Steroid compound, pharmaceutical compositions

 

(57) Abstract:

Steroid compounds or their salts corresponding to General formula (I)

where bo=1; A=R-, where R is the radical of a steroid drug substance, C1and C2represent bivalent radicals. The precursor of the radical B1must comply with the conditions of the pharmacological tests, the contents of which are disclosed in the description. The compounds I are useful in the treatment of inflammatory diseases, asthma and liver disorders. 2 N. and 8 C.p. f-crystals, 6 PL.

The present invention relates to new steroid compounds intended for both systematic and unsystematic use, and compositions based on them, for use in the state of oxidative stress and/or endothelial dysfunction. More specifically, the invention relates to compounds of steroid structure, which has anti-inflammatory, immunosuppressive and angiostatic activity (the so-called anti-inflammatory steroids) or gastrointestinal activity.

Compounds in accordance with the present invention are useful for therapeutic treatment of such pathological conditions is ensenaste and/or efficiency.

Under oxidative stress refers to the appearance of free radicals or radical compounds that cause damage to both the cells and the surrounding tissues (Pathophysiology: the biological basis for disease in adults and children McCance&Huether, 1998, pp.48-54).

Under endothelial dysfunction involve dysfunction related to vascular endothelium. It is known that damage to the vascular endothelium is one of the major reasons that can cause a series of pathological processes affecting various organs and systems of the body, as described in Pathophysiology: the biological basis for disease in adults and children McCance&Huether, 1998, p.1025).

It is known that oxidative stress and/or endothelial dysfunction is associated with various pathologies, as described below. Oxidative stress can also be caused by the toxicity of a large number of various medicinal substances, which greatly affects the effectiveness of their actions.

These pathological phenomena have chronic, debilitating body, and very often are typical for elderly people. As already mentioned, in the above mentioned pathological conditions used medicinal substance about the, due to oxidative stress and/or endothelial dysfunctions or characteristic of the elderly.

For the cardiovascular system: myocardial and vascular ischemia in General, hypertension, stroke, atherosclerosis, and so on

For connective tissue rheumatoid arthritis and related inflammatory diseases, and so on

- Respiratory system: asthma and related inflammatory diseases, and so on

For the digestive system: ulcer and non-ulcer dyspepsia, intestinal inflammatory diseases, and so on

For the Central nervous system: Alzheimer's disease and so on

For genitourinary: impotence, incontinence.

For the skin: eczema, neurodermitis, eels.

- Infectious diseases in General (Schwarz, Brady "Oxidative stress during viral infection: a review". Free Radical Biol. Med. 21/5, 641-649, 1996).

Further, the aging process itself can be considered as a valid pathological condition (Pathophysiology: the biological basis for disease in adults and children, pp.71-77).

Known medicinal substance with the introduction of their patients with pathologies associated with oxidative stress and/or endothelial dysfunctions, preterito.

Studies of drugs aimed at the search of new molecules with improved therapeutic index (the ratio of efficacy/toxicity) or low risk/beneficial effects, including for the above mentioned pathological conditions, in which therapeutic index of a significant number of medicinal substances is low. In fact, under the above conditions of oxidative stress and/or endothelial dysfunction many drugs exhibit low activity and/or high toxicity.

It is well known that therapeutic treatment of inflammatory diseases for pharmacological effects in the first place choose steroids. This class of drugs, among which we can mention, for example, hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, hypertension, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetonide, fluoqinolona acetonide, beclomethasone, acetoxyphenyl, and so on, has a significant pharmacotoxicology effects on various organs, and therefore, their clinical application, and the interruption leads to a number on the apeutics", 9th ed., page 1459-1465, 1996.

Among these toxic effects, it should be noted effects on bone tissue, which leads to changes in cellular metabolism and increase the likelihood of osteoporosis; the impact on the cardiovascular system, leading to hypertension; effects on the gastrointestinal system, leading to gastrointestinal disorders. See, for example, Martindale "The Extrapharmacopoeia, 30th ed., page 712-723, 1993.

To the class of steroid drugs also belong bile acid used in the treatment of diseases of the liver and biliary colic. Ursodeoxycholic acid is also used in some disorders of the liver (derros liver biliary origin, and so on). The tolerability of these drugs is greatly diminished in the presence of gastrointestinal complications (chronic liver damage, stomach ulcers, intestinal inflammation, and so on). In the case of bile acids oxidative stress also significantly affects the efficiency of drug substances: both the efficacy and tolerability chenodeoxycholic and ursodeoxycholic acid significantly reduced. It was found that particularly increases the undesirable impact of the s, hormonal diseases, tumors of the female organs. Mentioned steroids also have the above side effects, especially on the liver.

Based on the above prior art, it is almost impossible to separate therapeutic activity of side effects (see Goodman&Gilman's "The Pharmaceutical Basis of Therapeutics", 9th ed., page 1474, 1996).

Steroid compounds are completely different from non-steroidal anti-inflammatory compounds with chemical, pharmacological and biochemical points of view, as pharmacotoxicological the mechanism of action of nonsteroidal anti-inflammatory products based on the inhibition of one or more of cyclooxygenase (COX), while steroids do not affect COX and have more complex pharmacotoxicological mechanism of action is still not understood completely.

Indeed, it is well known that these two groups of drugs belong to different pharmaceutical classes.

Thus, there is a need to develop affordable steroids with improved therapeutic effect, i.e., providing and reduced toxicity and/or increased efficiency to their Monki, without showing the drawbacks of medicinal substances known from the prior art.

It has been unexpectedly discovered that the above-mentioned technical problems identified in the introduction of steroid drugs for patients suffering from oxidative stress and/or endothelial dysfunctions, or older patients in General, be solved with the help of a new class of drugs, which are described below.

The object of the invention are steroid compounds or their salts corresponding to the following General formula (I)

where b=1;

A=R-, where R is a radical steroid drug substances, as defined below;

=-Tin-X2-TBI,

where Tinand TBIthe same or different and represent CO, O, S,

X2represents a bivalent bridging group, such as an appropriate precursor To having the formula Z-Tin-X2-tbi-z’, where Z and Z’ represent independently H or HE selected from the corresponding compounds

birepresents O, S, NH, Tcrepresents O, S, when tbiis a (CO);

or Y represents Yaboutchosen from:

- alkylene group R'O R' is a linear or when possible branched residue C1-C20,

R, having the following structure:

instead of a hydrogen atom in CH groups, or instead of two hydrogen atoms in CH2the groups in this General formula may be present, the following placeholders:

in position 1-2: may be a double bond;

in position 3 may be =O HE;

in position 4-5: may be a double bond;

in position 6; may be Cl, F, CH3,

in position 7: HE may be;

in situation 9: you may be Cl, F;

regulation 11: may be HE, =O,

in position 16 may be of CH3HE

in position 17: HE may be, CH3,

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

R and R’, identical or different, may represent hydrogen,

R’ is-CH(CH3)-CH2-CH2-CO - or-CO-CH2O-.

Preference is codesexymovies acid, chenodesoxycholic acid.

The most preferred compounds of formula (I) are selected from the group consisting of:

-4-ether nitrocellulose 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acids;

-4-ether nitrocellulose 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid.

Predecessor In having the formula Z-Tin-X2-TBI-Z’, where Z and Z’ represent independently H or HE, is found in the test 4 or 5,

where test 4 consists of the following: this is an analytical determination performed by adding portions of the methanol solution of the precursor In a concentration of 10-4M methanolic solution of DPPH (2,2-diphenyl-1-picrylhydrazyl - free radical); after keeping this solution at room temperature without light for 30 minutes, measure the absorbance at a wavelength of 517 nm of the test solution and the solution containing only DPPH in the same amount that the test solution; and then calculate the inhibition of radical formation of DPPH caused by the relevant predecessor, in percent, using the following formula:

(1-AS/AC

where test 5 is the following: this is an analytical determination performed by adding an aliquot of 10-4M methanolic solutions of the precursors In the solution by mixing 2 mm aqueous solution of desoxyribose with 100 mm phosphate buffer and 1 mm solution of salts of FeII(NH4)2(SO4)2; after the temperature of this solution at 37°C for 1 hour add aliquots of 2.8% aqueous solution of trichloroacetic acid and 0.5 M aqueous solution thiobarbiturate acid in this order, heat the solution at 100°C for 15 minutes, and then measure the absorption of the test solutions at 532 nm; the inhibition of radical formation salt of FeIIcaused by precursor compounds b or B1or=-TC-Y-H, calculated as a percentage using the following formula:

(1-AS/AC)×100,

where ASand aCrespectively represent the magnitudes of the absorption solution containing clovey test 5, if the percentage of inhibition predecessors with free valences employed, as above defined, as described above, is greater than or equal to 50%.

Preferably the precursor compounds In (respectively the predecessor of X2in formulas (I)), which corresponds to the test conditions 4, selected from the following classes of compounds.

- Amino acids, selected from the following compounds: penicillamine (CV), N-acetylpenicillamine (CVI), cysteine (C-VII), N-acetylcysteine (VIII),

- hydroxyacids, selected from the following compounds: Gallic acid (formula DI), ferulic acid (DII), gentisic acid (DIII), citric acid (DIV), caffeic acid (DV), hidrocortisona acid (DVI), p-coumarin acid (DVII), vanillic acid (DVIII), purple acid (DXI):

Aromatic and heterocyclic one - and polyhydric alcohols, selected from the following compounds: hydroquinone (EVIII), methoxyhydroquinone (EXI), hydroxyperoxide (EH), coniferious alcohol (EHHH), 4-hydroxyphenethyl alcohol (EHHH), p-coumarin outie substances, which are the predecessors To receive in accordance with the methods known from the prior art and described, for example, in "The Merck Index, Ed. 12A, (1996), included here as a reference. If possible, can be used corresponding isomers and optical isomers.

Preferably the precursor compounds In (respectively the predecessor of the radical X2in the formula (I), which corresponds to the test conditions 5, selected from the following compounds.

- Amino acids: aspartic acid (PI)

The precursor compounds In the above-mentioned groups P, Q and R receive in accordance with known prior art methods described, for example, in "The Merck Index", Ed. 12A, (1996), included here as a reference.

Y3in the formula (III) is preferably selected from the following groups:

Most preferably Y3represents Y12 (pyridyl), substituted in positions 2 and 6. Communication can also be located in asymmetrical positions, for example Y12 (pyridyl)of the present invention of formula (I) can be converted into the corresponding salt. For example, one of the ways of formation of salts is as follows: if in the molecule one of the nitrogen atoms is sufficiently basic to form a salt, in an organic solvent such as acetonitrile or tetrahydrofuran, he interacts with the equimolar amount of the corresponding organic or inorganic acid.

Preferably in the formula of the compounds of the present invention are Y or Y’ of formula (III).

Examples of organic acids: oxalic, tartaric, maleic, succinic, citric acid.

Examples of inorganic acids: nitric, hydrochloric, sulphuric, phosphoric acid.

In steroid precursors preferably

R=CO-CH2OH, -CH(CH3)-CH2-CH2WITH.

Among steroid precursors are preferred are those which contain hydroxyl functional group in position 3 or in position 11 or have in the structure R’ is a hydroxyl or carboxyl functional group in the terminal position.

Steroid precursors And which should be mentioned as preferred are listed below, get them using processes, izvesti, for example, those described in the catalogue "The Merck Index", ed. 12, 1996, included here as a reference. These predecessors (in accordance with item Merck), where N2N, R, R’, R’ accept above values represent the following compounds: Budenoside, Hydrocortisone, Beclomethasone, Betamethasone, Chloroprednisone, Clocortolone, Cortisone, Corticosterone, Desonide, Desoximetasone, Dexamethasone, Diflucortolone, Flumetazon, Flunisolide, Fluprednisolone, Flurandrenolide, Meprednisone, Methylprednisolone, Paramethasone, Prednisolone, Prednisone, Triamcinolone, Ursodeoxycholic acid, Chenodeoxycholic acid.

Unexpectedly it was found that the products according to the invention of formula (I) in a state of oxidative stress have an improved therapeutic index compared with steroid precursors. As an illustration the results of the above tests for the following compounds (see table appended to the description).

Test 4 (test for predecessor, see Table III)

N-acetylcysteine 100% inhibits the formation of DPPH radicals from and therefore complies with the test conditions 4 and can be used as a precursor of b or B11if it meets the conditions of the test 5.

Test 5 (test for predecessor, see Table IV)

4-Thiazolidinedione acid corresponds to the test conditions 5, since the inhibition is 100%. Therefore, this compound can be used as a precursor In the formula (I).

Compounds according to the invention can be used for the same therapeutic indications are that drug precursor chemicals, but with the above advantages.

The compounds of formula (I) obtained using the synthetic methods described below.

The choice of reactions for each method depends on the reactive groups present in the steroid molecule, the precursor compounds which may be, as indicated above, bivalent, and precursor compounds C.

Reactions carried out using methods well known in the prior art, which allow to establish a link between steroid precursor compounds and precursor compounds, as described above.

When the reactive functional group of the steroid (e.g.,- COOH, -OH) participate in the formation of covalent bonds, for example of the type of slojnoe the Osho known from the prior art.

Here are some of the synthesis scheme for producing compounds according to the invention.

A) Synthesis of compounds of formula (I).

1. The synthesis of compounds formed by the interaction between the steroid and precursor compounds Century

1A. If steroid carboxyl functional group (General formula: R-COOH), and the functional group of the precursor compound, which binds to the carboxyl functional group has the formula XZ, and X is as defined above, a Z=N, then carried out of the reaction depend on the nature of the second reactive group present in the precursor compound Century

1a.1. If the second reactive group present in the precursor compound In is a carboxyl group, a General scheme of the synthesis involves the initial formation of gelegenheid steroid R-COHal (Hal=CL, Br) and subsequent reaction with HX group of the precursor compound In:

X2TBsuch as described above.

If two compounds, reacts, there are other functional groups COOH and/or NC, they must be protected before carrying out the reaction in shoots synthesis", Harward University Press, 1980.

Gelegenheid RCOHal receive in accordance with the methods known from the prior art, for example using thionyl or oxalicacid, RIIIor PVhalides, conducting the reaction in inert solvents, such as toluene, chloroform, DMF, etc.

In special cases, if the NC group, the predecessor of the connection represents NH2HE or SH, the steroid of the formula R-COOH first converted into the corresponding gelegenheid RCOHal, as described above, and then carry out the reaction with HX group of the precursor compound, in the presence of organic bases such as triethylamine, pyridine, etc. in an inert solvent, such as toluene, tetrahydrofuran, etc. at a temperature in the range of 0°C to 25°C.

Alternatively, the previous synthesis of a steroid of the formula R-COOH can be treated with an agent activating the carboxyl group, selected from N,N’-carbonyldiimidazole (CDI), N-hydroxybenzotriazole and dicyclohexylcarbodiimide, in a solvent such as, for example, DMF, THF, chloroform, etc. at a temperature in the range from -5°C to 50°C, after which the compound obtained is injected into the interaction in situ (i.e. without predvaritelnaya In obtaining the compounds of formula IA.1).

1a.2. If the predecessor connection contains two functional groups XZ, equal or different from each other, and X as above, and Z=N, then a steroid having the formula R-COOH, is first treated with an agent activating the carboxyl group, as described above in item 1A.1, and then carry out the reaction with the precursor compounds In which one or two reactive NH group is protected, for example, acetyl or tert-butyloxycarbonyl group; removing the protections at the end of the synthesis allows to regenerate the original functional group. The synthesis scheme is as follows:

where X, TBX2defined above and G is a protecting group functional group NH.

2. Synthesis nitrosopropane.

2A.1. If the connection is received at the end of the previous stage la, has the formula (IA.1), the acid may be converted into the corresponding sodium salt, which is used for the final connection, the following is known from the prior art methods, for example in accordance with one of the following synthesis schemes:

where TB, X2TBITCsuch as above, R4selected from CL, Br, Y such that the r, Iodine, HE. If R3=HE, the compound of formula (1A.1b) is subjected to galogenirovannyie, for example, such agents as RVG3, PCl5, SOCl2, h3+I2and then interaction with AgNO3in an organic solvent, such as acetonitrile, tetrahydrofuran. If R3represents CL, Br, Iodine, the compound of formula (1A.1b) interacts directly with AgNO3as specified above.

where R5=HE or other1C; R1C, R3and other symbols are defined above.

If X is a linear C4alkyl, the corresponding acid R-TB-X2-COOH interacts with triphenylphosphine in the presence of a halogenation agent such as CSAs4or N-bromosuccinimide in tetrahydrofuran, which leads to the compound (IA.1C),where R3=Br.

2A.2. If the connection is received at the end of the previous stage 1a, has the formula (IA.2), the corresponding nitrosopropane receive treatment halogencarbonic acid having the formula Hal-X1-COOH (X1 defined above), first as an agent activating the carboxyl group, as described above in paragraph 1A.1, and then the compound of formula (IA.2), which leads to a halogen derivative, which is I the reaction scheme is as follows:

where TB, X2, TB1TC, Y such as described above.

An alternative method is the use of halide l-X1-COCl, where Hal preferably represents Tsuboi VG, which can interact with the compound of the formula (IA.2).

1b. If the reactive functional group of the steroid is a group- (General formula: R-OH), the two functional groups present in the precursor compounds, can be the following:

1b.1. Carboxyl group, which interacts with the functional group IT is a steroid, and NC group, the latter reactive group of the precursor compound is In the same or other than the functional group of the steroid. The formula of the precursor compound is a formula of the following type: H-h-h2-COOH, where X and X2such as defined above.

Functional group H-X - precursor compounds In protecting methods known from the prior art, and the carboxyl group is reacted, as described above, according to the following scheme:

Upon completion of the reaction of the functional group NC predecessor To regenerate.

1b.2. The EU is the first agent, activating a carboxyl group, under the conditions previously described in paragraph 1A.1, and then carry out the reaction with the reactive group of the HE molecules of steroid. Other possible reactive functional groups HX type present in these two compounds should be protected, as described above. In the end you get a compound of the formula R-TB-X2-COOH (1V.2).

2b. Synthesis nitrosopropane.

2b.1. To obtain the final nitrosopropane proceeding from compounds of formula R-TB-X2-X-N (1B.1) obtained at the end of the synthesis described in paragraph 1b.1, the compound (1V.1) is injected into the reaction halogenerators formula Hal-X1-COOH, which is treated as described previously in paragraph 1A.1, or with the corresponding acid chloride of halogenate, the compound obtained is dissolved in an organic solvent, for example acetonitrile or tetrahydrofuran, and then carry out the reaction with silver nitrate.

2b.2. To obtain the final nitrosopropane of the compounds of the formula R-TB-X2-COOH (1V.2) obtained at the end of the synthesis described in paragraph 1b.2, the acid is converted into the corresponding sodium salt, which interacts with soedinenii with the above process end nitrosopropane. Alternatively, if X1is linear WITH4the alkyl acid (1B.2) is reacted with triphenylphosphine in the presence of a halogenation agent such as CSAs4or N-bromosuccinimide in tetrahydrofuran, and the resulting compound is dissolved in an organic solvent, for example, acetonitrile or tetrahydrofuran, interacts with nitrate of silver.

2b.3. Alternatively, the synthesis process described in paragraphs 1b.1 and 2b.1, in the first stage, the possible reaction of the functional group NH - precursor compounds In HX-X2-COOH with the acid chloride of halogenate having the formula Hal-X1-CO-Cl, where Hal preferably represents Br; and then the carboxyl function thus obtained compound interacts with the steroid of the formula R-OH. The third and last stage of the Hal group substituted by a group-ONO2in accordance with the process described in paragraph 2b.1. The reaction scheme is as follows:

where TC, TBITB, X2X1, Y such as described above.

In the previous scheme, alternatively, may be spent nitration acid of the formula (2B.3).

In the above PR is to react with the precursor compounds To directly use steroid with its reactive functional group.

Connection, which is the object of the present invention, were included in the relevant pharmaceutical compositions for parenteral, oral and topical application in accordance with well known prior art methods, together with the usual excipients; see for example "Remington's Pharmaceutical Sciences, 15a Ed.".

The molar quantity of active substance in these compositions is the same or lower compared with the amount used of the respective medicinal substance predecessor.

Daily input dose are the same or in this case lower than doses of medicinal substances predecessors. The daily dose can be found in the relevant publications on this subject, for example, in "Physician''s Desk Reference".

The following examples are given to illustrate the present invention and should not be construed as limiting its scope.

EXAMPLE 1

Getting 4-nitrocellulose ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid

where steroid precursor is ursodeoxycholic acid of formula (XL), and Predslava ester 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid.

To a solution of 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid (10 g, was 51.5 mmol) in THF (400 ml) is added triphenylphosphine (2.7 g, or 10.3 mmol) and tetrabromomethane (34,16 g of 10.3 mmol), then stirred solution using a magnetic stirrer at room temperature for 48 hours. The solution is filtered from the solid residue and then evaporated under reduced pressure. The resulting crude product was then purified by chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 7/3. Get 9 g of 4-bromatologia ester 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid. So pl. 86-89°C.

b) synthesis of 4-bromatologia ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid.

To a solution of (3,5,7)-3,7-dihydroxyfuran-24-OIC acid (2.9 g, 7,38 mmol) dissolved in chloroform (25 ml) and dimethylacetamide (25 ml), added with stirring 4-bromatology ether 3-(4-hydroxy-3-methoxyphenyl)-2-propanolol acid (2,73 g of 8.28 mmol). To this solution at 0°C and stirring N,N’-dicyclohexylcarbodiimide (2 g, 9.7 mmol) and 4-dimethylaminopyridine (100 mg, 0.81 mmol). After 1 hour, the mixture is heated to room temperature and after 24 hours the precipitate is filtered off and the solvent evaporated under reduced davleniya sodium sulfate evaporated solvent. The resulting crude product was then purified column chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/9. Obtain 2.5 g of 4-bromatologia ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid.

c) Synthesis of 4-nitrocellulose ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid.

To a solution of 4-bromatologia ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid (2.3 g, with 3.27 mmol) in acetonitrile (20 ml) and tetrahydrofuran (5 ml) is added under stirring silver nitrate (0.84 g, 4,94 mmol), then heated the mixture to 80°C under vigorous stirring on a magnetic stirrer for 6 hours. At the end of the reaction the precipitate is filtered off and the solvent evaporated. The resulting crude product was then purified column chromatography on silica gel, elwira a mixture of dichloromethane/ethyl acetate 3/7. Get 1.5 g of 4-nitrocellulose ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid. The total yield is 32%.

Elemental analysis

Calculated, %: C 66,55; N 8,08; N 2,04.

Found, %: C 66,59; N 8,14; N, 1,99.

An example of a pharmaceutical composition: tablets

To the howling acid, prepared according to example 1: 250 mg;

microcrystallin pulp: 100 mg;

glycolate starch sodium: 10 mg;

stearic magnesium: 20 mg

EXAMPLE 2

Getting 4-nitrocellulose ether 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid

where steroid precursor is chenodesoxycholic acid of the formula (XLI), and the predecessor is ferulic acid of the formula (DII)

This compound is obtained according to the method described in Example 1. The total yield is 28%.

Elemental analysis

Calculated, %: C 66,55; N 8,08; N 2,04.

Found, %: C 66,64; N 8,13; N 1,94.

EXAMPLE 3

Obtaining (11)-11,17-dihydroxy-21[N-acetyl-8-(4-nitroxymethyl)cysteineless]-pregn-1,4-diene-3,20-dione

Steroid precursor is prednisolone formula (LII), and the precursor of b is N-acetylcysteine formula (VIII)

a) Synthesis of N-acetyl-S-(4-bromobutyryl)cysteine.

A solution of 4-bromoethanol acid (5.1 g, 30,6 mmol) and 1,1’-carbonyldiimidazole (5,61 g, 34.6 mmol) in chloroform (50 ml) was stirred at room is stvoreny in N,N-dimethylformamide (5 ml), and ethylate of sodium (50 mg). After 24 hours the solution was washed with 1% model HC1 and brine, the organic phase is dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was then purified column chromatography on silica gel, elwira a mixture of ethyl acetate/chloroform 7/3. Get N-acetyl-S-(4-bromobutyryl)cysteine.

b) Synthesis of (11)-l1,17-dihydroxy-21[N-acetyl-S-(4-bromobutyryl)cysteineless]-pregn-1,4-diene-3,20-dione.

To a solution of N-acetyl-5-(4-bromobutyryl)cysteine (2.7 g, 8,64 mmol) and (11)-11,17,21-trihydroxypregn-1,4-diene-3,20-dione (3.2 g, 8,86 mmol) in tetrahydrofuran (100 ml) at 0°C and stirring N,N’-dicyclohexylcarbodiimide (1.9 g, 9.2 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol). After 1 hour, the mixture is heated to room temperature and after 24 hours the precipitate is filtered off and the solvent evaporated under reduced pressure. The residue is treated with ethyl acetate (150 ml) and washed with water (3×100 ml). After drying the organic phase over sodium sulfate evaporated solvent. The resulting crude product was then purified column chromatography on silica gel, elwira a mixture of chloroform/ethyl acetate 3/7. Get 0,94 g (11)-11,17-dihydroxy-21[N-acetyl-S-(4-bromobutyryl)cysteineless]-pregn-1,4-diene-3,20-dione.

To a solution of (11)-11,17-dihydroxy-21[N-acetyl-S-(4-bromobutyryl)cysteineless]-pregn-1,4-diene-3,20-dione (0.8 g, 1.28 mmol) in acetonitrile (10 ml) and tetrahydrofuran (5 ml) is added under stirring silver nitrate (0.4 g, of 2.35 mmol), then heated the mixture at 80°C under stirring on a magnetic stirrer for 20 hours. At the end of the reaction the precipitate is filtered off and the solvent evaporated. The resulting crude product was then purified column chromatography on silica gel, elwira a mixture of dichloromethane/ethyl acetate 3/7. Get (11)-11,17-dihydroxy-21[N-acetyl-S-(4-nitroxymethyl)cysteineless]-pregn-1,4-diene-3,20-dione. The total yield is 12%.

Elemental analysis

Calculated, %: C 56,59; N 6,33; N 4,40; S 5,04.

Found, %: C 56,63; N 6,38; N 4,36; S 5,01.

EXAMPLE 4

Obtaining (11)-11,17-dihydroxy-21[N-acetyl-S-(4-nitroxymethyl)cysteineless]-pregn-4-ene-3,20-dione.

Steroid precursor is hydrocortisone formula (LIII), and the precursor of b is N-acetylcysteine formula (VIII)

This compound is obtained according to the method described in Example 3. The total yield is 15%.

Elemental analysis

Calculated, %: 56,37; N is hydroxy-21[N-acetyl-S-(4-nitroxymethyl)cysteineless]-16-methylpregna-1,4-diene-3,20-dione.

Steroid precursor is desametasone formula (XLIV), and the precursor of b is N-acetylcysteine formula (VIII).

This compound is obtained according to the method described in Example 3. The total yield is 17%.

Elemental analysis

Calculated, %: C 55,68; N 6,18; N 4,19; S 4,79.

Found, %: C 55,72; N 6,22; N 4,15; S 4,75.

EXAMPLES OF PHARMACOLOGICAL TESTS

Acute toxicity

Acute toxicity was evaluated by introducing a group of 10 rats weighing 20 g single dose of each of the tested compounds, introducing connections at the mouth through a tube in the composition of the aqueous suspension of carboxymethyl cellulose (2% wt./vol.). The animals were observed for 14 days. None of the animals in the test group did not appear toxic symptoms, even after a dose of 100 mg/kg

EXAMPLE F1

Experimental in vivo model with methyl ester of NW-nitro-L-arginine (L-NAME): the effect of steroid precursor and the corresponding compounds according to the invention on endothelial dysfunction induced by L-NAME.

Selected experimental model described in J. Clin. Investigation, 90, 278-281, 1992.temat-pyruvate transaminase - GPT), vascular endothelium and cardiovascular system (increased blood pressure) caused by L-NAME.

Animals (rat, Long Evans, the average weight of 350-450 g) were divided into groups as described below. The group treated with L-NAME for 4 weeks was administered these compounds dissolved to a concentration of 400 mg/l in drinking water. There were formed the following groups (10 animals per group).

A) Control group:

1° group: impact: only media (saline),

2° group: impact: carrier + L-NAME.

B) Groups, which were injected drug substances:

3° group: impact: carrier + drug,

4° group: impact: carrier + drug + L-NAME.

Connections that have passed this test: hydrocortisone, desametasone, prednisolone, chenodeoxycholic acid, ursodeoxycholic acid and the corresponding derivatives according to the invention.

In groups of rats exposed to, respectively, hydrocortisone, desametasone, prednisolone and related compounds according to the invention, the determined blood pressure.

In groups of rats, p the corresponding compounds according to the invention, determined GPT.

Each drug was administered intraperitoneally 1 time a day for 4 weeks.

By the end of the fourth week was discontinued the animals ' access to water, and after 24 hours, animals were euthanized.

4 hours after the last administration of a drug was determined blood pressure.

The damage to the vascular endothelium was determined, as described above, the influence of L-NAME on the cardiovascular system (increased blood pressure). Liver damage was determined by assessing the content of glutamate-pyruvate transaminase (increase GPT) after the killing.

The results are presented in Tables I and II. Value (%) blood pressure and GPT expressed respect to the corresponding values found for the animals of the first control group. The average blood pressure in this group is equal to 105 mm RT.article.

The results obtained indicate that steroid precursors cause liver damage (chenodeoxycholic acid, ursodeoxycholic acid), and hypertension (hydrocortisone, desametasone, prednisolone). The GPT levels and blood pressure in rats, which were injected these soedineniya, which was introduced only L-NAME. On the contrary, the products according to the invention have better tolerability compared to the predecessors, even in animals that were not injected with L-NAME.

EXAMPLE F2

Test 4: Inhibition of the formation of DPPH radicals from some of the substances used to obtain predecessors In and B1.

The method is based on colorimetric test, in which the compound forming radicals, is used DPPH (2,2-diphenyl-1-picryl-hydrazyl) (M. S. Nenseter et al., Atheroscler. Thromb. 15, 1338-1344, 1995).

First prepare a methanol solution of the test substances in final concentrations of 100 μm. 0.1 ml each of these solutions add to the aliquot of the methanol solution of 0.1 M DPPH volume of 1 ml, and then the volume was adjusted to 1.5 ml After keeping the solution at room temperature without light for 30 min, measure the absorbance at a wavelength of 517 nm. Determine the decrease in absorption with respect to the absorption solution containing the same concentration of DPPH.

The effectiveness of the tested compounds against the inhibition of radical formation, in other words, antiradical activity, is expressed by the following formula:

(1-Athe ora, containing the test substance + DPPH, and the solution containing only DPPH.

The connection proposed for use as the precursor of b or B1in accordance with the present invention, corresponds to the test conditions 4, if it inhibits the formation of DPPH radicals from with efficiency equal to or greater than 50%.

Table III presents the results obtained in the specified test, the following compounds: N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gentisic acid, 4-thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid.

Table III shows the following:

N-acetylcysteine, cysteine, ferulic acid, L-carnosine, gentisic acid correspond to the test conditions 4 because they inhibit the formation of radicals caused by DPPH, with efficiency exceeding 50%. Therefore, they can be used as precursors of compound B in the synthesis of compounds of the present invention.

4-Thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid does not correspond to the test conditions 4, as they do not inhibit the formation of radicals of DPPH. Therefore, they can be used F3

Test 5: Inhibition of radical formation from FeIIcompounds used as precursors IN, B1or=-TC-Y-H.

0.1 ml aliquots of 10-4M methanolic solutions of 4-thiazolidinones acid and 2-oxo-4-thiazolidinones acid added to tubes containing aqueous solution formed by mixing 0.2 ml of 2 mm solution desoxyribose, 0.4 ml of 100 mm phosphate buffer (pH of 7.4) and 0.1 ml of 1 mm solution of FeII(NH4)2(SO4)2a 2 mm solution of Hcl. Then the tube is maintained at a temperature of 37°C for one hour. Then to each tube add 0.5 ml of 2.8% aqueous solution of trichloroacetic acid and 0.5 ml of an aqueous solution of 0.1 M thiobarbituric acid in that order. Control clear solution is prepared by replacing the above 0.1 ml aliquot of the methanol solution of the test compound in 0.1 ml of methanol. The tube was closed and heated in an oil bath at a temperature of 100°C for 15 minutes. There is a pink staining, the intensity of which is proportional to the number of desoxyribose subjected to radical oxidative cleavage. The solution is cooled to room temperature and measure their p is dikalov of FeIIthat is called a predecessor of b or B1or=-TC-Y-H (where the free valence is occupied, as defined above), determine the percentage by the following formula:

(1-AS/AS)×100,

where ASand aCare, respectively, the values of the absorbance of a solution containing the test substance + salt of iron, and the solution containing only salt of iron.

The results are presented in Table IV, which shows that both acids correspond to the test conditions 5, because they inhibit the formation of radicals of FeIIwith efficiency exceeding 50%.

Therefore, as a 4-thiazolidinedione acid and 2-oxo-4-thiazolidinedione acid can be used as precursors IN, B1or=-TC-Y-H to obtain the compounds of the present invention.

EXAMPLE F4

Example F1 was repeated with three groups of rats (each group consisted of 10 animals), while a control group did not receive L-NAME, and two groups received L-NAME; substances were administered intraperitoneally in accordance with the following scheme:

(a) control group (not receiving L-NAME): media (saline),

b) ellstein (10,4 mg/kg, 0,064 mmol/kg) with the same media

C) 2-Oh group treated with L-NAME (group C), has introduced a derivative of dexamethasone (42,5 mg/kg 0,064 mmol/kg) according to the invention (see note below). 5) in the same above-mentioned media.

In this experiment determined the vascular tolerance, there is an increase in blood pressure (damage blood vessels), in animals of groups b and C, expressed as a percentage ratio to the blood pressure in animals of group a, which was taken as equal to 100%.

The results in Table V show that the mixture introduced to the group b (the comparison group), evoked in animals more high blood pressure than the connection according to the invention (group C).

EXAMPLE F5

Example F1 was repeated with three groups of rats (each group consisted of 10 animals), while a control group did not receive L-NAME, and two groups received L-NAME; substances were administered intraperitoneally in accordance with the following scheme:

(a) control group (not receiving L-NAME): media (saline),

b) the 1st group treated with L-NAME (group d), at the same time introduced ursodeoxycholic acid (100 mg/kg, 0.25 mmol/kg) + Frolovo acid (49.5 mg/kg 0,064 mmol/kg) with the same Zloty (175 mg/kg, 0.25 mmol/kg) according to the invention (see note below).1) in the same above-mentioned media.

In this experiment determined the hepatic tolerability, i.e. increasing the level G (liver damage), animals in groups d and e, expressed as a percentage ratio to the level of GPT in animals of group a, which was taken as equal to 100%.

The results in Table V show that the mixture injected group d (the comparison group), evoked in animals, a greater increase in the level of GPT than the connection according to the invention (group e).

1. Steroid compound and the enantiomers, diastereoisomers and pharmaceutically suitable and their salts having the following General formula

where bo=1;

A=R-, where R represents the radical of a steroid drug substances, as defined below;

=-Tin-X2-TBIwhere Tinand tbithe same or different and represent CO or O, S;

X2represents a bivalent bridging group, such as an appropriate precursor To having the formula Z-Tin-X2-tbi-Z’, where Z and Z’ represent independently H or HE="ptx2">

Is a bivalent radical-Tc-Y-, where

Twith=(CO) when tbirepresents O, S; Tcrepresents O, S, when TBIis a (CO);

Y represents Y0selected from linear or branched residue C1-C20, accelerometry

R, having the following structure:

where instead of a hydrogen atom in CH groups, or instead of two hydrogen atoms in CH2the groups in this General formula may be present, the following placeholders:

in position 1-2 may be a double bond;

in position 3 can be =HE;

in position 4-5 may be a double bond;

in position 6 can be Cl, F, CH3,

in position 7 may be HE;

in position 9 can be Cl, F;

in position 11 may be HE, =O,

in position 16 may be of CH3HE

in position 17 HE may be, CH3,

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

R and R’, identical or different, may represent hydrogen;

inania under item 1, where steroid precursor selected from the following compounds: Budenoside, Hydrocortisone, Beclomethasone, Betamethasone, Chloroprednisone, Clocortolone, Cortisone, Corticosterone, Desonide, Desoximetasone, Dexamethasone, Diflucortolone, Flumetazon, Flunisolide, Fluprednisolone, Flurandrenolide, Meprednisone, Methylprednisolone, Paramethasone, Prednisolone, Prednisone, Triamcinolone, Ursodeoxycholic acid, Chenodeoxycholic acid.

3. Connection under item 1 or 2, where Y is a linear or branched residue of C1-C6accelerometry.

4. Connection PP.1-3, where the precursor of steroid selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid.

5. Connection PP.1-3, where the precursor of steroid selected from prednisolone, hydrocortisone, dexamethasone.

6. Connection on p. 1, where the enantiomers, diastereoisomers and pharmaceutically suitable and their salts selected from the group consisting of

-4-ether nitrocellulose 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acids;

-4-ether nitrocellulose 3-[4-[(3,5,7)-3,7-dihydroxyfuran-24 Biloxi]-3-methoxyphenyl]-2-propanolol acid.

7. Connection and attachment of hepatic disorders.

8. Compounds and enantiomers, diastereoisomers and pharmaceutically suitable and their salts according to any one of paragraphs.1-3 and 5 for use in the treatment of inflammatory diseases and asthma.

9. The pharmaceutical composition according to any one of paragraphs.1-3 and 5, containing the active compound in the ratio of 20-90 wt.% and pharmaceutically usable excipient in a ratio of 10-80 wt.% for the treatment of hepatic disorders.

10. The pharmaceutical composition containing the active compound according to any one of paragraphs.1-3 and 5, and a pharmaceutically suitable excipient for the treatment of inflammatory diseases and asthma.



 

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