are presented in Table 4.

As shown in Table 4, showed a significant increase in dry weight tissue after incubation with solvent or SIPC. After incubation with hydrocortisone the calcium content decreased and not increased the dry weight of bone. This shows that treatment with hydrocortisone adversely affect tissue growth.

EXAMPLE 2F.

The study of some cardiovascular parameters.

The impact of the products tested on some cardiovascular parameters is camping, as described by Gardiner et al. "Effect of dexamethasone on local hemodynamic responses to liposaccharide in rats, in consciousness: the impact of selective endothelial antagonist: SB 209670". VG. J. Pharmacology, 117, 49 R, 1996. Animals were treated with solvent (physiological saline solution, sodium chloride 0.9 per cent, subcutaneously), hydrocortisone or GKN (10 mg/kg) subcutaneously. Heart rate and blood pressure were measured 4 hours after processing.

Table 5 presents the data obtained in the form of percentage changes compared with control values.

The results presented in Table 5, show that the product of the present invention, GKN, does not affect the measured cardiovascular parameters. On the contrary, hydrocortisone, used in this technical field, causes an increase in pressure, and heart changes.

EXAMPLE 2G.

The study angiostatic activity in rats

Male Wistar rats weighing 180 to 200 g, were used according to the method described by Andrade et al. "Quantitative in vivo studies of angiogenesis in model rats with sponge". Brit. J. Exp. Pathol. 68, 755-766,1987. The neovascularization was evaluated in relation to the flow of the blood through implanto133Heh, equal to 10 μl, was injectively in the sponge, using a small plastic cannula. Using a detector of gamma rays, residual radioactivity in the implant and133Heh excretion was measured after 6 minutes as a percentage of the initial value. The validity of this method for measuring neovascularization was recently demonstrated by Hu et al. "Correlation excretion133Heh, blood flow and histology for the model rats with sponge for angiogenesis. Further studies with angiogenic modifiers". Lab. Invest. 72, 601-610, 1995.

Test compounds were administered subcutaneously dose of 10 mg/kg from 1 to 13 days after implantation.133Heh measured on day 14 after subcutaneous implantation, then animal omerville and record the weight of thymus and spleen.

Table 6 presents the data obtained regarding the effects of the tested products on the neovascularization and the weight of spleen and thymus.

Obviously, SIPC, is likely to cause a noticeable angiostatin effect without changing the weight of the spleen or thymus, in contrast to comparable product.

From all the data presented in Tables 1-6, it is clear that pharmacodynamic activity - anti-arthritis, immunocap is a, known from the prior art.

EXAMPLE 3.

Dexamethasone 21-(4-bromobutyrate) [II]

Dexamethasone [I] 3.5 g (8.9 mmol);

4-Bromobutyrate 4,06 ml (35 mmol);

Potassium carbonate 4.9 g (35 mmol);

Tetrahydrofuran 70 ml.

A solution of compound I in tetrahydrofuran portions handle 4-bromobutyronitrile (0,81 ml x 5) and potassium carbonate (0,98 g x 5) within 7 hours. The mixture is stirred overnight, the solvent is evaporated under vacuum and the residue treated with ethyl ether and water. The organic layer was separated, washed with water and dried with anhydrous sodium sulfate. After evaporation of the solvent the residue is purified on silica gel column flash chromatography, using as eluent tert-butylmethylether/hexane 1/1, getting:

less polar compounds 1.0 g;

- derivative II 1.5 g (so pl. 184-187oC; yield 31%)

TLC: tert-butylmethylether/hexane 2/1.

Dexamethasone 21-(4-nitroxymethyl) [III] (connection DXN)

Compound II 1.5 g (2.7 mmol);

Silver nitrate 2.4 g (14.1 mmol);

Acetonitrile 250 ml.

A mixture of compound (II) and silver nitrate in acetonitrile is heated under reflux for 7 hours. After filtration of inorganic salts Rast the water, dried with anhydrous sodium sulfate and evaporated under vacuum. The residue is poured into ethyl ether and filtered, obtaining 1.27 g of pure compound III as a white solid (so pl. 183-185oC; yield 90%).

TLC: tert-butylmethylether/hexane 2/1.

Attached the following forms:

- scheme of the synthesis;

- NCX 1005 downloads 1;

- NCX 1005/1 analysis.

EXAMPLE 4.

Learning activity on the accumulation of leukocytes.

Male mice albino line Swiss (27-33 g) were maintained on a standard chow pellet diet with the use of tap water with the addition of libitum. The experiment was carried out in accordance with Perretti et al. (Perretti M, E. Solito , Parente L. "Evidence that endogenous interleukin-1 is included in the migration of neutrophils in experimental acute inflammation in rats and mice", Agents Actions, 35, 71, 1992). Animals pre intraperitoneally treated simhasanam (1 mg/0.5 ml), taking this time 0 (time 0). Two hours later were injected intravenous dexamethasone (1 mg/kg) (Example 3-I), DXN (Example 3-III) (1 mg/kg) or phosphate-saline buffer solution (PBS). Animal omerville after 4 and 24 hours from the time 0, collected wash liquid and count different cells with subsequent okryu the tested compounds caused simhasanam the migration of leukocytes in mice. Obviously, nitro-derivatives of steroid much more actively than dexamethasone.

EXAMPLE 5.

The study of antiproliferative activity in cells of smooth muscles of the respiratory tract.

The smooth muscle cells of the respiratory tract cultivated by conventional methods for explants. Tissue was collected in a sterile vessel containing PBS, penicillin and streptomycin. Under sterile conditions for tissue cultures fabric cut into small pieces (weighing approximately 1 mg) and placed in a standard medium containing 20% serum fetal cow (FCS) for a few days (the medium was changed every 2-4 days).3H-thymidine was measured for DNA fraction of cells cultured in 48-hole tablets. Cells were cultured to confluence in medium containing 10% FCS. Cells were deprived of serum for 24 hours before adding 10% FCS with different concentrations of steroids. After 24 hours 3H-thymidine was added to the cells for 4 hours. Cells were washed in phosphate-saline buffer and ethanol. DNA was extracted with a solution of sodium hydroxide and3H-material was counted by scintillation. The data of these studies were obtained in holes, each of which was presented in three EC is entered results received by the inhibitory effect of test compounds on cell proliferation of smooth muscles of the respiratory tract. Obviously, nitro-derivatives of steroid much more actively than dexamethasone.

The synthesis of 1.

Synthesis of prednisolone 21-[(4'-nitroxymethyl)benzoate) (NO-prednisolone)

< / BR>
A) Prednisolone 21-[(4'-chloromethyl)benzoate].

To a solution of prednisolone in tetrahydrofuran (230 ml) was added triethylamine (with 4.64 ml) and 4-(chloromethyl)benzoyl chloride (6,29 g). The solution is stirred at room temperature and in a day was added triethylamine (with 4.64 ml) and 4-(chloromethyl)benzoylchloride (6,29 g). The solution was stirred at room temperature for 24 hours. The solution is evaporated in vacuum and the resulting crude residue was treated with ethyl acetate and water.

The insoluble residue was filtered, rinsed with ethyl acetate and dried in vacuum. The organic layers were treated with sodium sulfate and concentrated under reduced pressure. The residue was purified by the method of quartz-gelinas chromatography, eluent methylene chloride and methylene chloride/acetone 8/2. Product (16,53 g) was obtained as a white solid.

C) Prednisolone 21-[(4'-nitroxymethyl) benzoate].

Restoule in the reverse flow in the dark for 35 hours. The precipitate (silver salt) was filtered and the solution is then evaporated in vacuum. The residue was purified by the method of quartz-gelinas chromatography, eluent chloroform/acetone/tetrahydrofuran 4/1/1 and tetrahydrofuran. Product (13.3 g) was crystallized from tetrahydrofuran (450 ml)/n-hexane (250 ml), to obtain 10,34 g of a white solid. The melting point to reach 232.5oWith DSC.

1H-NMR (200 MHz, DMSO, ppm): 8,15(2H, d); of 7.75 (2H, d); was 7.45 (1H, d); 6,28 (1H, dd); 6,04 (1H, s); 5,80 (2H, s); 5,46 (1H, d); 5,16 (1H, d); 4,43 (1H, m); 2,63 was 1.06 (13H, m).

13C-NMR (200 MHz, DMSO, ppm): 205, 298; 185, 594, 171, 023; 164, 962; 157, 118; 138, 099; 129, 759; 129, 126; 127, 023; 121, 580; 88, 725; 74, 096; 68, 362; 55, 443; 51, 168; 47, 265; 43, 916; 33, 992; 33, 146; 31, 453; 30, 955; 23, 554; 20, 878; 16, 560.

Synthesis of 2.

Synthesis budezonida 21-[(4'-nitroxymethyl)benzoate] (NO-budesonide).

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A) Budesonide 21-[(4'-chloromethyl)benzoate]

To a solution of budezonida in tetrahydrofuran (100 ml) was added triethylamine (1,62 ml), 4-(chloromethyl)benzoyl chloride (2,19 g). The solution was stirred at room temperature and after 4 hours was added triethylamine (1,62 ml) and 4-(chloromethyl)benzoyl chloride (2,19 g). The solution was stirred at room temperature for 24 hours. The solution is evaporated in vacuum.

The crude residue was treated with ethyl acetate and water.

The organic layer is-gelinas chromatography eluent - methylene chloride/acetone 10/1. Product (6,53 g) was obtained as a white solid. The melting point 106-110oC.

Century Budesonide 21-[(4'-nitroxymethyl)benzoate]

The solution budezonida 21-[(4'-chloromethyl)benzoate] and silver nitrate in acetonitrile (100 ml) was stirred in a reverse flow in the dark for 25 hours. The precipitate (silver salt) was filtered and the solution evaporated in vacuo. The residue was purified by the method of quartz-gelinas chromatography, eluent n-hexane/ethyl acetate 6/4. Product (4,65 g) was obtained as a white solid. The melting point 96o(DSC).

1H-NMR (300 MHz, DMSO, ppm): with 8.05 (2H, d); 7,63 (2H, d); to 7.32 (1H, m); of 6.17 (1H, d); 5,91 (1H, s); 5,67 (2H, d); 5,31-of 5.00 (2H, s); 4.75 V-4,72 (1H, m); 4,34 (1H, m); of 2.51(2H, m); and 2.26(2H, m); 1,98-of 1.94 (4H, m); 1,59-and 1.54 (4H, m); of 1.39 and 1.35 (5H, m); 0,96-0,85 (7H, m).

Synthesis of 3.

Synthesis of dexamethasone 21-[(4'-nitroxymethyl)benzoate]

< / BR>
A. Dexamethasone 21-[(4'-chloromethyl)benzoate]

To a solution of dexamethasone in tetrahydrofuran (100 ml) was added triethylamine (1.77 ml) and 4-(chloromethyl)benzoyl chloride (2.4 g). The solution was stirred at room temperature and after 24 hours was added triethylamine (1.77 ml) and 4-(chloromethyl)benzoyl chloride (2.4 g). The solution was stirred for 24 hours. Then the solution is evaporated in vacuum. The crude residue about the high pressure. The residue was purified by the method of quartz-gelinas chromatography, eluent - methylene chloride/acetone 9/1. The product is 6.19 g) was obtained as a white solid.

Century Dexamethasone 21-[(4'-nitroxymethyl)benzoate]

The solution of dexamethasone 21-[(4'-chloromethyl)benzoate] and silver nitrate in acetonitrile (100 ml) was heated to 40oWith over 190 hours in the dark.

The precipitate was filtered and the solution evaporated in vacuo. The residue was purified by the method of quartz-gelinas chromatography, eluent n-hexane/ethyl acetate 6/4. The product was led from tetrahydrofuran/tilapia. Product (4,22 g) was obtained as a white solid. The melting point 176,8oC.

1H-NMR (300 MHz, DMSO, ppm): with 8.05(2H, d); of 7.69 (2H, d); to 7.32 (1H, d); 6,21 (1H, d); 6,11 (1H, s); 5,79 (2H, d); 5,52(1H, d); 5,43-5,11 (3H, m); 4,34 (1H, m); only 2.91 (1H, m); 2,80-2,24 (5H, m); 1,95-0,98 (14N, m).

Synthesis of 4.

Synthesis of hydrocortisone 21-[(4'-nitroxymethyl)benzoate]

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A. Hydrocortisone 21-[(4'-chloromethyl)benzoate]

To a solution of hydrocortisone in tetrahydrofuran (20 ml) was added triethylamine (0,192 ml) and 4-(chloromethyl)benzoyl chloride (0.26 g). The solution was stirred at room temperature and in a day was added triethylamine (0,192 ml) and 4-(chloromethyl)benzoyl chloride (0.26 g). The solution was stirred at room temperature is x2">

The organic layers were treated with sodium sulfate, concentrated under reduced pressure. The residue was purified by the method of quartz-gelinas chromatography, eluent - methylene chloride/acetone 9/1. The product (0.6 g) was obtained as a solid substance.

Century Hydrocortisone 21-[(4'-nitroxymethyl)benzoate]

A solution of hydrocortisone 21-[(4'-chloromethyl)benzoate] and silver nitrate (2,39 g) in acetonitrile (90 ml) and tetrahydrofuran (70 ml) was heated to 40oWith in the dark. Silver nitrate (0,77 g) was added once a day for five days. The precipitate (silver salt) was filtered and the solution evaporated in vacuo. The residue was purified by the method of quartz-gelinas chromatography, eluent n-hexane/ethyl acetate 6/4. The product (2 g) was obtained as a white solid. The melting point 209o(DSC).

1H-NMR (200 MHz, DMSO, ppm): of 8.09(2H, d); of 7.69 (2H, d); 5,74 (2H, s); 5,62 (1H, s); 5,54 (1H, s); the 5.45 of 5.05 (2H, dd); was 4.42 (1H, m); of 4.35 (1H, m); 2,60-0,9 (23H, m).

Pharmacological experiments.

Pharmacological experiment 1.

Anti-inflammatory effect of prednisolone 21-[(4'-nitroxymethyl)benzoate] (NR-prednisone and prednisolone in a model of chronic inflammation; chronic inflammation in mouse Croton oil in the form of chronic air bag.

Separate groups of animals were euthanized at 3, 7 and 14 day. Carcasses were chilled for 24 hours and then dissected into pellets and dried at a temperature of 56oC. After drying the granulated tissue was weighed.

The results are shown in table 9 and presented as % of the formation of granular tissue compared with the control group, the measured value in the control group is the base value (100).

The results show that the NO-prednisolone was more effective than prednisolone in reduced formation of granular tissue.

Pharmacological experiment 2.

The effect budezonida 21-[(4'-nitroxymethyl)benzoate] (NO-budesonide) and budezonida on histamin when caused by the narrowing of the bronchi in Guinea pigs.

Male Guinea pigs weighing 250-300 g were try before the start of the experiment.

Histamin (3 mm dissolved in 0.9% Zalina) was administered into the nose only 20 g aged 24 hours and 15 minutes after exposure, respectively, to test the connection and functioning of the passage of air was measured pre-and at intervals of 10 minutes after the exposure with Histaminum.

Animals were exposed to test compounds: NO-budesonide (635 g/ml) and budesonide (448 g/ml) dissolved in a mixture (DMSO 20%, ethanol 10%, Salin 70%) or solvent (DMSO 20%, ethanol 10%, Salin 70%) presented as aerosols and used with air under a pressure of 20 lb. psi at a rate of 0.5 ml/min in a sealed square room within 15 minutes.

The whole body is healthy Guinea pigs were used to monitor the functioning of the air and was recorded as a specific conductivity of air (SGaw). The animal was placed in the extended position through a mask. The animal ran in a sealed room, and a respiratory air flow measured by pneumotachography and pressure transducer. The pressure in the room was also measured. Drop in (SGawshows the narrowing of the bronchi and the specific conductivity of the air (SGaw), was expressed as % changes from the baseline values of the bar is p at 100% histamine, prevents the narrowing of the bronchi and that budesonide at equivalent molar dose in relation to well-known compound on the contrary accelerate the narrowing of the bronchi, let Histaminum.

1. Nitroethene corticoid compounds of General formula

B-X1-NO2,

where has the following structure:

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where Z is hydrogen or F;

in position 17 can be group him or at position 16, 17 may be group

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the dashed line in position 1, 2 means possible double bond, and when in position 9 is F, in position 1, 2 is of the double bond in position 20, the group, in positions 16, 17 cannot be group

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R" is a group

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X1is a bivalent connecting bridge selected from YO, where Y is linear WITH2-C5alkylen or Y1where Y1< / BR>
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2. Connection on p. 1, which is represented by a structure of prednisolone, budezonida, dexamethasone or hydrocortisone.

3. Connection on p. 1, intended for use as pharmaceuticals.

4. Connection on p. 2, designed to receive medications, such as corticoids.

5. Connection on p. 4, are the immunosuppressive medications.

7. Connection on p. 4, designed to get angiostatin medicines.

8. Connection on p. 4 intended to receive asthma medication.

 

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6 tbl

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